I believe the conventional wisdom is that, at least in humans, living longer has been selected for. See the Grandmother hypothesis. Because infant and children humans are so much weaker and fragile than infants of other species, we have adapted to live longer to provide support to our children as they rear their own children.
I don't think there's a clear answer, this hypothesis was developed to help explain why human beings lived significantly past the age of menopause. Though I am by no means an expert in this field. That being said, given the number of genes you share with each subsequent chain of your lineage exponentially decays, I would expect the fitness benefits of aging longer to rapidly dwindle.
I think it is important for people to become weaker and infertile as they grow old, because otherwise they would be competing with their own offspring for status, resources and mates. That kind of cross-generational strife would be terrific for tearing apart families, tribes and societies. Perhaps we evolved to age as we do because those proto-humans that did not tore each other to pieces?
I believe there is a strong difference between selection for lifespan and the grandmother hypothesis, which is really needed not because of long life, but because of long (well, relatively long) life past menopause, where you really needs some special kin selection (advantage not on yourself, but on multiple individuals sharing part of your genes.) because normal selection predict the fitness after reproduction to be 0, by definition. So only indirect effects are present, in the form of helping (GM hypothesis) or hurting (consuming their resources).
For the reproduction lifespan, it should always be a positive in term of fitness, because living longer allows to produce more offspring, trivially....Kin selection may interfere, indeed, but for it to select shorter life there should be a pretty big hit on fitness of many offsprings (1/2 of your genes) or grand-offsprings (1/4) just by your existence. I do not think this is a likely explanation, because your own consumption of resource is no greater than the one of your competitors, so I thing dying off to let your used resource go to your kin does not work out mathematically. It does only makes sense in group selection, but group selection is not considered a valid explanation anymore. The only example I see where dying off is directly selected because of kin selection is some animals dying off to feed off their (very numerous) offsprings. This happen in some spiders iirc (sometimes with a twist, where the male feed off the female some of the time), and there I can see how death pays off in term of amount of offsprings succesfully reaching reproduction age, so in term of fitness....
The "short" lifespan is mostly explained (and I think this is a very convincing explanation) by tradeoff of extended lifespan vs other things, like added fitness at young age (faster growth, or other short-term advantage at the price of lifespan), because there is always a time preference linked to "accidental" death: the biological lifespan is longer than the actual one, because of all the non-age-related deathcauses (sickness, predation, accident). So a long biological life always have diminishing return in term of fitness, which means any tradeoff will defavor immortality. The equilibrium (average biological life expectancy) depends on the actual set of tradeoffs in a particular organism (I guess it depends on general organisation, so past evolution, which often put a lot of contraints on future possinble adaptations), but also on the rate of "accidental" death and offspring production rate: low offspring production rate and/or low accidental death rate means longer life. This is one explanation for the longer lifespan of flying creatures, compared to non-flying ones with similar size. Less accidental death rate because flying is a very efficient escape mechanism, maybe lower offspring production rate (because flying usually take more time, as half-flying may be dangerous) -> longer lifespan. The prime example is Bats vs non-flying small mammals.
Humans have quite low offspring production rate and accidental death compared to similar-sized mammals (and, but it's far less clear, compared to close apes). We also have longer lifespan, but not hugely so (compared to chimps)...So it kind of make sense. This also makes me believe there will likely be tradeoffs linked to "easy" anti-aging drugs, because the current lifespan is already a tradeoff...
It seems like evolution _should_ select for a thousand years and pumping out a baby every year. But instead we cease to be able to reproduce decades before we actually die.
One theory I've heard is that it's parasite-related and the same reason that most complex organisms reproduce sexually rather than asexually. If you live long enough with the same DNA then eventually parasites will become very good at targeting you, specifically. Better for your genes to keep swapping around as much as possible to stay a moving target.
Women stop being able to reproduce because of aging. The female reproductive system has to function better than the male one in order to bring a viable fetus to term, and it also is much more dangerous to the woman when it malfunctions. women die from reproductive tract issues more frequently than men do for a reason.
There were a handful of papers at one point that suggested adult female mice might be capable of neo-oogenesis but that didn’t pan out. We do appear to be born with as many oocytes as we will ever have.
I’m not sure this is precisely correct. A woman’s body could stop aging and she’d still reach an end to her reproductive lifespan at some point. Women can’t make more eggs, so once you run out of what you were born with, that’s the end. Technologically this might change at some point and we might be able to make more oocytes for someone in vitro, but naturally we have what we have.
If that were the case, we don't grow old and keep pumping out babies until we die, we would probably not live much longer than we already do - especially prior to modern medicine. As others have mentioned, dying in childbirth is a real thing and a real problem. Having thousands of babies would simply increase the death rate to a point where it's certain what (barring something else happening sooner) women would die from in their lives. Once women consistently lived to the point where they died in childbirth, there would be no point in women having any greater lifespan at all. Therefore, evolution should prioritize what gets a reasonable number of births per woman, and then prioritize other things (like the grandmother hypothesis or whatever).
Are humans actually a good example to look at when considering the general question of the evolutionary value of longevity and reproductive windows? I could be mistaken of course but I thought that a confluence of strange selective pressures resulted in the rather extreme difficulty of reproduction for human women and that the vast majority of mammals have a much easier go of it.
I think that just raises the question to another level - why do humans die in childbirth? For lack of a better alternative explanation, we are presuming that there is a tradeoff involved that selected for what we have now, and that by going a different direction we would have lost out on some other metric.
That does presume that rabbits (or name your highly fertile mammal) wouldn't hit the same wall we are talking about with humans. Most mammals in the wild have very high likelihood of dying to various non-birth causes. If those other causes went away, maybe more would die in childbirth as well. Meaning, it would be more advantageous for them to get better at basic survival than to continue increasing their ability to procreate.
A lot of variation in natural lifespan seems to be based on "how good is this creature at avoiding being killed and eaten?"
Creatures that are bad at that generally have a short lifespan.
Creatures that are good at that tend to live significantly longer.
This suggests that living a longer period of time is beneficial, all other things being equal, but it can't be selected on if you aren't living that long.
So mice don't live very long at all because they all get killed and eaten.
Humans notably have extremely long lifespans for creatures their size, and indeed, in general, which suggests living longer has a significant biological advantage for them.
Indeed. You just have to add some biological tradeoff between decreased aging, and increased fitness/unit of time to see that in case of many non-age related deaths, increased fitness/unit of time will be selected against decreased aging. And such tradeoffs are easy to find: scars heal wounds faster but prevent perfect regeneration, faster growth to reproductive age vs more controlled growth, increased energy efficiency vs better waste cleaning, better immune response vs more autoimmune problems,....
extremely long lifespans, well, it depends. Compared to the other apes, we live longer, but not crazily longer. Longest living chimps reached 65-70 years in captivity....and they weight 50 kg. So we are not that special compared to our nearest cousins. the bodysize->lifespan scaling seems to be 0.15-0.3, so if humans are 75 kg, chimps 50, and lives 65y, taking a 0.2 exponent you expect a human to live 65*(75/50)^0.2=70.5. I guess with the relatively small chimp sample, and captivity conditions, humans would be recorded having a 75-85 max lifespan. Maybe about 15% than you would expect...
I fear that we won't get to find out promptly (read: while I could benefit) because of the FDA's stubborn insistance that aging itself isn't a disease (making it harder to meet ethical critera are a were).
More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
I'm a fan of exploring these ideas but it's not cool when bio-ethicists work to justify our emotional impulses rather than working to correct them when they disagree with our best rational reconstructions of morals.
Nir Barzilai, the scientific director of the American Federation for Aging Research (AFAR), seems to be much more optimistic about FDA support. He is currently leading the TAME trial, whose end goal is to get the FDA to approve aging as a treatment indication. He and Jamie Justice said in an interview with the Foresight Institute that the FDA had been very helpful in establishing trial guidelines that would lead to this goal.
I just interviewed Nir Barzilai for my Live Longer World podcast! And yep he mentioned how the TAME trial is meant to serve as a template to get the FDA to approve drugs to target the biology of aging itself.
"More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously."
I'm less harsh on this intellectual habit than I used to be, given that tinkering with human biology and social relations in particular can have long-term side-effects that no-one predicted. e.g, contraception and abortion paradoxically made it easier for men to keep mistresses, which led married women to retaliate with 2nd-wave feminism in the 60s/70s and was most likely a huge contributor to the soaring divorce/illegitimacy rates we've been seeing ever since.
The consequences of our currently rapidly ageing population and shrinking birthrates (most especially in the developed world and China but rapidly becoming a global issue) are so potentially terrible that I'm not going to turn down anything that helps offset those problems, but I think it's naive to imagine that radical longevity won't have significant long-term drawbacks as well, even if we can't logically nail them down right now (and a few plausible downsides have already been proposed.) A lot of the time, these conservative instincts are actually right.
(To be clear, I'm not suggesting the pill and abortion-access had no benefits or that it would be practicable to roll them back- that genie is out of the bottle and it's quite possible the net benefits to human well-being outweighed the erosion of marriage norms. But I don't think the people who were/are worried about the social consequences had no valid perspective, even if they couldn't quite nail down the why beforehand.)
Perhaps... but I honestly consider the stigma surrounding eugenics to be fuelled entirely by selective remembering and double-standards (20,000 lobotomies in the US alone prior to the 1960s didn't cause us to ban psychiatry or spend most of a century insisting that the brain was not the seat of intelligence.)
While I agree that eugenics as concept probably didn't deserve to be tossed out wholesale by the post-WWII world order, the idea that the stigma is fueled "entirely" by selective memory strikes me as a bit fatuous. Likewise, comparing the ill-effects of popularized and politically charged eugenics to those of early psychiatry is...well, disproportionate in the extreme is probably the polite way to put it. Practical eugenics has been a major factor in the biggest genocides and the nastiest caste systems of the last couple of centuries. Literally some of the worst things that have happened to humanity in recent memory.
So the scope of the atrocities in question (psychiatric motivated vs. eugenics motivated) is out of whack. Additionally, the comparison of the rejection of eugenics to "insisting that the brain was not the seat of intelligence" doesn't fit. This would only make sense if the anti-eugenics contingent insisted that genes don't play a role in life outcomes (granted, some people do make this argument, but most don't). The more common and, I think, more serious argument against eugenics is this: while genes have a huge impact on life outcomes, we aren't at a point yet as a species where we can confidently say whether certain genetic traits are desirable or not (excluding those which cause disease, obviously). And if we were to start identifying particular genes as desirable or undesirable, our social structures may not be secure enough to prevent our species from sliding towards a genetically homogenous Gattaca-style dystopia.
Anyway, with all that said, I more or less agree with your point.
"This would only make sense if the anti-eugenics contingent insisted that genes don't play a role in life outcomes"
This was more-or-less the practical position of the academy for most of the last century whenever any specific divergence in gender, class or racial outcomes was discussed, and it is effectively an assumption that most of our social policy regarding education and welfare is still predicated on. To this day, any politician suggesting a moderate and humane version of a eugenics program, such as paying meth addicts to use long-term birth control, altering tax structure to favour middle-class fertility, or subsidising access to embryo selection or sperm banks, would be committing career suicide- certainly if he or she explicitly justified this on genetic grounds.
"...comparing the ill-effects of popularized and politically charged eugenics to those of early psychiatry is...well, disproportionate in the extreme is probably the polite way to put it."
I don't accept that charge. Roughly 70,000 people were forcibly sterilised under eugenics programs in the united states. Lobotomisation is arguably worse than sterilisation, and when you add in other therapies such as early forms of electroshock, insulin shock or heroin medication, I think one can make a completely plausible argument that psychiatry destroyed as many lives as formal eugenics movements in the US and most of the developed world.
Comparisons with 20th century genocidal regimes- most obviously the Nazis, Imperial Japan and the like- also fall under the heading of double standards. If we had reacted to Trofim Lysenko and the Holodomor, or the Killing Fields and Great Leap Forward, in the same way as Mengele and Auschwitz, we would have spent most of century insisting that class did not exist, banning all public policy based on the idea that people are shaped by their environment, and demonising the notion that the rich might be exploiting the poor. I have no idea why the left gets to impose these lunatic double-standards on the conversation.
I would also point out that genocidal regimes have been as frequently motivated by resentment of a more-successful ethnic group as by the demonisation of a less-successful ethnicity, precisely based on the idea that- in the absence of genetic ability differences- the more-successful group must owe their pre-eminence to conspiracy or exploitation. The Nazis disowned IQ tests (a separate but not totally unrelated concept) precisely because the data from such tests kept contradicting their notions of jewish and slavic inferiority. If a belief in genetic advantage can lead to atrocity, and the *absence* of belief in genetic advantage can lead to atrocity, what exactly is the risk-free belief system we are supposed to adopt?
Lastly, while historical caste systems can certainly be nasty and much of the data here remains unclear, there is the outside possibility that some of the religiously-motivated marriage practices and sexual mores of pre-modern human societies effectively functioned as a kind of 'soft' eugenics program, and may even have helped make the Great Divergence possible. I don't want to jump to conclusions, and I'm not saying we don't have more liberal alternatives for tweaking the gene pool today, but it can't be dismissed on technical grounds either.
"Anyway, with all that said, I more or less agree with your point."
I appreciate that, and I don't mean to jump down your throat. It's just that I really think our society has a screw loose on this topic.
" And if we were to start identifying particular genes as desirable or undesirable, our social structures may not be secure enough to prevent our species from sliding towards a genetically homogenous Gattaca-style dystopia"
Sorry, missed this part, but I have a few extra comments here- there seems to be a common assumption that the use of embryo selection or gene-editing would lead to higher genetic uniformity, and I want to push back on this in three ways.
1. If we were to identify every locus in the genome where a minor allele was beneficial or a major allele was harmful, it would in some sense be mathematically trivial to flip the frequencies around- 'make every common bad gene rare and every rare good gene common.' The result? Identical genetic diversity. Massive gains in fitness.
2. Most genetic diversity is either useless or bad. This follows from the simple observation that 80% of our DNA is junk and most mutations that affect function are harmful (absent other selection pressures, entropy always increases.) There are certain kinds of *phenotypic* diversity we want- a diversity of talents and personalities to solve different economic and social problems, and perhaps a diversity of skin tone, hair colour and body types for either aesthetic reasons or to adapt to different climates (which is why they evolved in the first place.) We don't particularly want a diversity of crimes or a diversity of cancers.
3. In principle, exotic options like horizontal transfer or designing genes from scratch could allow humans to add brand new material to their gene pool- either borrowed from elsewhere in the kingdom of life or synthesised from first principles. (This could potentially be useful when colonising places like Mars, so that colonists can tolerate higher CO2 levels, radiation, or perchlorate contamination. Just a thought.)
In other words, I think these concerns about 'loss of diversity' are overblown.
There is nothing wrong with Eugenics itself. What's bad is the methods. Yes, it's obviously bad to kill off / sterilize\* "wrong" kind of people (nevermind the criteria weren't even sensible). It's bad because it's murder.
That doesn't imply gene therapy, designer babies and such are bad "because this is Eugenics, which is bad". This reasoning doesn't make any sense.
\* On topic, IMO it'd make sense to make anti-aging drug conditional on giving up rights to unrestricted procreation in order to deal with population explosion - certainly a better solution than killing people, which is what opposition to anti-aging proposes, pretty much.
Also, some solution to balance political power. Because while Scott says it's not a problem... eh, it might be. Plenty of people today claim "boomers" control politics.
"Also, some solution to balance political power. Because while Scott says it's not a problem... eh, it might be. Plenty of people today claim "boomers" control politics."
Yes, I've made this point in another thread. Your suggestion for making immortality conditional on childlessness... I mean, in principle it could work, but I suspect the necessity of this measure won't become obvious until society is already close to some malthusian wall, and at that point it's probably too late. Unless our species gets a lot more rational over the coming centuries, which I suppose isn't impossible.
Eh. I don't know if obtaining that level of evidential rigour is even possible in our current academic climate, but I think I first heard the idea put forward here.
By a citation I did not mean literally a Chicago style citation or something alike. Just evidence. It is possible that such evidence is present in the video you included but i fear I do not hve the time to watch 50 minutes of video just to be sure there is. Is there any way you could direct me to some direct evidence? Maybe a number of notable feminist claiming their motivation was misstress related for example. Or failing that could you summerise the point.
If you claim that the climate is so bad that you wouldn't be abble to give any evidence whatsover, that would be too convienient to be true at all I believe. That would imply your claims are unfalsefiable.
I'm struggling to try and dig up something more concrete, but I know this is a fairly widespread argument among conservatives and the theoretical arguments seem fairly sound. There's a specific rundown on the topic here coming from an academic thesis, if it's any help.
I suppose it's possible I'm just wrong about this, but the odds that the pill and abortion-access had no impact on the general culture or that those cultural effects were purely good seem slim to me.
Two quick counter-arguments against that line of reasoning:
1) For every new technology, there are dozens of "predictions" about negative side effects. It is extremely difficult, even impossible, to determine which of those predictions will come true, and to what extent. That general argument could have been used to suppress all beneficial changes and progress in the history of humankind. Just think of all the negative long-term side-effects that this new-fangled bipedalism could bring!
2) The societal benefits from contraception and, to a lesser degree, abortion, are so much higher than the supposed drawbacks from more men keeping mistresses, that I can't even call this a "tradeoff" with a straight face. So even if this negative effect would have been reliably predicted, it was worth it.
Besides: Is the proportion of men "keeping mistresses" really higher than, say, 100 years ago?
I'm fairly sure the incidence of adultery and illegitimacy is indeed higher, and one of the negative side effects of the breakdown in marriage (or at least a coincident trend) has been a collapse in birthrates below sustainable levels. The side-effects of the latter could be potentially catastrophic over the next few decades (which is part of the reason why I'm tentatively in favour of anti-ageing therapies to try and offset the other side of the demographic equation.)
I realise all technologies carry risks as well as rewards- even things like the printing and social media, which might have seemed likely purely technical engineering developments at the time, have had seismic ramifications on the social fabric. It's tough to draw the line. I'm just saying that blind optimism is a little unwarranted.
> one of the negative side effects of the breakdown in marriage (or at least a coincident trend) has been a collapse in birthrates below sustainable levels
Countries' fertility rates going negative is a cross-cultural phenomenon that is seen in pretty every single developed country worldwide, and is most highly correlated with decreased infant mortality and economic opportunities. Basically, people have more interests than just popping out babies which detract from those interests, and they don't need to have a lot of kids they no longer die before they reach maturity.
"Countries' fertility rates going negative is a cross-cultural phenomenon that is seen in pretty every single developed country worldwide"
Yes? And which of these countries have not seen increasing divorce and illegitimacy?
"...they don't need to have a lot of kids that no longer die before they reach maturity"
As I have already pointed out and videos I linked to explain in excruciating detail, these birthrates have gone way below replacement fertility, and there are reasons to expect this to result in economic stagnation at best and catastrophic social collapse at worst.
> Yes? And which of these countries have not seen increasing divorce and illegitimacy?
Plenty. Italy and Malta, for example. Below mean divorce rate, extremely low fertility rates (near 1). Plenty of representatives among developed nations, including Ireland, Greece. Compare for yourself:
> these birthrates have gone way below replacement fertility, and there are reasons to expect this to result in economic stagnation at best and catastrophic social collapse at worst.
Maybe. Social security depends on growing populations, but immigration can make up the difference for now. At some point we may have to reckon with the fertility rate issue, but I still don't see a significant causal association between the breakdown of marriage and the collapse of fertility rates, which is the only point I was disputing.
"which led married women to retaliate with 2nd-wave feminism in the 60s/70s"
The Female on Male spousal homicide rate decreased sharply in the US over that period.
"The consequences of our currently rapidly ageing population and shrinking birthrates are so potentially terrible"
I don't follow. Is the global population supposed to increase forever? Unless space travel and energy become very cheap, that sounds like it could have a problematic end. A lot of human problems go away if the population is smaller. And that will be even more true as automation replaces the need for manual labor.
"The Female on Male spousal homicide rate decreased sharply in the US over that period"
Homicide rates in general decreased over this period, but this was coincident with large increases in incarceration and also improvements in medical technology (which turn a lot of potential murders into aggravated assaults.) One can plausibly argue that present-day homicide rates would be much higher otherwise.
"I don't follow. Is the global population supposed to increase forever?"
I think you misunderstand. Birth rates are far below replacement levels across much of the developed world at present. (Conversely, if death rates drop to near-zero due to perfect anti-ageing therapies, this actually will cause global population to increase forever unless birth rates drop to near-zero, which will create some of the problems you mention.)
I already mentioned some of the problems with ageing demographics in a previous post, but there's a video on the topic here. Automation can address some of these issues but not others, and relying heavily on automation will arguable exacerbate problems like income inequality and unemployment (moving a shrinking workforce into high-skilled professions assumes that all your workforce can be retrained to do high-skilled jobs, which is rarely true.)
Yes homicide rates decreased in general, but I'm pointing to a trend in spousal homicides apart from that. (Though charts which break out victims by race as well as gender seem to show a different trend, so I'm not certain exactly what's going on.)
Do you have a link to the full article? Male intimate homicides declining faster than women's is interesting, but I'm not seeing a comparison with homicide more generally.
Wow! That's a really interesting statistic. Do you have any theories about what might have caused that?
The obvious explanation is that the new easy availability of divorce meant that women could more easily escape abusive marriages and so weren't driven to kill their husbands in self-defense. (The majority of wife-on-husband homicides are at least claimed to be cases of self-defense against abuse.)
This would match up with the significant decline in suicides by married women in states that liberalized divorce laws.
But the very surprising result that husband-on-wife homicides *didn't* significantly decline to remotely the same extent would seem to argue against this.
Maybe the fact that abused wives are most likely to be murdered *when they attempt to leave* meant that more divorces exerted a counteracting pressure which increased the husband-on-wife homicide rate?
But in that case you would also expect the wife-on-husband homicide rate to increase, if there were an increased number of attempted lethal attacks on wives thwarted by wives killing husbands in self-defense.
It does seem, though, that most cases of abused-wife-on-abusive husband homicide that I've read about aren't self-defense in the narrow sense of fighting off an immediate lethal attack, but more attempts to escape a generally unbearable situation by attacking when the husband is off-guard.
And then one has to consider the striking fact that America is the only country on earth where wives kill (or at least *used* to kill, before the recent divergence you pointed out) husbands at a rate remotely comparable to the rate at which husbands kill wives. The obvious explanation here is that America has more guns and "God made man and woman, Colonel Colt made them equal"--but this utterly unique gender similarity applies even to non-firearm homicides.
Given that societies where wives are proportionately much less likely to kill husbands include both those that are equally or more gender-egalitarian than the US (NW Europe, the rest of the Anglosphere) and those that are less gender-egalitarian (everywhere else), as well as both societies that are less violent overall (Western Europe, the rest of the Anglosphere, East Asia) and those that are more violent overall (Latin America), it seems really hard to come up with a cultural explanation for this.
I don't have that much more to contribute in terms of understanding root causes, except that It seems there's a stark divergence between trends as they apply to black men and caucasian men. Black men saw a decrease in homicide victimization at least comparable to women. With black men removed from the picture, the caucasian male victimization rate is nearly constant from 1976 to 2002, if smoothed out.
None of this is what I would have predicted, so I hesitate to speculate.
Of course, the two graphs give different total victimization rates, such that the two studies must have different definitions of what constitutes 'intimate partner violence.'
I'm not sure I can comment on these trends in more detail, but I will point out there is a mountain of evidence for gender symmetry in domestic violence (despite predominant aggressor policies that assume the opposite and can make it quite risky for men to call police to deal with violent women.)
I think "the problem without a name" -- educated women expected and expecting to be content with running households-- was a major driver behind second wave feminism.
Oh, absolutely! The 1950s was particularly rigid, recovering from WWII, and prompted a backlash. And with appliances and industry replacing a fair bit of housework (who darns their socks these days?) and educated women having fewer children then... yeah. Means, motive, and opportunity. ;-)
There may have been a kind of tipping point, also. Housewives live better lives if there are other stay-at-home parents for them to work and socialize with. Working women do better in the workforce if women working in the workforce is common and some women are in management. So there are probably some collective interests at play as well which could develop to critical mass.
There are perfectly reasonable arguments to be made that some recalibration of gender roles was both feasible and desirable in the wake of the medical and labour-saving innovations of the early-to-mid 20th century, but women's life-satisfaction peaked in the 1970s and has declined steadily ever since despite enormous legislative and economic changes in women's favour.
Feminists have predictably ascribed this to 'increasing awareness of patriarchy' and dismissed a mountain of evidence that, on the average, conservative women, married women, and part-time-working or stay-at-home mothers are happier than liberal, unmarried or full-time-working women. But 80% of women preferring less workforce participation doesn't make GDP go up in the next fiscal quarter.
Reasonable summary here. I'd expect the picture changes somewhat if you look at how women feel about it at 25 vs. how they feel about it at 60- it's more of a long-term investment strategy than instantly hedonic- and there could be various selection effects going on.
There are some women who just aren't cut out for marriage and kids and conversely there are some women who positively love kids from day 1, but that doesn't mean you can't formulate policy based on averages.
>I'm less harsh on this intellectual habit than I used to be, given that tinkering with human biology and social relations in particular can have long-term side-effects that no-one predicted. e.g, contraception and abortion paradoxically made it easier for men to keep mistresses, which led married women to retaliate with 2nd-wave feminism in the 60s/70s and was most likely a huge contributor to the soaring divorce/illegitimacy rates we've been seeing ever since.
I'm not certain what caused stage 2 feminism, but it's conspicuous that it caused the 2 income trap. This indicates that the leaders may have not been powerful women, but rather corporations seeking to cheapen labor.
At any rate, to whatever degree birth control contributed to the ideas of powerful people, you have left elitism out of the analysis. It didn't happen because of middle class housewives being unhappy or something.
The two-income-trap is something I have mixed feelings about, since it's probably a real effect and there's no question that short-sighted economic minmaxing pressures have a huge effect here (aside from supplying corporate labour, women also contribute much more to luxury goods consumption than men do.) At the same time, the only way around those pressures is to bar women from the workforce, which feels a bit procrustean.
I think Nancy Lebovitz pointed out in a nearby comment that educated women wanting to have some career outside the household was probably another factor once infant mortality reductions and labor-saving devices made it practicable. It's just that Moloch keeps eating our fertility to make GDP go up.
_Sex and Destiny_ by Germaine Greer may be of interest. It's about Family-centered cultures compared to commercial cultures, and part of her point was that commercial cultures pull labor out of families.
She spent some time among Italian peasants and was very favorably impressed. If you read with attention, you'll find some drawbacks to Family cultures. If your Family is bad, you have no alternatives. Barren women are badly treated.
Still, I'm wondering whether part of what's happening in the modern world is damaging institutions which work well some of the time to protect people against the failure modes of their institutions.
No system is perfect, but I think the modern welfare state and some attention to individual variation would compensate for the drawbacks you mention. But I think it's pretty hard to refute the idea that some reversion to family norms is going to be needed to keep our societies sustainable, unless those anti-ageing therapies kick in in a big way.
"This indicates that the leaders may have not been powerful women, but rather corporations seeking to cheapen labor. "
Why not both? Movements are a confluence of interests. There were plenty of midwestern housewives who wanted careers and independence. It's not like 2nd wave feminists don't exist. I've talked to them. Haven't you? The fact that some of their interests matched up with corporate interests likely made the movement much more likely to succeed.
Results and intentions are different things, in any case. I don't think that we can say "because the War on Drugs was disproportionately harmful to African Americans then that means no powerful African Americans advocated for it." African American leaders did support the War on Drugs and then saw their communities bitten by that movement.
My impression is that the war on drugs as it pertains to afro-american neighbourhoods is one of those problems where you have to dig through multiple levels of cynical obfuscation to get at anything like the truth, but roughly, it's a chicken-and-egg situation where residents who mistrust and fear the police (and/or can be intimidated by local drug gangs- "snitches get stitches") refuse to cooperate with the justice system, which makes the justice system malfunction, which in turn prompts the police to get creative about securing arrests and convictions (in which respect the somewhat flexible application of US drug law is, ah, helpful.) And around it goes.
This particularly generates mistrust when residents see people being locked up over relatively minor drug offences while murder and rape cases go unsolved. (In reality, many of the perps being put away for drug offences are in fact responsible for murders and rapes, and the police often have reasonable evidence to this effect, but it's easier to make a drug charge stick than a murder charge, and the former can get perps off the streets long enough to break up criminal orgs and buy a few months of peace before some other drug gang emerges to fill the gap in the market.)
Liberals often complain that these drug laws were formulated in order to artificially increase arrest rates in black neighbourhoods and that black americans are much more likely to be put away for drug offences despite similar levels of drug use compared with whites- in a sense this is true, but it glosses over the fact that whites can sell drugs to eachother without committing murder at 5 times the national average (even in desperately poor areas like white appalachia.) The squeaky wheel gets the grease.
Another popular suggestion is to just legalise drugs entirely, but the truth is that the social effects this change in legislation would have are deeply uncertain. No-one really knows what percentage of violent crimes are prevented by using drug laws to periodically sweep gang members off the streets vs. what percentage of violent crime would be prevented if the black-market drug trade didn't funnel so much money in the direction of criminals. The results could be net positive, net negative, or a complete wash (setting aside the possible effects of drugs themselves being more easily available.)
Failing that, your options are (A) massively improve equipment, training and manpower available to police, and focus on both street presence, witness protection and prosecuting murders and other serious crimes, which will probably require federal funding since a lot of these cities are skint broke, (B) identify individuals with a high risk of violence (i.e, psychopaths) early in life and use some combination of diagnosis and monitoring to minimise their criminal entanglements, (C) create stable, respectably-paying jobs that don't require advanced academic skills so that non-psychopaths are less tempted by the money in crime and less like to use drugs to self-medicate depression, and (D) start taking anti-dysgenic policies seriously, because that's likely to be an accumulating problems over multiple generations (gene therapies, sperm banks, project prevention, middle-to-upper-class fertility incentives, et cetera.)
But of course, none of this will happen as long as the right's only acceptable response is By Your Bootstraps and the left's only acceptable response is Education Conquers All.
> so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
This is how the trolley problem worked for self-driving cars. Something that would hardly ever come up in the real world, and if it did there was an obvious solution[1], but millions of man-hours wasted on it.
[1] the solution is "hit the brakes and hope for the best"
Yeah, so far as self-driving cars are concerned I'd agree. "Drive slowly enough to not hit people in the first place" is what they'll effectively be obliged to do regardless.
Well that's a total non-starter, it's not like the mass of cars is ballast, it's necessary for them to function. Altering bonnet shapes to make pedestrian collisions less fatal is definitely an area worth investigating thoroughly, though.
You could make cars lighter. Particularly if there were regulations requiring cars to be lighter, so that you didn't try to be extra heavy to protect your occupants from the even heavier other vehicles ramming into you.
> "Drive slowly enough to not hit people in the first place" is what they'll effectively be obliged to do regardless.
I doubt it. If we cared enough about that outcome, we'd already be requiring people to do it. The speed limit shows the places we do care: school zones have very low speed limits comparatively.
I think the current default is sensible in principle - cars are required to drive slowly and cautiously near pedestrian crossings, and pedestrians are otherwise assumed to stay out of the road. Children can't be assumed to behave sensibly, and so roads with many children expected have lower limits.
Now, as to the actual detail, car braking technology has improved dramatically over the last decades but speed limits have tended to go down, and (at least where I live) speeding fines are a substantial source of revenue for the state government... One begins to suspect that safety is no longer the sole or even primary motivator.
> More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
I think anti-aging people should be silent about their focus on curing aging, and instead point to the symptoms directly. Population is... bad... enough to be anti-anti-aging once there's hope of actually solving the problem IMO.
> fear that we won't get to find out promptly (read: while I could benefit)
The National Lampoon did a bit in 1970 about Science being on the verge of solving all the ills of aging. Not in time for their readers - presumably teens and twenty somethings - of course.
I've never understood this argument. A cure for aging would cure all aging related diseases and would be approved easily. Statins had an easy path to approval for just putting a small dent in one aging related disease. The FDA is terrible, but it's not the bottleneck in curing aging.
There is something repellent about the idea of professional ethicists, bio- or otherwise. A biologist who cares a lot about being ethical ? -- sure, I love that guy. But someone who calls himself a bio-ethicist? Seems like making a career out of claiming the moral high ground. Prigs.
Bioethics is just a name for a particular kind of philosophical ethics concerned primarily with the human body, medicine, and biology.
Mostly, they’re not claiming any moral high ground. Like all ethicists, they’re just trying to think through difficult moral dilemma’s and determine the optimal outcome.
We all engage in bioethics. Abortion is a bioethical debate. So is human experimentation, or the FDA approval process, or the COVID vaccine.
I think bio-ethicists specialize in "this why people shouldn't have what they want" without considering that what people want might have some good points.
That weirdly sounds like a viable idea, although recruiting high-quality trolls might be challenging (how do you know they're not trolling you with their applications?).
Look, you just take the most common DNA letter at every place. If there were enough random errors to make that come out wrong you'd be a puddle of goo.
But there's no mechanism that allows a hundred cells to pool all their DNA together and compare them. How does a cell know what to repair when the nearest reference copies are locked behind two layers of membranes?
I'm vaguely aware of methods to allow far fewer checks than one might expect to obtain very good accuracy. Of course, that does nothing about the *physical* problem
Stem cell potential declines with age even with induced pluripotent stem cells. The right thing to do if you're paranoid about this is freeze some of yours ASAP, like some people do with umbilical cord, and then take the most common DNA on a base pair basis *there*
If you're going to be paranoid about what parts of yourself are irretrievably lost to time, don't freeze cells that can be deduced later, keep a diary.
I have a lot to respond here, but don't have time to write a full response tonight, so here's a shorter one. I might revisit this later.
David Sinclair is definitely a hype machine, but some of what he's hyping might actually work. Resveratrol is not one of those things (pharmacologically it sucks), but partial epigenetic reprogramming (with OCT4/SOX2/KLF4 or other transcription factors) is. In particular there was a very cool paper recently about restoring vision in aged mice: https://www.nature.com/articles/s41586-020-2975-4
Anyway, I'll believe he can reverse aging when he shows me a 5 year old mouse.
I think messing with mTOR will be necessary, but not by simply down-regulating it. Rather, we need to strategically break links in the entangling of the mTOR and FOXO3a networks, and add ways we can turn subsets of both networks on and off ourselves.
The mTOR network activates mostly things that take lots of energy, like growing, reproducing, and fighting off disease. The FOXO network activates mostly defensive things. It's very hard for genes deep inside your body to know what's going on outside, and evolution likes to accrete things onto existing systems, and bistable switching systems are simpler and more stable than tristable or multiple switches. So we have dozens of major functions whose activation have all been dumbed down to "energy high => mTOR active" vs "energy low => FOXO3 active". We have to turn on all the energy-wasting, damage-producing mTOR systems every time we need any one of them, AND to turn off lots of repair and stress-resistance systems. And we have to turn off fun things like growth and libido every time we need to activate any FOXO3 system. It's a dumb design. We'd probably win a lot of lifespan if we could switch some things on and off ourselves, say by ingesting a chemical that will flip a genetically-engineered regulator on or off, instead of flip-flopping the whole network.
I get the impression that mice are really weird, and most of the things that work on mice don't work on large mammals. Is anyone trying these things on animals which are a closer analogue to humans? (I realise of course that sitting around for fifty years waiting for chimpanzees to die of old age isn't really a convenient experiment either.)
I mean, one obvious problem with the mouse argument is that mice probably haven't evolved to have long lifespans to begin with, whereas humans have. So it's possible many of the things we "fix" in mice are things that are already fixed in humans.
Have we really evolved to have long lifespans? Or are we just better at not dying? Evolution didn't really fix us; we did that ourselves. We stopped dying from polio, fever, parasites, appendictitis, and even kidney failure, and no genes are responsible for that. The fact that we get decrepit and senile in our old age suggests that if anything, evolution *doesn't* want us to have a long life.
I think it's more likely that smaller animals are more vulnerable to aging. All the damage of aging accumulates in small bodies at the same rate as large bodies, so it catches up with them far sooner.
The natural, ancestral environment human lifespan is one of the longest lifespan in the animal kingdom, a record that stands even when compared to all now-extinct life. Most animals do not live to 30. Hunter gatherers frequently lived to 70.
Considering our children are not capable of caring for themselves till multiple generations of mice have died, I think we can say we've evolved to live long.
Note also that people happily lived the best part of a century throughout history (and got senile). It was less frequent due to illnesses but the underlying point that a human who stays healthy to that point can easily live over three quarters of a century suggests we did evolve to allow long lives. Evolution probably optimised surviving to a younger age (past childhood, to the grandparent stage maybe) but it therefore allowed a long lifetime.
As for senility, elderly dogs and cats get this, at a much younger age than humans (including the breeds of dog that are as large as people), which suggests it's a common late-life failure mode in mammals living beyond their prime. It's probably not evolved so much as not been evolved away as so few mammals at that stage of life have children that there's no real evolutionary driver to not be senile.
I thought our children aren't capable of caring for themselves because if they gestated to when they would be, they'd no longer fit through the birth canal. We've evolved to have unusally long childhoods, sure, but I don't think that's the same thing as evolving an unusually long lifespan.
Senility in large dogs is a fair point, but I'm more curious to aging in similar primates. Chimps live to 50-60 years in captivity, with the oldest living chimp being about 77, which is not that much different from humans. Did the same evolutionary pressures apply to them, or did we further evolve to get that 10-20 years extra?
Apparently, chimpanzees have a pattern of mortality that's distinctly younger than that of all human hunter-gatherer populations except for Pygmies.
This paper argues that abnormally short average lifespans in Pygmies--closer to those seen in chimpanzees than in any other hunter-gatherer group--is what lies behind the selection they faced for early puberty, which in turn led them to stop growing early.
Now, this paper attributes high Pygmy mortality to the greater dangers of their jungle environment--high disease burden and poor nutrition--rather than to any genetic tendency to early senility.
Reading it, I was very curious to learn if Pygmies taken out of the jungle and given a modern Western standard of health care and nutrition would still age faster and die younger than other humans, but they said nothing about that possibility.
Also, Pygmy life expactancies, while much lower than for other hunter-gatherer groups, actually seem pretty comparable to the life expectancies of some pre-modern agricultural populations that faced extremely poor nutrition and high disease burdens--and yet none of these populations underwent anything like the same selection for early puberty.
As I understand it, larger dogs don't live as long as smaller dogs. I don't know about lifespans for different sizes of wild canines.
I believe part of the extended lifespan for children is grandmothers (perhaps especially maternal grandmothers) helping to care for children.
Longer lives are associated with not resembling a prey animal. Large size, communal living, poison, armor, and flight correlate with longevity. Bats are very long-lived for small rodents.
You can't combine all of the longevity factors, but I wouldn't mind some sf about about long-lived flying poisonous communal turtles, maybe on a low gravity planet.
Considering how little care (most?) turtles show their young, could they be communal? Although I have read about a sci-fi amphibian race who like frogs lay and fertilise eggs without sex, and therefore with minimal concern for parenting. They aren't portrayed as having families but rather select factions to join, and I think are suggested to have high childhood mortality. Christopher Nuttall's Ark Royal saga from memory. Do I suppose alternative models of community might apply.
Mammals with a long maturation period tend to have long life spans, because the parents need to be around to raise their offspring long after they're born. Humans have one of the longest maturation periods of any animal out there, if not the longest, hence, we also have evolved to have relatively long lifespans.
It's been tried in monkeys for calorie restriction (less cumbersome than primates but still lots of trouble) https://www.nature.com/articles/ncomms14063 you will notice the effects are much more noticeable for healthspan (morbidiy curve) than lifespan but sample is anyway small
Even if we did manage to avoid people raising fake ethical concerns the problem is that there aren't that many compared to mice, specially when you get to actual primates. We'd have to get everyone to agree on the best experiment (epigenetic? stell cell reprogramming? organ replacing?) and then if something goes wrong and we get a fake conclusion because of some quirk or incomplete experiment that could anchor us away from potentially good solutions
Mammal lifespan is very much a factor of mammal size, plot age and size on a graph and the results are uncanny. All mammals are basically the same system scaled to a different size, at the extremes limited by elements of the circulatory system. Shrews couldn't be any smaller because a heart can only be so small and still be viable; if blue whales were any larger, their aorta couldn't handle the pressure required to maintain bloodflow. Yet both of them (and us humans) over the duration of our lives experience on average the same number of heartbeats!
Is there an actual scientific proof of this? I've vaguely accepted it as true for much of my life, but it is such a just-so fact that I think I'd like to have my willingness to accept the idea bolstered by some actual evidence.
Here's a site that crowdsources people digging through biological documents to verify this. They have 175 species plotted, and humans are by far the biggest outlier.
I get the impression that mice are peculiarly susceptible to dying of cancer, such that "curing cancer" and "extending lifespan" correspond much more closely in mice than in humans.
I believe in the book when Sinclair was talking about the Yamanaka factors, he asked the reader to imagine that you start getting into your 40s or 50s and are diagnosed with age. You go in to a clinic for treatment and they use the Yamanaka factors until you become 20 again and you do this over and over. I'm not sure that is possible but that idea got me really excited when reading this book.
I'm interested in taking resveratrol and NMN but I don't really know about this stuff and it seems so speculative. How badly can you hurt yourself with these?
Low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him.
@metaclesus is right. Resveratrol doesn't do much. NMN is safe but upside may be overblow, at least for younger folks. There is only one study that shows lifespan benefits with NR. Some people report feeling anecdotally better on NMN, but it's mostly older folks and could be placebo. You can get a good number of NAD benefits by exercising & fasting instead of taking NMN. It's expensive. That being said, if you wish to experiment with it, it's safe!
Oh and metformin is the other drug that is safe and has healthspan benefits. However, it can blunt increases in muscle mass, not muscle strength, if taking it with exercise.
Isn't it mainly effective for people with metabolic problems? Apart from it being a diabetes drug originally, I've read that the published effects mix a big effect for unhealthy people with minimal effect for the metabolically healthy.
This is based on an n=1 sample, but I take high-dose metformin (2000mg/day) for its alleged lifespan benefits and although I can't make any claims about its effectiveness in that regard, it definitely has some dramatic effects. I've gone down a belt notch without any intentional change in diet and my blood sugar is near the bottom of the normal range, which I think is where you want it to be.
I don't do intermittent fasting but I think if you wanted to, metformin would also make it a lot easier, since you'd get fewer hunger cravings.
It's most commonly used as a Type 2 diabetes drug! The studies that have been done are people above 65 and they showed that those who took metformin had 17% less mortality than healthy people not taking metformin. That being said, it's possible that the healthy 65 year olds could have benefited from it maybe because they weren't as metabolically healthy as a younger person (even though they were "healthy" for their age).
It is an open question whether metformin will be beneficial for people in their 20s, 30s, or 40s specially if they are exercising & metabolically healthy. That being said, I don't think it has side effects, except for blunted gains in muscle mass, not muscle strength!
My next podcast will be with Nir Barzilai who researches on metformin if you're interested in learning more :)
I read Sinclair's book last year, did a bit of research, and started taking NMN daily in sublingual powder form - it's quite cheap and at least harmless. I'm 54, pretty healthy and active, and can report feeling anecdotally better, though that could be a placebo and obviously it will be another few decades before any major positive effects on my mitochondria kick in.
Good to know, Patrick! Yes sounds like a lot of people above 50 seem to anecdotally report more energy on taking NMN. I'm in my 20s and I was taking it, but didn't notice a difference, but who knows! Agreed with you that it's harmless and placebo effect is still strong, so if it's having a benefit that way, so be it :)
I'd be curious to see more studies being done though because so far there is very little data except one study that shows minor lifespan benefits with NR in mice
> And finally, what’s the worst that could happen? An overly literal friend has a habit of always answering that question with “everyone in the world dies horribly”. But in this case, that’s what happens if we don’t do it. Seems like we have nowhere to go but up!
I am always surprised that there isn't much, much more support for anti-aging research. I'd figure that everyone expects to age and no one wants to. So the government/billionaires/whatever should be showering the research with money. Yet that doesn't seem to be the case.
I suppose that depends on what you define as 'shower'... For perspective, Jeff Bezos alone is probably spending ~3.7x more per year (~$1b) on 'make rocket go boom' than Altos has raised total ($270m). Or to put it another way, Altos's capital of $0.27b is 0.01% of Jeff Bezos's net worth ($205b?).
I think the key issue is that we know how to make rockets go to space, but so far are pretty iffy on anti-aging (and cancer, for that matter.) One could reasonably assume that we are not close to the "shower money on it and it will happen faster" state for those things yet. Medicine, at least, seems to be one of those fields where you can't spent 9x as much and get results 9x faster.
Perhaps it doesn't look like it as much from the outside, but as a cancer researcher, I would say that not only do we know a lot about cancer, but we've used that information to dramatically improve treatment (and in many cases cures) for cancer over the past half-century. Despite a public perception that there's nothing happening in cancer, we've been making steady progress.
I agree that 9x more spending is probably not going to result in 9x more results, but we are seeing some progress for all the effort we've been putting into the problem. From where I sit, I fully expect that my children will not understand why the idea of cancer was such a scary thing for previous generations.
I don't doubt that you are right. I wonder though how much advancement is a question of more money and more researchers and how much it is just a question of time. The diminishing returns for adding additional researchers (what I assume is happening with more money) seems to have gotten steep, such that adding another researcher is nearly zero value add when it comes to speeding along research. That seems to be the case in just about all fields at the moment, at least on average, but of course that leaves a lot of room for specific fields having a lot better return.
I am just pessimistic on where we are on the "spend money -> get results faster" curve in general when it comes to science, or at least the science that gets funded by NHS, NIH, etc. The quality of research in general is so low that I think money spent realigning incentives is more useful, but then again fixing the incentives in science is probably well beyond what a few really rich people can do.
I agree that basic research needs a complete overhaul. The dilemma you face as a researcher is:
1. Work in an obscure field nobody cares about until you win a Nobel or get kicked out for never doing anything 'important'.
2. Work on the new 'hot topic' and rush to publish.
With strategy (1) you can take your time and do the research right, but you'll never have the money to do so. With strategy (2) taking your time to do the research right will never pay off, because someone will scoop you and get their work published first, or if it was wrong all you'll be able to do is publish a controversial 'corrective' paper that people will be annoyed at you with until they finally accept your careful work demonstrating that people were rushing to judgement. Meanwhile, the person who was willing to rush publication will get accolades and advancement whichever direction the research went. And since the 'careful research' direction isn't viable anyway, they can keep rushing publications for a whole career so that the errors that would have been corrected with careful research just get subsumed into the general morass of the 'replication crisis'.
Not sure what the solution is, but throwing more money at the system isn't likely to fix it. It'll probably just make it worse.
As someone who works on the clinical development side (from a small pharma perspective) I have to say that a lot of the research we might otherwise want to rely on is sloppy at best. Still, there's a lot of careful research being done downstream in the clinic. But clinical development takes years before you get data on each expensive trial. While benchwork gets results much faster at a fraction of the price. If we wanted to accelerate clinical development across the board, we would set high standards for academic research so less bad science got into the clinic before it was corrected.
For $XXX you can make a rocket go to space, and know that it will happen. How much does anti-aging cost? We don't know, because we haven't got anti-aging and the "best" stuff we have is highly speculative and often falls into hype like the author here. If you were 60 years old and had infinite money, how would you spend it on anti-aging? Lots and lots of baseline research projects, I would suppose, but they aren't likely to pan out for many years, if ever. Bezos will likely be dead or too far gone by the time this research (realistically) gets anywhere. If he wants to throw some money into pet projects, which he is, on the off chance that we get a sudden breakthrough, then he's already covered on that. Throwing more money into it at this stage of research is probably just throwing money away.
The rocket analogy to anti-aging would probably be something more like this - For a billion dollars you can take away one year of aging, so a 60 year old can become 20 again by spending $40 billion up front and then $1 billion per year after that (or alternately, remain at a stable age for $1 billion a year but not reverse aging). If such a technology existed, I would bet Bezos would be using it.
I think most Americans oppose anti-aging research. Western religions are based on the fear of death, and we've spent over 2000 years convincing each other that death is good and life is bad, and that society would be ungovernable if people didn't have a life after death to be both hopeful and fearful about. Many important Western philosophers, for instance Plato's Socrates, Jesus, Schopenhauer, Freud, Baudrillard, and Foucault, thought that death is good or desirable. A larger number, plus Buddhism, claim that death is better than life (because life is nothing but suffering).
(Oddly, most Americans also oppose the right to die.)
The NIH and FDA both explicitly oppose anti-aging work. The FDA says aging is not a disease and hence drugs against it can't be approved. The NIH refuses to fund research that targets aging rather than one particular disease of aging (although the National Institute of Aging recently floated these general aging research topics: https://www.nia.nih.gov/research/blog/2021/09/check-out-nias-new-cleared-concepts-aging-research ).
The FDA has approved treatment for Progeria. They don't have any problem with treating aging diseases, you just need to actually be able to define what you're treating.
To define something as a disease, you'd have to actually define what that thing actually is. Aging is ill-defined and may not be one thing; in fact, a lot of theories of aging suggest it is actually many things. This would also explain why trying to fix one thing doesn't result in immortal mice; even if you fix one thing that kills mice, the other thing will kill them instead. You'd have to fix all the things to get an immortal mouse.
I suspect that aging is DNA damage AND epigenetic damage AND fault accumulation AND probably numerous other things added together.
It's not one thing, it's all the things, so you're not going to be able to make a single "anti-aging" treatment, you have to treat each of the parts of it.
If someone developed a drug that, say, greatly reduced harmful mutations, thus acting as preventative for cancer and various other aging-related genetic diseases, I don't think that the FDA would have any problem with approving that; it's no different than a vaccine, in the end.
I am also skeptical of the idea that most Americans would oppose anti-aging research, given how successful various types of fake anti-aging products are financially, and how most Americans are in favor of living longer, healthier lives.
Assuming it doesn't involve eating less french fries, anyway, because really, if it does, what is the point? :V
I'd agree with this. I'm actually moderately optimistic that effective anti-ageing therapies will be developed over the next couple of decades, given that the incentives are so enormous.
The FDA considers progeria a disease, but not aging. It seems likely that a drug which reduced aging would also delay progeria, and thus the drug could be approved for progeria, and legally prescribed for anyone. But it also seems that the chance of your doctor writing you a prescription for that drug to reduce your normal aging would be similar to the chance of your doctor writing you a prescription for a muscular dystrophy drug to help with your bodybuilding, i.e., none.
Re. "I am also skeptical of the idea that most Americans would oppose anti-aging research, given how successful various types of fake anti-aging products are financially, and how most Americans are in favor of living longer, healthier lives."
Well, I'm more confident that most philosophers and bioethicists oppose anti-aging research, and that most people who would be politically activated by a potential cure for aging would be against it.
Recall the book that President Bush 2's "President's Council for Bioethics" published, which mostly warned against trying to improve humans, as being an affront to "human dignity". A country that elected a president that selected a council so firmly opposed to life-enhancement tech can't be very enthusiastic about extending lifespan.
What's amusing to me is the never-addressed glaring contradiction between thinking that life is bad, and having children is one of the loftiest acts of virtue. The one in which you condemn the person you're supposed to care about the most to a lifetime of suffering.
It's not a glaring contradiction at all. Most people who have children (me among them) think life is worth living on net, or at least lives similar to our own, but only *conditional on it having an end*.
There's no more contradiction in this than "I like movies, which tell a coherent story that ends, more than Spider-Man comics, which have decades long incoherent serial nonsense".
You may not agree, and that's fine, but it's not a hard position to understand, or contradictory or even obviously wrong. It is a *preference* for a certain kind of life story.
I don't disagree in the sense that involuntary immortality would be much worse than inevitability of death. However, being able to determine its time and the manner without the certainty of eventual decrepitude would be much preferable to me (and to the vast majority of people I'm pretty sure). Of course, all evidence points to the universe not caring about our preferences whatsoever, and the prospects of this changing remain dim.
Your summary of the religious position is too simplistic, so you're missing why the nuance can exist and the contradictions aren't contradictions.
Life includes suffering, and inevitably will. If you stopped aging, you would still die in car crashes and have heart attacks from high cholesterol. Living forever (and still enjoying life, rather than living in a bubble for safety) is a worthless pipe dream and always will be. Hedonism offers no worthwhile benefit, only the appearance of worth on a short timeframe. People will get tired of hedonism the same way they get tired of anything else. By attempting to fulfill temporary and ultimately meaningless objectives, you only end up with false hope and growing frustration as you continue to seek out new and more exciting alternatives.
The only things that really matter and provide real value are our relationships with other people, and even more so with the eternal God. Death, and aging itself, are benefits because they encourage us to build those relationships and value the relationships over the material. Having children is a matter of creating social bonds and exemplifying the ideal of relationships. Never existing isn't a help, because there are real things that exist and that are good - those relationships. Material accumulation or hedonistic pleasure, on the other hand, are not ultimately beneficial. Growing older and dying are catalysts for us to pass along our knowledge, positions, and wealth to the new generations, building relationships with the new as we transition out of life. Take those things away, and there's no reason to interact with young people and create relationships (or have children), leading to an inevitable stagnation and endless hedonistic pursuits that will never actually solve our problems or bring us peace. We'll become more and more frustrated by the pains we still experience, losing the calmness and peace that comes from accepting our inevitable death and living a life that promotes others instead of running that hedonistic treadmill.
I wasn't summarizing "the religious position". I listed specific philosophers and one specific religion, which all specifically said death is better than life, or death is desirable. As in repeatedly writing "All life is suffering", and telling people the greatest thing they could possibly hope for is real death, as Buddhism does, and as many Western philosophers have done. I think I could have listed all the existentialists as well, but I didn't because I haven't recorded specific quotes by them on the topic.
(In the case of Jesus, death is better than life only for /some/ people. Although actually it's difficult to know now when he was talking about an afterlife, and when he was talking about a kingdom on Earth. He, or his followers, weren't interested in differentiating the two.)
Sure, but there can be more suffering or less suffering, and less suffering is better. Without this assumption, many things we do would not make sense, for example medicine in general.
> People will get tired of hedonism the same way they get tired of anything else.
Then I'd leave it for them to find a hobby, or perhaps kill themselves.
> our relationships with other people
Which are sometimes interrupted by those people dying.
If death is so good, why don't we make a law to kill everyone when they get 30? (Enough time to have kids and keep the humanity existing. Unless perhaps extinction is also good.) This would be even more awesome than what we have now, wouldn't it?
Those 20 something people could then tell each other wisely sounding scary stories about the horrors of their ancestors living to their 50s or 80s leading utterly meaningless lives full of material accumulation and hedonism.
Logan's Run would be the most famous fictional example of that society, it's an idea that has certainly been explored before. Good point that it's a useful analogy here, much as reading Flatworld helps understand the implications of a 4th dimension
This may be a stupid question: If the FDA doesn't consider aging a disease, couldn't a "dietary supplement" claim to "cure/prevent/slow aging" without needing to be regulated as a drug? That seems better, at least for availability-after-development, although maybe not for getting research funding or profits.
It's a good question. I don't know what chemicals qualify as "dietary supplements", but they do all seem to be natural products. I don't think a chemical not occurring in nature could be sold as a dietary supplement, but I don't know. I do recall a case about 25 years ago, when a wrinkle-removing cosmetic was taken off the market by the FDA with the argument that it must be a drug, not a cosmetic, because it actually removed wrinkles, and therefore was a drug, and therefore had to formally prove to the FDA that it removed wrinkles. I wish I remembered more specifics, but I don't.
Here is a vague FDA policy and a list of dozens of actions against cosmetics:
"if a product is intended to make lines and wrinkles less noticeable, simply by moisturizing the skin, it’s a cosmetic...if a product is intended, for example, to remove wrinkles or increase the skin’s production of collagen, it’s a drug or a medical device."
Judaism is clearly in favor of living in a way that Christianity isn't, though Christianity isn't simply pro-death. It's complicated and I don't have all the details.
I read an account of a bio-ethics and longevity conference (probably can't find the link), and the only person in favor was a rabbi.
Christianity thinks of itself as not-anti-life because it's contrasting itself with Manichaeism, purer Platonism, Gnosticism, and other popular philosophies of the 3rd century which said that all physical reality is inherently evil. St. Augustine concluded that physical reality must be *capable* of perfection, because God was incarnated physically. Christian theologians make a big deal of this, but really, the difference between "matter is corrupt 100% of the time" and "there was this one bit of matter 2000 years ago that wasn't corrupt" is not that big.
I really think the primary thing is expectations management. I think people get really upset (or think they will get really upset) if they get their hopes up and end up being disappointed. And so people learn this psychological defense mechanisms to avoid letting their hopes get up in the first place. And this is a problem because if we believe we can't do this thing, we'll never try and so we never will.
The medium matters for the message. A lot of the anti-aging people are social misfits who have blown all their weirdness points already and keep going on about how bad the people who don't support them are.
And normies see them and think "the first people to be immortal are going to be *those* people??"
Some good PR firms would really help with messaging. The major problem is that it involves a lot of the current crew sitting down and being quiet.
>A lot of the anti-aging people are social misfits who have blown all their weirdness points already and keep going on about how bad the people who don't support them are.
I don't know anyone like this. Certainly Sinclair isn't like this, he seems extremely normal and I haven't observed an ounce of victim complex from him. The other big name is Aubrey de Gray, who is certainly eccentric and weird but I also haven't observed a victim complex from him.
What I could understand your "going on about how bad the people who don't support them are" could be about, is the criticism that they have for people who don't support anti-aging research at modest levels compared to research into other diseases which have broad support.
>The major problem is that it involves a lot of the current crew sitting down and being quiet.
Again I'm not sure who you are referring to as the "current crew" but again I emphatically don't believe this is the problem. I think the main problem is that most people do not conceive of life extension to be remotely within the realm of realistic scientific progress within our lifetime.
Most anti-aging stuff is a scam. People are rightfully leery of it. Doubly so because we don't actually know what aging is, and my guess is that aging is probably many things.
Billionaires don't have *that* much money to spend. The real money is in the middle class, which has far less money individually, but who number in the hundreds of millions, as opposed to ten to twenty or so.
As it happens, people have a fairly short time horizon on death. When they are actually suffering from a fatal disease -- after the first heart attack, say, or when cancer is diagnosed -- then they will indeed spend a large fraction of their income on trying not to die. So the money available to treat active disease that will predictably lead to death shortly is substantial.
On the other hand, ask your generic 25-year-old whether he would donate 25% of his before tax-income to longevity research -- or have his taxes rise by 50-75% to pay for it -- which is what it would take, not milions but billions of dollars -- and he would laugh. Maybe 0.5-1%, sure. But that won't cut it.
You could certain siphon off a few billions from free daycare or community college, "infrastructure" or refundable tax credits, or any of the other massive wealth-transfer programs the Federal government runs that add up to a trillion or so per year, but I rather suspect the political pushback would be fatal.
>25% of his before tax-income to longevity research -- or have his taxes rise by 50-75% to pay for it -- which is what it would take, not milions but billions of dollars -- and he would laugh. Maybe 0.5-1%, sure. But that won't cut it.
Let's halve that as a conservative estimate for my lazy math, you don't think $60B a year wouldn't dramatically increase our odds of making good advancement in longevity research (specifically, something like a 25% increase in life expectancy for people with access to such healthcare)?
My impression is that 1% of 13% is 0.13%, so if you raise the average tax bill by 1% you get an extra 0.13% in revenue.
Anyway, if you want 7.5% more revenue, it follows the average tax bill has to rise by 7.5% and yes I rather suspect a lot of people would get crabby about that. Supposedly the average Federal tax bill was around $15,000,so you're talking an extra $1100 a year. I would guess if you went on the hustings and said we're going to raise your taxes by $1000 a year to fund longevity research you might very well get a fair amount of pushback.
This. I'm constantly surprised by how chilled almost everyone is about they fact that they and literally everybody they ever loved are going to die, most likely in pain.
The simplest answer to "Why doesn't the body already do this?" is anti-aging isn't free: it costs resources the body can use on other things, like manufacturing sperm or cogitation or even burning for warmth. Animal lifespan varies based on a lot of things but it tends to be shorter in animals that can expect to die by accident or predators because in those animals there is no evolutionary benefit to adaptations for increased lifespan beyond a certain point. Meanwhile, birds that are the same size as mammals that can be expected to live 3-5 years will live 80 years, because flight and their relative intelligence means birds are much less vulnerable to predators and accidents and local food shortages.
Personally I think Algernon's law is absurd and betrays a lack of attention to the natural world and the constraints of evolution.
I mean, this is just exactly one of the exceptions described here, right? https://www.gwern.net/Drug-heuristics#loopholes It falls under Gwern's exception 3, or Bostrom's exception 1 or 2.
Isn't there a big evolutionary advantage to shorter lifespans, at a point? Natural selection of best fitness works faster when people have a few kids and die, and then their kids select for suitability and have more kids, rather than the same people just popping out effectively the same evolutionary generation forever
Overpopulation is a problem for species, not individual genes. Remember: group selection is bunk, scarce resources only makes individuals compete more desperately.
Chiding that we "remember" a progressive dogma? What an odd way to reason through a problem. The above-mentioned flaw in Algernon's Law is near trivially correct, but it will probably take Paige Harden-type gentle coaxing for the larger part of the polite establishment to recover its sense.
"Evolution doesn't favor kids" is true of individual evolution. It is not true of species evolution(competition among species). Species evolution favors kids in several conflicting ways.
Consider sexual vs. asexual reproduction. With asexual reproduction, the population doubles rapidly but you get less evolution (only from mutations) and less variation of the gene pool. Given two populations 1 reproducing sexually and the other asexually, the asexual one virtually always wins due to reproduction rate and finite resources.
Sexual reproduction is half as fast (2 gametes are needed to create 1), however there is far more genetic variation. This leaves the species more adaptable to changing conditions. Since both of these two reproduction methods coexist(millions of years later), it follows that each has benefits in different scenarios.
Yes but this really isn't "species evolution" though it looks like it to us. IIRC the correct term is "lineage selection." Sounds pedantic, but it is an important distinction.
It seems like the other relevant dimension here is that we're talking about aging. Evolutionary selection for slowing down aging seems… complicated.
Perhaps slowing down aging increases lifespan, but doesn't affect your younger years. In this case, you've already passed on your genes (or not) before having a longer lifespan matters.
Creatures that die early have little selective advantage in living longer - they're mostly going to die by age one anyway, so what's the point of a gene that helps you live from age 2 to 3?
Living longer is upside, but most creatures can't achieve that. Those that can often do.
Algernon's law is indeed as absurd as the novella that spawned it - a sentimental sci-fi about a dying mouse as I recall... plus Algernon is just a silly name (apologies to any actual Algernons here) hence Wilde
It's a short story, later developed into a novel, called "Flowers for Algernon". There is a mouse in it, but it is notable as the subject of a revolutionary surgical procedure to increase intelligence. The researchers need a human subject, and they find one in Charlie Gordon, a mentally retarded man. The operation works and vastly increases his intelligence, but things don't go well.
As the mouse begins to behave erratically and regress then dies, so Charlie realises the same will happen to him and he loses all his intelligence and ends up as he began.
Oh yes, it's coming back to me... so would you rather get vastly increased intelligence, but knowing you'll regress to a vegetable after a while, and a mouse will die for you, or continue in your current state of blissful ignorance?
Precisely. No such thing as a free lunch, but calories are a hell of a lot cheaper than they used to be so there ought to be a lot of very nice lunches out there indeed that modern humans can now afford where once we couldn't.
Only ~1/2 way through. But you haven't mentioned my fav. aging idea. Aging is the response of a multi-cellular organism to cancer. (One cell going crazy and dividing forever.) There is a limit on the number of cell divisions for non-reproductive cells. (most of your body.) When you reach the limit, cells stop dividing and repairing and you get older. The limit stops cancer at least to first order...
I'm going to be so, so, so upset if aging is conquered a few years after I die, or when I'm in my 80s and it's too late for me, or some such thing.
The cosmic unfairness of it! — I want to live forever (or at least "way longer than current human lifespans", and the same for those I love) more than *anyone else I've ever met*; and I live in a time when the spiritual sort of immortality looks more unlikely than it did when "I dunno; magic?" was the best answer available for "how does any of this work?", but the physical sort looks absolutely possible and likely to happen *someday*...
... and I end up one of the poor bastards trapped without the comfort of an eternal heaven waiting after death, *or* the exhilarating freedom of endless experience stretching out to the cosmic horizon? And the latter could possibly be mine, except we spend our time and resources on frivolities that don't matter at all if you don't have *time*? (— whereas solve aging, and you can have all the frivolity you want... literally! you *can't* have all of anything you want, now, because you're going to become decrepit and die!)
I forgot if I had a point. I think it's just that I'm upset. Interesting book review and I want more like it, though.
Maybe being the generation that were born too late to be comforted by religion and too early for science to conquer death, is the way karma finally catches up with Boomers.
I take solace in watching the end of homo sapiens as designed by evolution.
Even if we were born too early, this is a fundamental, species-wide change that will never happen again, and have the front row seats - we can work on it, in fact!
I can guarantee that you will not be upset if anti-aging comes along after you're dead.
It sounds more like you don't feel that you are using your life properly now, and are looking for ways to buy more time so that you can experience what you want while you still can. Might I suggest re-evaluating your life priorities, and how you spend your time now? As someone who you would call very religious, I can vouch for the spiritual lifestyle, even if there were no eternal heaven. There's a peace that comes from not pursuing pointless worldliness, and I would encourage you to check it out.
Unfortunately, no amount of re-evaluating your life priorities and living spiritually can give you extra 1000 years of time... unless anti-aging is somehow involved.
Yes, we should spend the time we have as well as we can, but that it not an argument against wanting more time.
1) You will not enjoy more time if you continue spending it the way you aren't enjoying now. 1a) If you cannot retire or otherwise stop doing what you are required to do now (work, etc.), then you can't change your life as you would want.
and
2) If you are truly happy in how you are living your life, you don't need 1,000 years in order to enjoy it. You can appreciate the days you have, rather than seeking out what you lack.
This doesn't even get into the utility value of Heaven or the reality that even "immortal" people that never age would still die frequently and often unexpectedly - meaning you can't count on that 1,000 years under any circumstances.
I’m not sure what your point is. Whether it’s early retirement or mindful meditation, anything good you can do in a short lifespan can literally be extended and multiplied a hundredfold given a longer lifespan. It doesn’t matter if it’s 10 more years or 100 or 1,000, it is a strict superset.
Conversely, won’t any valid argument that an un-extended life is just as desirable as an extended life, also mean that a life cut short by disease is just as desirable as a life that isn’t?
Yes. None of us live very long in terms of human history, let alone geological history. That someone might live a few more years than another person matters far less than the quality of their lives. A well-lived life to age 60 is far better than a poor life to 80. Adding 20 more years to that poor life probably makes things worse!
You might not be a big fan a patriotism, but many countries, the US heavily among them, celebrate the death of young soldiers - not because of the death, but because of the purpose of their lives. And this is not just Army propaganda garbage, but genuine grass roots feelings of individuals, including the relatives of people who died in military service. Death in self-sacrificial ways is often considered a major positive, even if the death itself is also considered sad.
There is a side concern about how human relationships are affected by an "early" death. Someone with small children and a spouse that depends on them dying is a different kind of situation than someone who lives alone (all else equal).
As someone who is truly happy with how ve is leading vis life right now: Yes, of course I would like to have more of it! Why wouldn't I?
Of course that doesn't diminish the fact I'm enjoying it now and it doesn't make it a "need", any more than someone who dies abruptly (e.g. due to a traffic accident) in their mid-teens and had a great childhood "needed" to reach adulthood, but it's still a shame to just... stop after a few decades, for no reason than that some decades have passed? It seems like a lot of wasted potential and a lot of unrealised happiness to me.
I'm fine with only giving longevity to people who want it and think it will help them, there's certainly no need to force it on anyone, but why withhold it altogether? The argument to me sounds like "it makes no sense for this subgroup to have it, so let's not have it at all", but you probably don't actually mean that - or do you?
(And this is completely side-stepping the part where aging itself is a really unpleasant process. I'm healthy and in my mid-thirties, but this is still qualitatively different from a decade and a half ago, and I'm not looking forward to the presently inevitable further deterioration.)
I guess my main thought is that we would not enjoy immortality very much at all, and would inevitably run into the same problems we have and just grow more discontent with it all. Some others have made comments in line with my thinking regarding fear of danger, lack of purpose, delayed maturity, and other issues.
I wouldn't try to keep anyone from taking a treatment that made them (potentially) live longer. I am trying to add a different perspective about life, and help people realize that the happiness they think they could get from immortality, but don't have now, is very unlikely to materialize. This seems even more important to me, given that there isn't an immortality option and I'm responding to someone (OP) that seems to think they need immortality in order to reach happiness. It isn't true, and he would be better off if he could find a more suitable path to his own goals on a timetable that actually works for him.
Thanks for the response. That's fair and an entirely reasonable position to have; apologies for misunderstanding the point you were trying to make. I do admittedly disagree with your first paragraph quite strongly (as in, I do think we would enjoy immortality - I don't think it would be a panacea for happiness, not at all, but I think it would be a very strong net gain even just to erase the suffering of aging), but I understand your position better now and thank you for going out of your way to explain it a little more.
There are things I think I would like about immortality-- one is getting better at things.
And let me tell you, aging is starting to have an effect and it's bad even though I don't have a very bad case of it.
You seem to be arguing against the idea that immortality will make life completely wonderful. I'm sure there are people who believe that, but you don't have to have any such delusions to want immortality.
Why do you think OP is not enjoying their life? "I want more of X, much more! - Oh, that just means you're not enjoying X you have" is exactly the opposite of how we reason about everything else.
I find contentment in my daily life, which is much more satisfying for me than when I sought endless earthly experiences. I used to daydream of being immortal a lot, and was very concerned with a feeling of dread about growing older and eventually dying. It caused me a lot of worry, similar to what the OP is saying. But I am getting older, and frankly that's okay. I can't say that all of the experiences of aging are super awesome, but they are no longer overwhelming, because my priorities no longer require that I live forever to meet some crazy expectations for my life. As I have come to accept the reality of life, I see much more clearly the futility of my previous perspective. Even if I were to stop aging or become 25 again, that doesn't solve any of the underlying issues - partly because there will always be problems and frustrations (including death) and partly because material pursuits are endless.
Well, never aspire to anything beyond what you already have is certainly one way to reduce negative emotions, but not everybody's ultimate goal in life is to minimize negative emotions.
And in any case I'm not sure how any of this answers my question, you seem to be just projecting your experiences on the OP.
I personally believe immortality to be overrated. Considering that one needs to constantly forget quite a bit to remain sane (we couldn't possibly remember every moment so vividly as to be able to relive them on demand and still be attached to the moment), our lives are a slow rolling cycle of rebirth anyways. Even so we accumulate mental clutter that weighs us down -- you're only young once.
I say it's better to do a hard reset every once in a while, and start from scratch, except with the added benefit of leaving behind all your worst qualities and replacing them with the best parts of the person you love even more than yourself. I think having kids is a preferrable alternative to living forever.
> leaving behind all your worst qualities and replacing them with the best parts of the person you love even more than yourself
This is romanticizing well past the point of misleading yourself. If this were the case, every generation would be significantly better than the generation previous.
Having children is great, I'm sure your kids bring you endless joy, but this kind of romanticism sounds like flinching away from the uncomfortable truth that without a bunch of technological progress you're going to die (literally, not figuratively) in just a few dozen years.
My favourite human biology fact, the most mind blowing to me, is the fact that if you live to be 100, your odds of surviving to 110 are 0.1% (source https://en.wikipedia.org/wiki/Supercentenarian) . Human bodies just disintegrate at that point. It's also amazing, when you think about, that the world's oldest woman only lived 1.5x as a long as the average woman in a developed country. Whatever one thinks about Sinclair, it's amazing how strong the barrier is to exceptionally long life and more people need to be studying this.
No seriously, I remember Dmitri as a drunken lout Alyosha was always trying to clean up after. Meanwhile Ivan was above it all, having interesting conversations with Satan.
I think I read the following somewhere: "when I was young, I thought I was like Ivan. However, the older I got, the more I realized how we all really are Dmitris". This rings true in many ways to me.
It's an interesting point, but almost why I don't like him. It's not that I think I'm Ivan per se, it's that Ivan, Alyosha and even Smerdyakov were each exceptional in some way while Dmitri was just a person of normal appetites and below average self-control. Hence he's the least memorable brother.
I chose the pseudonym partly just out of Russophilia, and partly because Ivan's propensity for intellectual exploration seemed right for this blog. Ivan would read ASX.
That's true, and it seems to go very much against the "humans are like cars" idea. The lifespan distribution of cars looks totally unlike that of humans.
The lifetime distribution of humans looks more like the lifetime distribution of Oscars speeches. Some end awkwardly early, some end right on time, and a few go over time but are quickly cut off by the producers.
The start of the human death increase looks like a bell curve, it just has a much steeper slope on the far side. So it seems to be semi-normally distributed, but it's harder to go long than it is to go short.
One obvious reason for this is that only one thing has to actually kill you, so as you get older, the odds of having more than one potentially fatal problem goes up.
> My favourite human biology fact, the most mind blowing to me, is the fact that if you live to be 100, your odds of surviving to 110 are 0.1%
I wonder why, through. What's the barrier? We can mechanically replace many organs. Wouldn't it work to just keep supplying the brain with oxygenated blood with necessary nutrients? What causes death then, if you subtract rest of the organism away?
The context in which this verse is given seems to make it clear that God is saying he will flood the earth in 120 years from that time, not that humans will only live to 120 years. So Noah had lots of time to prepare for the flood.
This is the key question to me on Sinclair's hypothesis. Surely the amount of epigenetic damage that people undergo varies widely by large factors and so there should be individuals who survive much longer than other individuals, but that's not what we see, most people die around the same age. And dogs for instance die much younger than us, but why would their epigenetic harm be so much more aggressive than ours? Their environment is very similar to ours. This to me is strong evidence that animals have an active system trying to kill them, like planned obsolesce rather than just wearing out. The most plausible theory as to why we have this I have heard is that it is about parasites. The longer you live the more parasites you attract. Eventually most of the soma is no longer about reproducing the original genes but supporting the replication of parasitic genes, which is obviously bad for the original genes. As evolution will work to prioritise the survival of genes, not the soma survival, the best approach is for the genes to be periodically placed in new, parasite free soma, and to kill off the previous soma to avoid competition for resources from that old soma which is now largely parasitic. As well as avoiding resource completion, this means the old soma parasites are also prevented from infecting the new soma. I think this might be why we see visible signs of ageing in older people, a signal to the young to avoid the icky parasites.
I believe the parasite theory is now largely accepted as to why there is sex, so definitely it can provide strong evolutionary pressures.
If it is true that we have a system activity trying to kill us because it is better for reproduction, this means Algernon's law doesn't apply to this situation. If we can turn it off then this is bad for new soma, but good for the old. I really don't care if after 200 years I can no longer reproduce my genes.
The basic concept of Algernon's law has always bothered me. I don't think it actually holds much water, at least, not in the way that it's commonly used. The human body may well be perfectly optimized for our hunter gatherer lifestyles of the past, but that has very little bearing on how well optimized it is for today. We used to have very real energy input constraints, and that meant the availability of food was a major factor in the objective function our bodies were optimizing for. That constraint is effectively gone today. There may be quite a few biochemical switches that are tuned for energy scarcity that we could easily dial way up/down without harm, and without any real contradiction to Algernon's law.
Similarly, aging and decay are potentially epiphenomena of gene progression. Nature isn't optimizing for immortality of individuals, its optimizing for immortality *of genes*, which it achieves just fine by killing you after you've had your kids. There is no reason to think evolution tried and failed to make us immortal, and therefore no strong a priori reason to think that there shouldn't be low hanging fruit in that domain.
> Nature isn't optimizing for immortality of individuals, its optimizing for immortality *of genes*, which it achieves just fine by killing you after you've had your kids.
Interesting framing! I completely agree that genes ultimately only optimize for their own propagation, not necessarily the longevity of their carriers -- but the phrase "after you've had your kids" seems to smuggle in the assumption that there is necessarily a fertile period that stops at some point. Wouldn't you expect evolution to, all else equal, favor genes that encourage longer reproductive periods in their carriers?
Example: if a new allele slowed aging-related deterioration by 0.1% and had no downsides, its carriers would have more children than competing alleles', and it'd probably reach fixation. And this would keep happening until there were no more low-hanging, tradeoff-free longevity fruit to pick.
> but the phrase "after you've had your kids" seems to smuggle in the assumption that there is necessarily a fertile period that stops at some point. Wouldn't you expect evolution to, all else equal, favor genes that encourage longer reproductive periods in their carriers?
You're right, and I should have clarified this further. I think the fully spelled out logic goes something like this:
Let's say that the energy required to maintain perfect health is a linear function of age. This would mean that at a certain age the aggregate utility of an elderly person declines below that of their offspring. Under such a scenario, it's clear that under energy scarcity senescence makes sense.
It obviously doesn't even have to be as extreme as a linearly increasing function. It could even plateau at some point. Like, let's say the energy cost to live a normal human year is 100, but the energy cost to live that same year while also repairing any accumulated damage is 120. The evolutionarily optimal strategy is not necessarily to spend the 120, even if that 120 is available in the environment. The tribe that chooses to spend 20% extra energy hunting more, or fighting better is going to outcompete the immortal tribe*.
We can certainly imagine countervailing factors like accumulated knowledge operating in favor of the immortals. But that makes it then just a question of what the parameters of the model are, which is exactly the point. The point being that there are many parameterizations of the evolutionary function for which Algernon's law (as its used here) does not hold.
*That* being said, I do think there is a better version of Algernon's law that is legitimate. Which is that there should be no easy optimizations to the human body that don't consume more energy, or otherwise disrupt competitiveness in a primitive context.
Great comment. To add to it, I think that for human societies to function, and for the genes of the individuals who make up those groups to propagate, the "generational rhythm" is important. As the young come of age, the old must make way for them, or risk societal unrest which can pose an existential risk.
You can't have ambitious and energetic young people if you have adults that remain ambitious and energetic for many decades, long enough to breed multiple generations of more ambitious and energetic young people; you would end up with far too many pretenders for far too few crowns.
Human biology acts as a great stabilizing force: as our children grow up and start asserting themselves, we have aged enough to become just weary enough to be glad there's someone else to help shoulder the burden, instead of being threatened by them. The common theme of epic tragedies are parents who outlive their welcome, and children who grow old without the space to grow up.
"There is no reason to think evolution tried and failed to make us immortal, and therefore no strong a priori reason to think that there shouldn't be low hanging fruit in that domain."
I knew someone would've made this point in the comment section. Thank you for making it. :)
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant."
This seem incorrect, due to dosage effects. The doses that organ-transplant recipients use are much higher than those used for longevity purpose. There is even some evidence that rapamycin enhances immunity at lower doses. Here's some further discussion with references: https://peterattiamd.com/rapamycin-risks/
Agreed with you! Low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him.
The other thing going on which kicks in after the 30-40% improvement is telomere shortening, making more and more cells senescent. This is also something which might have an easy fix once you solve the “all kinds of cancers” problem.
I want nanobots that go around removing senescent cells, cancer cells, arterial plaques, aggregates, unfriendly bacteria, etc. Like an artificial immune system that is way better than the natural one. That could extend lifespan by a lot, even before you program it to mess with Yamanaka factors.
"Cure aging, and the whole concept of life expectancy goes out the window" I am surprised at this comment - I would've thought it's obvious it doesn't. At 70, the probability of dying in the next year is slightly under 2% (albeit substantially higher for men than women). If you could stop aging at 70, then you'd have a 50-50 chance of living until 104. (0.98^34 is about 0.5) What if we could roll back aging to 21? 21 year olds have around a 0.08% chance of dying in a given year. That means you'd have a 50-50 chance of living to about 850 years old. (0.999167^950 is about 0.5) That's barely into the biblical lifespan territory. (Source of actuarial info: https://www.ssa.gov/oact/STATS/table4c6.html)
The distribution would have an expected value, but it would be a very different distribution--specifically, an exponential one. The self-similarity means that if your expected lifespan at birth was 1000, then your expected lifespan at age 500 would be 1500, and at 100 would be 2000, and at 2000 would be 3000, and so on. There wouldn't be the idea that "everyone dies by age X" anymore.
Even though the distribution is different, almost everyone would die by a certain age.
Your framing of the situation as "if you survive to X, you will expect to survive Y%
longer" is interesting. I imagine that life extension enthusiasts in general think of it
that way, but I see it as a cognitive distortion.
Being ageless is equated with being immortal, because accidents don't seem inevitable.
To me, though, they seem even more inevitable than aging.
I agree with an exponential model. My equation is simply "<years> = log <total survival rate> divided by log <one year survival rate>" - the latter being 99.9167%, give or take.
So, as I wrote, ageless people of the future might have a life expectancy at birth of
under 1,000 years.
After about 5,500 years, only 1% would still be alive.
After about 27,400 years, only one person out of 7.9 billion would be alive.
So people would live around 10 to 200 times as long as now.
Maybe that sounds fine, but to me, it means life wouldn't be fundamentally different. We wouldn't get to travel the galaxy at plausible speeds, and we wouldn't see Andromeda collide with the Milky Way, or the continents reshape, or the Sun become a red giant, and so on. If we were lucky enough to live much longer than average, then we'd see all the people we ever knew die before us, as people do now. Because of the distribution, more people would suffer that unhappy state, wouldn't they?
Ageless people might be risk averse, but if I could be 21 again, and in perfect health,
I would definitely spend more time enjoying alcohol and motorcycles than I do now.
To clarify, senescent cells are not exactly an unwelcome process in our body. Cells can become senescent to avoid malignant transformation into cancer cells - one of the characteristics of senescent cells is their lack of proliferation. It fits into a broader theme where aging and cancer are two sides of the same tradeoff, biologically speaking. Keep the cancer at bay, and you age faster. Suppress aging and you suffer from cancer. So in this paradigm aging is an in-built protection from cancer, and messing with it (injecting Yamanaka factors, extending telomeres) has a price.
From the publicity standpoint I think the easiest application of anti-aging research is improving the lifespan of our pets, turning cats and dogs into life-long companions. I can think of very few people who would object to that. The regulation in this area is probably much more lax, allowing biohackers to experiment with next-generation treatments and report the results.
However, I'm skeptical that the same anti-aging treatments that work on mice, cats and dogs would make a strong impact on humans. We still don't know why, mechanistically speaking, mouse tissues have a shorter "expiry date" than human tissues. Extending lifespan in animals could be as easy as identifying the mechanisms that keep humans from dying in their 20s and transferring these mechanisms to animals. To extend lifespan in humans we would need to either identify biological mechanisms that keep whales alive for 200+ years and steal those, or come up with the novel ideas ourselves.
Perhaps senescense has a similar role in a macro view as well? Through aging, old humans are removed from the high rungs of the hierarchies so that societies can evolve. Old dogs loathe new tricks, so we need turnover to make sure our collective book of tricks corresponds to our changing environment. Old people still have great value, but it's better if they are not quite as sharp, energetic and ambitious as the young, so that they are willing to take a step back when the next generation is ready for the stage.
Re: stem cells: Do stem cells always know what sort of cell to differentiate into? Would stem cells in the kidney always turn into kidney cells and not lung cells?
It depends what kind of chemical signals those cells receive, or rather what particular gradient of different signals, so in the kidney you would presumably be getting a lot more 'i-am-a-kidney' signals and a lot fewer 'i-am-a-lung' signals.
A separate issue would be tissue that's a heterologous mix of cells, like the pancreas, how do you get just the right number of islets vs. ductal cells for instance
I would be very interested in seeing a post on the relationship between cancer and ageing at a cellular mechanism level.
Cancer is a return to the unicellular world. Differentiated cells of multi-cellular organisms such as lung, liver, brain etc becomes dedifferentiated as cancer progresses. Cancer cells also use the significantly more inefficient pathway of anaerobic respiration, as opposed to aerobic or mitochondrial respiration, because the latter pathway was developed for an environment where efficient production of energy was desirable. Who else uses anaerobic respiration? Prokaryotes.
This has implications for us because when glucose is abundant, why care that aerobic respiration is 18x more efficient? Simply use anaerobic respiration, which is much faster and has the byproduct of generating lactic acid which can be used to kill neighboring cells for resources, just like bacteria and other unicellular organisms do. Rapamycin that Scott mentions, is a toxin secreted by a bacteria for this purpose. This is why obese people are significantly more likely to die of cancer. This is also where mTOR comes into the picture.
The other common way to get cancer is for cells to be exposed to chronic stress. If all your lung cells are abused by toxins in cigarettes, eventually they stop hoping that order will be restored, forget about the fact that they're supposed to be lung cells since it's getting impossible to function as one anyway, and revert back to their underlying programming of being a unicellular cell alone in this world, where cooperation no longer matters and survival must come at whatever cost.
At first glance, ageing and cancer seem to be two sides of the same coin. Cancers keep multiplying, just like bacteria, and are remarkable at survival because they are simply unicellular organisms that care only about their survival, to hell with everyone else. Most stay contained because our immune system is incredibly well suited to kill cells it doesn't recognize. But the war on cancer shows slow progress because we keep trying to find targeted ways to kill an organism that has undergone billions of years of evolution to survive. The organism simply evolves another way. Survival of the fittest.
Senescent cells help prevent cancer in a way, by dying off after their telomere cap is hit. Cancer cells aren't constrained by the telomere cap and can keep dividing. Increasing telomere length would reduce senescent cells, but that would increase the likelihood of cancer via cells gone rogue. But perhaps not, if the immune system could be kept healthy.
Jason Fung's The Cancer Code is a great intro to this paradigm.
Actually cancer cells don't use anaerobic respiration, they use glycolysis. I think you may be conflating the two processes. Anaerobic respiration refers to respiration using something other than oxygen as the final electron acceptor and is common in bacteria. Glycolysis can happen regardless of oxygen and is common in many organisms and cell types (including cancer cells and in other highly proliferative normal healthy cell types in our bodies). Aerobic respiration is most efficient at producing ATP, but glycolysis has many other benefits that are favorable during proliferation. Metabolites from glycolysis are necessary for making several molecule types within the cell. If cells are growing and dividing, building materials for more DNA, proteins, fatty acids, etc are critical. Of course energy is also critical, but as you say, if glucose abundance isn't a limiting factor, then why use a method that does not make those other useful molecules and does cause oxidative stress and unnecessary breakdown of carbon skeletons?
I think this mechanism is fascinating in its own right. Take the skin, for example. You need to constantly renew the cells of the skin, so doesn't that mean you have a bunch of rapidly dividing cells that live forever? Yes and no. Yes, because you have a bunch of rapidly dividing cells, but they're not the same as the ones that live forever. This is due to the stem cell/progenitor cell system.
The adult stem cells at the basal lamina (the base of the skin) aren't restricted in their number of divisions, but they only divide about once a week. They're not restricted in their number of divisions, but they are severely restricted in their rate of division. When they do divide, they often give off a progenitor cell. (Except in the case of wound healing.)
These progenitor cells divide rapidly, but are only able to do so for a small number of times before their telomeres get too short and shut down further division. They get to go for about a week, creating all those cells you shed every day, but then they have to stop and die. These cells are limited in their number of divisions, but are not limited in their rate of division.
This system allows stem cells to look senescent most of the time, which avoids cancerous growths. It allows the proliferation to happen in a controlled, two-step manner. Rapid division is limited to cells that are going to die anyway.
Interestingly, there are a few schools of thought on where cancers can originate. Sometimes, cancer might originate from progenitor cells that either acquire the ability to extend their telomeres, or they just don't bother to care about genomic stability anymore. Those kinds of cancers would be rapidly dividing, and might be very susceptible to therapy that specifically targets rapid cell division.
Other types of cancers might arise from adult stem cells, though. These cells might still only divide infrequently, but give off cancerous progenitor cells that grow out the tumor. These cancer stem cells would be difficult to beat with traditional chemotherapy, since they're unlikely to all be dividing at the same time, no matter when you start chemo. Even if chemo worked, it would look like a complete ablation of the tumor, with no visible lesions left, but then surprisingly come back stronger the next time when it doesn't have to contend with the patient's immune system anymore.
The temptation to hit the patient harder and longer to 'get them all' would work in the case of progenitor cell cancers, but would exacerbate stem cell cancers. Hard to tell which you're dealing with from pathology alone.
Thank you, this is a great review and I'm glad you touch upon what "people who are not sinclair" think because some of the stuff in the book is hyped.
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant. Organ recipients take it sometime to quiet their immune system down to the point where it stops rejecting the transplant, but it’s not a lot of fun."
^That point is not entirely correct. Rapamcycin gets a bad rep due to its history of being used as an organ transplant drug. But low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him if people want to learn more on Rapamycin: https://youtu.be/BL67DhNepfg
"But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me."
^Yes there is a tradeoff because these activities like exercise & sauna are hormetic stressors. That means that a little bit of stress causes your cells to hunker down and extend lifespan. However, there is a limit where overdoing these hormetic stressors can lead to chronic stress. For example, if you are perpetually fasting, you will obviously die!
Similarly, exercise is in fact a stress to the body and causes low-level inflammation. But that's "good type of stress" where your cells learn to become resistant. Overdo exercise and you might be stressing your body more than what's good life lifespan and healthspan.
In other words, there is a sweet spot for these stressors!
Maybe I just see the most dystopian perspective on everything, but I have a bad feeling about the societal effects we would see from the development of immortality serum.
I don't imagine anyone being forced into immortality, but I can absolutely imagine life becoming impractical otherwise.
For example, increased lifespan means increased potential for labor extraction. More possible working years means greater debts could be repaid. Maybe the 100-year home mortgage becomes a thing, contingent on your compliance with anti-aging treatments, of course. Maybe then the price of houses scales to match what people can finance, just like we see with student loan availability and tuition fees rising.
Or on the other hand, suppose that people who are getting this serum are primarily those who have retired on their investments. How large of an ownership class can society bear?
In college, the frats that I knew the mortgages of had 40- or 50-year terms.
> Their heirs would still be a perpetual ownership class with even basic financial literacy.
Yet that very rarely happens. Out of thousands or tens of thousands of potential perpetual estates, the only one that looks to have survived 3+ generations is the Vanderbilts.
Your grandchildren will not share your personal finance ethics. But if the people who build the estates linger on for a long time, they can keep the fortune alive indefinitely.
On the other hand, "shirtsleeves to shirtsleeves in three generations."
The person who started poor and made a fortune is likely to be better at making more than his children and at not dissipating it than his grandchildren.
On the other hand, the fact that the grandparents are still alive when the grandchildren become adults means that the fortune is divided among more people, so less for each.
The thing is, it wouldn't fundamentally change the market for labor. A house costs a certain amount to build because that's what it costs to pay people to build it.
Immortality would completely destroy retirement, though. People might "retire" periodically but you'd almost always run out of money sooner or later.
Why do you think that 3% is optimistic? The SP500 has _averaged_ 10.9% yearly over the last 50 years. I have always seen 4% (of initial nut) as the safe spot. This is because 90%(citation needed) of the time a market wide investment (SP500) started at a random date in the last 50 years would have increased rather than decreased.
The reason for that caveat is that if a strong market decline coincides with your retirement date you can end up with an overall declining nest egg(due to the withdrawal of 4% of initial rather than current nut).
I don't know if we are just talking past each other here. I was trying to convey that 4% is fine in perpetuity, so long as you don't start your retirement at the beginning of a downswing. If SP500 is 10.9% average annually, your only risk is that you hit (something like) 3 down years and suddenly your 4% (of nut) is 12%(of current value). That would likely not be recoverable. (3 average years would result in 1% declines in current value)
On the other hand, if you had 3 up years then you are 30% up and your 4% withdrawals are effectively 2.7% + you have a 30% cushion.
Side note: median and average net worth are dramatically different for American net worth(e.g. >75 year olds $255k vs. $958k). Likely far more so for college grads(smaller pool), although I was not able to find that data.
The ideal solution, in my view, is that you retire from doing work you don't like doing, continue to do any work you do like doing. I'm retired — and continuing to spend fourteen hours a week on writing projects.
"A house costs a certain amount to build because that's what it costs to pay people to build it."
I thought main reason why houses cost a lot is that there is limited amount of space in areas where people want to live, and prices rise when more people want to live in same area, often with more (not less) room in their house.
Ricardian rent was actually invented by Malthus (but Ricardo invented Marshallian quasi-rent, so it comes out even). And Ricardian rent explains the rent of agricultural land, which is in fixed supply, not of houses, which get built.
"agricultural land, which is in fixed supply," That may be what economists think. But it is only true in the short run. The Dutch would tell you that God made the world, but the Dutch made the Netherlands. Much of their best land used to be under the waves of the North Sea. Similarly in the US Midwest, there are hundreds of square miles of highly productive land that were unusable because of Malaria until they were drained. There is similar story about the Po River Valley in Italy.
> A house costs a certain amount to build because that's what it costs to pay people to build it.
You mean "because that's what people are willing to pay for it". We're now 3D printing houses, which is *substantially* cheaper, but I don't expect the full savings will be reflected in lower costs. The innovator keeps a heftier profit margin than his competitors.
Well if those downsides come true and become unbearable, you'll still have an option of going back to the good old ways of non-existing at the age of 100, by killing yourself.
Im not going to address the entire review for the sake of brevity. But to the core of your question, I will try to argue for the anti-aging efforts and validity.
So, what could be an almost insurmountable problem for cells in a mature animal, but trivially vanishes when you clone a cell into an embryo?
In a few words; the consistency of unmethylated/methylated DNA. Meaning, the cells that grow from the clone are free of DNA methylation, because they have been pre-selected for healthy nucleuses, and therefore the complimentary DNA (cDNA) will be true to original form. The cDNA then goes through its regular processes in transcription then the many forms of RNA and respective processes of translation follow resulting in properly expressed proteins. So, not all cells or cell types are prone to DNA methylation at the same rate or even the same rates from the same hazards and it is because of this that cells progressively fail to transcribe and translate original DNA into proper proteins at high fidelity. As the cell health of the organism dwindles during senescence, proteins and growth factors alike are not being coded for at the rate needed and we see organ failure, cancer, etc. It only takes one serious break in the chain and we have big problems. That's what makes the biology so astonishingly robust and delicate at the same time.
Furthermore, as DNA is progressively compromised, cell division ceases to produce intact differentiated cells and those unsuccessful cells are destroyed by immune functions like those of macrophages. This is very similar to the destruction of an unviable fertilized egg in the blastocyst stage. Still there is no ultimate atavististic feature built into genetics... so once stem cell types have differentiated, that's the end form for potentiality. Although potentiality is limited by the number of viable daughter cells it is also governed by the expression of those cells.
Enter epigenetics. In epigenetics, this revision to a previous state is the goal of upregulating the sirtuins to a degree that all of the methylated DNA will be successfully cleaved back to its original unmethylated code. Not to be confused with changing or reversing cell type (genetics), but to keep the multipotent cells functioning efficiently. Granted I, too, have my doubts about the limit of sirtuin capabilities but remain optimistic about stem cell therapies and gene therapies.
Sirtuins are not the only way to regain optimal cell health from the DNA up. There are ways to shuttle in specific growth factors (to address your point about kidney cells or differentiated cell types more broadly) like engineered stem cells transfected with lentiviral vectors programmed to overexpress carefully selected growth factors that are specific to the target area. This is the area that I am focused on now, but the more communal-power focus on anti-aging the longer we may live to see our loved ones grow and the longer we may not weigh on them like a shadow of ourselves. Or better yet, the longer we will have to think of good solutions to difficult problems. Maybe we'll even get to relax after everything is patched up.
Anyway, I have applied for the ACX grant because a friend pointed me here. This is my first time on the board. I am currently a grad student in a related field but I need funding to complete my next course and hopefully do a PhD in neuroscience... support is warmly welcomed. So, too, would be an understanding PhD mentor, but alas.
The problem is that most clones actually fail. Only about 10% don't. This would be entirely consistent with the idea that cell damage is in fact quite common.
You are right. Most clones fail and cell damage is unavoidably part of life insofar as it is necessary before death. Species of clones is also going to greatly change the percentage of clones that survive and what age they survive to is also highly dependent on the species cloned at this point... and I don't know why half of my post is hidden from me... length restrictions? UI? substack newbie present
This is the case for mammals, but in the case of frogs it's higher (with some oddities like non-gamete donation from adult frog leads to tadpoles that don't turn into frogs)
You either need a principled reason why amphibians would be much less bothered by DNA damage or accept mammal cloning is harder and we still botch it a lot and only get it right a few times by something like throwing darts and hitting bull's eye (which I think is the case). 10% for mammals seems to me like an optimistic number, https://www.karger.com/Article/Fulltext/452444#ref7 says ". Efficiency of SCNT is still rather low, with success rates of 0.3-1.7% per reconstructed oocyte and 3.4-13% per transferred SCNT embryo "
(One should also count, on the other direction, that most abortions are unintentional/non-induced, only like 30% of human zygotes can actually produce a healthy baby, most result in miscarriages, often before the woman is even aware she's pregnant. IIRC, shorted lived mammals aren't that bad at this. It remains unproven age-related damage of gametes is the cause, though it does go up with age)
Uh, the answer for the amphibians is that the ones that they cloned were all very young. From that paper, "transplantation of nuclei from endoderm cells of Xenopus laevis donors ranging from late blastulae to swimming tadpoles".
Sucess rate in mammals is still probably much lower controlling for relative age, but I'd need to see if someone has collected that data specifically for mice or other cloned mammals.
A comment on why it is harder to clone mammals than amphibians: some amphibian eggs can be 10,000 microns wide while human eggs are about 100 microns wide. This scale makes fertilization much more accessible for the frog eggs. Secondarily, amphibians may also be more resistant to DNA damage as well as easier to clone due to factors like oocyte size. On top of this, there is the complexity of the organism that increasingly provides places for a clone to fail with how many successive developmental steps that are need to be completed before maturation.
If we eliminate disease and aging, the only remaining causes of death are accidents, suicide, and murder. The chances of meeting a violent end become higher as those who favor suicide gradually eliminate themselves.
The stakes become higher for anything risky that you do. If you are 24 and have lived a third of your life already, jumping out of an airplane for your quarter-century birthday may seem a reasonable risk. But if you are 24 and have lived a tiny, tiny fraction of an unfathomably long life, then that risk, no matter how small, may seem terribly irresponsible. Leaving your house may seem terribly irresponsible, because there is so much to lose.
This may be the best reason for everyone choosing to live in the metaverse if we solve aging. If you jump out of a plane there and the parachute doesn't open, you just come back into the game as a new character. The stakes become reasonable again.
Even better, you can come back in as a new character and suppress your memories so you don't remember the previous incarnation. Then you get to experience novelty again!
Underrated comment right here. Freedom from aging without freedom from true danger will really take the fun out of the life. Do you want to live forever in the metaverse?
What is the punishment for murder now that its AYL is infinite? Do we have to make all reckless behavior severely punishable (drunk driving now is a murder charge regardless of outcome? ) as you're taking hundreds of years of life away?
Death is actually a pretty small component compared to physical and mental impairments from unsafe activities. Imagine blinding yourself doing something "stupid" at age 30, or losing an arm or a leg, or paralyzing yourself. Lots of activities have a fairly low chance of causing permanent damage, that over the course of 80 years may not be a big deal, but over 1,000+ years would be much more likely. That could include drinking and drugs, and a whole host of activities we now consider normal.
It's a common sci-fi trope that people who never age become amazingly risk-averse, and from what I've seen of humans, it's a completely accurate trope.
"The chances of meeting a violent end become higher as those who favor suicide gradually eliminate themselves."
Hang on. I don't see how that works. In a world where disease and ageing don't exist, perhaps death-by-violence will comprise a rising percentage of total deaths as suicidal people eliminate themselves (assuming we're not producing suicidally-inclined babies at replacement level). But how does that change the likelihood that *you* will die a violent death?
Seriously, is there any form of probability calculation that yields that result? I mean, I don't see how it causally makes sense.
Are you suggesting that, once the suicidal people are gone, there will be fewer total humans left over for the violent murderers to choose from, thereby raising your risk of being killed violently by an undiscriminating murderer for lack of alternatives?
Do suicidal people influence those around them to resist the urge to commit murder?
I'm really not prepared to raise my personal estimated-risk-of-violent-death each time I hear about someone in my community committing suicide.
> there will be fewer total humans left over for the violent murderers to choose from, thereby raising your risk of being killed violently by an undiscriminating murderer for lack of alternatives?
It's just the Monty Hall problem. You currently have 5 ways to die: disease, age, accident, murder, suicide. Per Fight Club, "on a long enough timeline, the survival rate of everyone drops to zero". If you eliminate disease and age, the probabilities of the other outcomes necessarily go up, since the probability you will die eventually must add up to 1.
Thanks. I figured it must be something along those lines.
This actually taps into some deeper features of probability estimation where I frequently get hung up. Perhaps there's a good source for teasing these things out?
To me, using the whole-population death statistics to determine your own chances of dying of x seems like using a large-scale framework with population-level information to solve a small-scale problem that necessarily involves using personalized information. I might reasonably population-level information as my prior for estimating the chances of dying of x, but I would feel like I was missing most of the information necessary for actually deciding my chances of dying of x, to the point of potentially misleading myself.
Example: say I'm a person who never drives and I have a heart condition. If cardiac arrest is totally eliminated from the rest of the population as a cause of death, you could look at that information and say my chances of dying by cardiac arrest have gone down and my chances of dying in a car accident have necessarily gone up. But that's nowhere near the truth. Even if you use population-level information as your prior, you're starting with a set of priors that are so far from reality, it seems to undermine the task of estimating relative death probabilities with any accuracy.
Is there a formal way to describe the phenomena I just touched on?
> Example: say I'm a person who never drives and I have a heart condition. If cardiac arrest is totally eliminated from the rest of the population as a cause of death, you could look at that information and say my chances of dying by cardiac arrest have gone down and my chances of dying in a car accident have necessarily gone up.
Yes, the statement is always with the implicit "all else being equal". But if you get better or more precise information such that all else is not equal, then you have to update the probabilities using Bayes' theorem.
"In Jonathan Swift's 1726 satirical novel Gulliver's Travels, the name struldbrugg (sometimes spelled struldbrug)is given to those humans in the nation of Luggnagg who are born seemingly normal, but are in fact immortal. Although struldbruggs do not die, they do continue aging. Swift's work depicts the evil of immortality without eternal youth.
They are easily recognized by a red dot above their left eyebrow. They are normal human beings until they reach the age of eighty, at which time they become dejected. Upon reaching the age of eighty they become legally dead, and suffer from many ailments including the loss of eyesight and the loss of hair.
Struldbruggs were forbidden to own property:
"As soon as they have completed the term of eighty years, they are looked on as dead in law; their heirs immediately succeed to their estates; only a small pittance is reserved for their support; and the poor ones are maintained at the public charge. After that period, they are held incapable of any employment of trust or profit; they cannot purchase lands, or take leases; neither are they allowed to be witnesses in any cause, either civil or criminal or economic, not even for the decision of meers (metes) and bounds."
Because:
"Otherwise, as avarice is the necessary consequence of old age, those immortals would in time become proprietors of the whole nation, and engross the civil power, which, for want of abilities to manage, must end in the ruin of the public."
There is an origination called the Gerontology Research Group. one of their activities is tracking the oldest people in the world. Supercentenarians who are 110 years old and older. They take pains to validate their ages via government and private records. Here is a link to their table of living supercentenarians
There are 17 of them out of the ~7 billion living humans today. The oldest is will be 119 years on 2 Jan. 2022. She is older than any person they have tracked since Jean Calment of France who died 1997 at 122 years and 164 days. https://grg.org/SC/SCindex.html
I would posit that 125 years is a hard upper limit on human life spans. Some creatures, such a Galapagos tortoises and some whales live much longer than that. But, all living things grow old and die in their time.
Gen.47
[7] Then Joseph brought in Jacob his father, and set him before Pharaoh, and Jacob blessed Pharaoh.
[8] And Pharaoh said to Jacob, "How many are the days of the years of your life?"
[9] And Jacob said to Pharaoh, "The days of the years of my sojourning are a hundred and thirty years; few and evil have been the days of the years of my life, and they have not attained to the days of the years of the life of my fathers in the days of their sojourning."
No-no, not all living things have built-in senescence, are you forgetting perennial plants, most fungi, bacteria, and among animals, the legendary hydra?
"pterostilbene, a more bioavailable resveratrol relative. The other pill is nicotinamide riboside.
Those are the two ingredients in a product called "Basis" that I have been taking for many years. It's only a sample size of one but my biological age, as defined by whatever genetic markers Elysium, the company that makes Basis, uses, was measured a year or two back as about a decade lower than my chronological age.
But then my mother, who didn't take Basis, died at about a hundred and her brother at older than that, so I may just be lucky in my genes.
"you’d have to correct the DNA in every cell in the body (using what template? even if you’d saved a copy of your DNA from childhood, how do you get it into all 30 trillion cells?)"
The template problem is easy; you just take a majority vote of fifty cells. Unless they tend to all have the same mutations, that should get you back to the original.
The distribution problem is harder. In principle you do it with nanotech cell repair machines, but that is going to be quite a while. Possibly a tailored virus?
I really wanted to see more discussion of this. Which cells are breaking down, and how easily are they replaced?
Can I make myself a young-version-of-me liver, and then replace half of my liver with that one? (I'm not a biologist but I seem to recall from high school that the liver is fairly uniform as an organ.) What about my bone marrow, can I just inject some younger marrow in?
Replacing all my red blood cells with a young copy sounds easy enough. I have no idea how to do it with skin.
This is consistent with my understanding as well. Livers are supposedly able to completely regenerate from as little as 10%; if you have liver cancer, and it hasn't spread to anything else, a surgeon could (AFAIK) simply remove the cancerous part and let the rest regenerate on its own. (I imagine you'd have to also take reasonably good care of yourself while it does, including drinking no alcohol.)
Regeneration of all your blood cells is the basic goal of a bone marrow transplant, and we know those can work. (Fun fact: this can also completely change your blood type.)
Skin is regenerated with grafting from elsewhere on your body, but it takes a lot longer, won't look quite the same, and I'm pretty sure I'm just handwaving a great deal here. I think it's pretty hard.
“Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself?”
The reason this argument fails is that immortality isn’t actually evolutionary beneficial. Take two people, one of whom is immortal for biochemical reasons, and a regular human. The human, knowing their clock is ticking, is likely to have children quickly, stick around to help with the grandchildren, and then die. Whereas the immortal person seems like they wouldn’t in such a hurry to have kids, meaning they would be unlikely to pass on their genes as quickly. Consider how birth rates fall as life expectancy goes up, and you can understand why evolution would want to sabotage the body in some way, so that it doesn’t outlive its usefulness or waste time doing things besides copying its genes.
Given how difficult it was for humans to control their fertility for a long time, it seems unlikely to me that biological immortality would be in any way disadvantageous.
Not to mention the obvious fact that natural selection has caused humans to live abnormally long lifespans.
Trees have an advantage in living longer since they don’t grow infertile like humans do, and otherwise have a different reproductive strategy. I address why this is important in my response to Titanium dragon
Infertility is a side effect of aging. Menopause is caused by aging, and happens because female reproductive systems have to work much better than male ones to produce viable embryos. Male infertility is more obviously caused by aging a well, as many older men are still fertile.
But what would be the advantage in living longer from an evolutionary perspective? You’re infertile by this point, so there’s no chance in passing on your genes further, so I don’t get why it would be evolutionary advantageous to continue to live, consuming resources that could be better used by your children and grandchildren.
1) Infertility is a side effect of aging, so you wouldn't become infertile.
2) Per selfish gene theory, it doesn't actually matter how many children you have, what matters is how many of your genes are hanging around. Being immortal means your genes are always hanging around.
Brett Weinstein's argument seems to be that senescence isn't a bad outcome but a trade off. Immortality always converges on cancer (or IS cancer), so a universal max replication count (however fuzzy) avoids cancer (for the cancers that don't escape the mechanism), but guarantees aging and death. Aging is the body's answer to cancer.
Lab mice accidentally and systemically have been selected for long telomeres and are good at healing and live a long time, but tend to die a lot from cancer (even when we're not guaranteeing it).
I was going to mention the mice telomere thing as well, so I'm glad you saved me the trouble. It has serious implications about efficacy of drugs we test, and I haven't yet thought through what it implies for the claims Sinclair is making. (Bret discovered the issue by thinking about how telomeres and lab mice supply work, asked a breeder to confirm, and her response was along the lines of "holy cow, you might be right". There's an interesting YT video where Bret's older brother, Eric, calmly but angrily rips him a new one for not writing this up in enough detail to get the Nobel Prize Eric is 100% convinced Bret should have won.)
Bret seems to have a moral hangup about anti-aging research as well. In his opinion, people ought to accept the lifespans we currently have and just appreciate it as such.
I think the best argument against making most of the population immortal today is that in a couple centuries, we will have engineered the entire population to be vastly more intelligent and fitter than they are today.
That said, even if we did achieve biological immortality, at present rates of accidental death, you'd probably make it to roughly 600 or so on average.
Bot sure how many people would agree to sacrifice their lives to give way to a better more intelligent species, but I myself am definitely in the "Nope" camp.
Has anyone ever looked at aging through the lens of a human/chimp comparison? We live decades longer than our closest relatives, which are themselves a long-lived mammal. What are the biological differences that makes that difference? If you figured that out, maybe you could crank up those differences.
Going to mention Kim Stanley Robinson's Mars trilogy (and his earlier novel Icehenge) here in case people are inclined to ctrl-F for his name like I was. As an exploration of the consequences of 500-plus-year lifespans I actually don't find the Mars books that interesting. That part of the science fiction is mostly a way to keep the same characters around through a several-hundred-year terraforming project. Robinson also exaggerates the Malthusian / environmental-risk / social-upheaval aspects of longevity, which is typical for him.
Icehenge mentions an interesting idea, though, which is that people seem to "peak" pretty young (physically in particular, but mentally too-- the example Robinson uses is chess champions), as in: soon after they mature. So even with strong anti-aging tech it seems likely that experience of the added years of life would be more like being 50 or 60 or 70 than, say, 30. There might be a feeling of decline and/or stagnation the whole time.
I think most of the decline in chess strength is due to aging (less physical energy) and lack of motivation (I've been at this for twenty years"). See e.g. Carlsen's remarks on the current World championship match. The first problem would be solved by curing aging. The second can not be solved, but if you live for ever you can just switch to a different activity when you get bored of the first one.
The gating factor on colonization is not technological, it's commercial. Why would you use a ton of energy to get to another planet just to haul shit back that you could have found on earth? Europeans didn't sail the globe and establish colonies out of a sense of adventure, they did it to get rich or die trying. Any space colonization effort is going to need the former half of that equation; right now we just have the latter.
I think drawing parallels from European exploration can be misleading. European exploration was primarily commercial because people knew that they could make a staggering amount of money by directly importing spices from the Indies. The spices brought back by the one ship of Magellan's expedition that completed the first circumnavigation - and it was the smallest ship - more than paid for the cost of the entire 5 ship expedition. The funders of Drake's circumnavigation got a 5000% return on their investment. In these circumstances, financial incentives would naturally predominate - we'd already be on Mars if anything similar was realistically achievable.
But successful exploration and settlement can take place for predominantly non-commercial motives. Puritan settlement of New England, Cook's 18th century voyages and the subsequent settlement of Australia, Alexander the Great's explorations and settlements, Antarctica today, too many examples to list really, but overall I don't think that most historical exploration and colonisation has been undertaken primarily in order to make money for investors. It can happen even if there's no good financial reason to do it.
The idea of turning Mars into a prison colony has always been a popular way of getting permanent human settlement to work in sci-fi. Perhaps if some private prison contractor finds a way to persuade a compliant super-wealthy autocracy that deportation to Mars is preferable to Siberia, maybe you could make it work. But I still think you'd need to break the laws of physics for the economics to ever pencil out. Technoeconomics is still the gatekeeper between the possible and the actual.
Is there an SF story out there about humanity running into so much risk with various disease research that it ends up driving interplanetary colony research just so we can set up a giant cleanroom?
There was a post eight months ago on LessWrong where John S. Wentsworth, an "independent AI researcher" according to LinkedIn, gave a summary of his understanding of how aging worked:
A summary (by me, a complete non-expert) would be:
The symptoms of aging (atherosclerosis, sarcopenia, etc.) are basically caused by too much inflammatory factors (SASP) and reactive oxygen species (ROS). Senescent cells release both.
SASP is released normally by senescent cells in order to tell the immune system to kill them.
ROS is generated by the normal action of mitochondria, and causes DNA damage. ROS goes up when the cell is in a DNA-repairing state - mitochondria become less efficient, producing less energy as part of the repair process, and therefore more ROS, which can in turn cause more damage.
Normally, cells have low levels of DNA damage and low levels of ROS. But after passing some threshold after enough stress has happened to the cell, the ROS damages the DNA faster than it can be repaired, and the cell becomes senescent.
The core cause of aging is suggested by the author to primarily be because of transposon proliferation. Transposons are genes that copy themselves; when they do this, they cause DNA damage. Most transposons in the genome are dead - no longer able to proliferate due to evolutionary accident; they make up about 50% of the genome.
Maybe 100 or so active transposons remain, and these are tightly controlled by epigenetics to prevent them from being expressed. However, as part of the DNA repair process, the epigenetic mechanisms (e.g. sirtuins) are drawn away from repressing them to go help fix the DNA. When that happens, they'll manage to copy themselves. These make future DNA repair attempts more inefficient, and a certain level of transposon proliferation represents the threshold beyond which DNA repair fails and the cell becomes overwhelmed by ROS damage. Transposons also make senescence permanent; once they've been given free reign to copy themselves due to the failure of the DNA repair system, they will proliferate and damage DNA until the genome is beyond recovery, even if the excess ROS were to be cleared away.
One particular thing about transposon proliferation is that it occurs in stem cells too; a stem cell that has a high level of transposon proliferation, but not enough to render it senescent, will cause the cells it forms to quickly become senescent themselves. So the ultimate cause might be said to be an overall increase in the rate of cells senescing, causing body-wide overexpression of SASP and ROS, due to more and more stem cells getting overloaded with transposons at sub-senescent levels.
As to why organisms don't get overloaded with transposons with each successive generation - someone in the comments mentioned that the gonads have very high levels of epigenetic control against the areas with active transposons; this has the side effect of hindering DNA expression overall (which maybe explains why fertility is so hard, and requires so many attempts to succeed).
I think it foolish for us to think we will live on past our time. We are not made out of incorruptible gold and adamant. We are dynamic balances between energy and entropy made out of water, sugar, oil, and protein, in an intricate pattern. We should appreciate the miracle of life and know that it is brief.
Thornton Wilder's novel The Bridge of San Luis Rey is a meditation on the meaning of life and random death. In it the Friar Brother Juniper witnesses the collapse of a bridge and the death of five travelers who were on it. He minutely investigates their lives and searches for the reason, if any, behind their deaths. The novel ends with the Abbess' observation: "There is a land of the living and a land of the dead and the bridge is love, the only survival, the only meaning."
Shakespeare The Tempest Act IV Prospero
Our revels now are ended. These our actors,
As I foretold you, were all spirits and
Are melted into air, into thin air:
And, like the baseless fabric of this vision,
The cloud-capp'd towers, the gorgeous palaces,
The solemn temples, the great globe itself,
Ye all which it inherit, shall dissolve
And, like this insubstantial pageant faded,
Leave not a rack behind. We are such stuff
As dreams are made on, and our little life
Is rounded with a sleep.
Gen. 3:
[17] And to Adam he said, ...
[19] In the sweat of your face you shall eat bread till you return to the ground, for out of it you were taken;
you are dust, and to dust you shall return."...
[22] Then the LORD God said, "Behold, the man has become like one of us, knowing good and evil; and now, lest he put forth his hand and take also of the tree of life, and eat, and live for ever"
[23] therefore the LORD God sent him forth from the garden of Eden, to till the ground from which he was taken.
[24] He drove out the man; and at the east of the garden of Eden he placed the cherubim, and a flaming sword which turned every way, to guard the way to the tree of life.
Eternal life isn't about living past your time. It's about your time never ending.
We should appreciate our brief lives. And if we manage to make them less brief we should appreciate them even more. Lots of meaning and beauty can be extracted from our finitness. People have been doing it through out the history. This idea is very well explored. But don't you think, that we can explore other ideas as well?
Have you tried to imagine how much beauty and meaning can be extracted from a life that can last for thousands of years? Or one that truly never ends? Or one that can be ended only by your own volition? It's a completely new ground to explore and so much more new and beautiful things to say!
It seems, that in your mind eternal life would cost us all the beauty of Shakespeare and Thornton. It's a false trade off. These treasures of old will stay with us to experience and understand. However, we will also get many others.
Woody Allen wrote: “I don't want to achieve immortality through my work; I want to achieve immortality through not dying. I don't want to live on in the hearts of my countrymen; I want to live on in my apartment.”
"These treasures of old will stay with us to experience and understand. However, we will also get many others."
From whom? The same old guys are not going to invent new arts. If death disappears, so does new life.
Science, we are told, progresses one funeral at a time. If we live forever we will lose scientific progress. The arts are the same.
I love Mozart, but I also love the Beatles. I love Michelangelo, But Caravaggio knocks me out. And JMW Turner astounds me. Further, painting died some time after Van Gogh. Will something take its place? Not if the current generation does not depart the stage.
Fortunately, i am not worried about your scenario. It won't happen. There are hard upper limits on human life spans. Nobody has ever been verified to have lived more than 123 years.
"Science, we are told, progresses one funeral at a time. If we live forever we will lose scientific progress. The arts are the same."
There's no reason to expect this is true at least for science. New scientists tend to make the big breakthroughs and paradigm shifts, but what else could be the case? The old scientists stop making huge progress precisely because, you know, they AGE. They have less energy and their cognitive ability declines until they can no longer even work any more.
Imagine the greatest scientists alive today, imagine if they never aged. They could operate at their biological peak indefinitely and would continue accumulating knowledge and skills over time. This should be expected to produce great outcomes. Maybe novel minds create novel ideas, but great minds working indefinitely ought to produce more progress than billions of new mediocre people ever will. Imagine if John von Neumann and his greatest contemporaries had been able to live forever at peak health. Do you really think the novelty of new mathematicians would be worth sacrificing the greatest working indefinitely?
I can't help but think this "new people make new ideas" view is simply an artifact of a world in which old people are aged and lose energy and cognitive ability.
Sorry dude. your fantasy is nice. "it seems a crime that we should age" (Elton John "Friends"). But it is not the way the world is or that men are. We are limited beings. It is our tragedy and our glory. Get thee a heart of wisdom.
> I think it foolish for us to think we will live on past our time.
Modern humans live to be around 75..80 years old, on average. This is a pretty big jump from the historical average of 40..50. Are we living "past our time" ? Should we stop ? How do you decide what a person's appropriate "time" is, anyway ? Actually, who retired and made you Azrael ?
Don't confuse average life expectancies with the biological possibility of living a certain time. The 40.5 figure includes an enormous number of children who died quite young, an enormous number of young women who died in childbirth, and a very substantial number of men who died from war and violent attacks.
But, from great antiquity, men understood that our years stretched out farther than those horizons. Psalm 90, written ~25 centuries ago, famously says: [10] "The years of our life are threescore and ten, or even by reason of strength fourscore; yet their span is but toil and trouble; they are soon gone, and we fly away."
A few centuries later but still about 1700 years ago, the Sages wrote in the Mishna (Avot 5:21): "At thirty the peak of strength; At forty wisdom; At fifty able to give counsel; At sixty old age; At seventy fullness of years; At eighty the age of “strength”; At ninety a bent body; At one hundred, as good as dead and gone completely out of the world."
What our time is, is not for me to determine. I know, empirically, it is limited and, in comparison to human history it is brief, and in comparison to geological time, evanescent. I am not arguing or judging, just observing.
I am fond of the resolution of Ps. 90 [10] in [12]: "So teach us to number our days that we may get a heart of wisdom."
> and a very substantial number of men who died from war and violent attacks.
It sounds like you might be splitting hairs at this point. Sure, that man might have lived to be 80, had he not gone to war. But this man here also could've lived to be 80, had he not died of gangrene, or pneumonia, or cancer. Where do you draw the line ? Should we stop treating pneumonia and cancer ?
> I know, empirically, it is limited and, in comparison to human history it is brief, and in comparison to geological time, evanescent.
Well, in that case, doubling our lifespan shouldn't make much of a dent, in the long scheme of things...
My point o averages vs. individual biological possibilities stands. Your Ms. Woodbury is a historian, not an actuary. And even as a historian she did not look at demographic data.
War and sub-war violence are not features of individual biology, they are features of society and politics, and so vary from time to time and place to place. Demographers and actuaries separate them out for purposes of analysis.
Perhaps there will be a revolution in science which raises life expectancy significantly for some. Likely there will be tradeoffs. Some will when, some will lose. My question is this: come such a revolution: do you feel lucky?
I feel certain that medicine will continue to advance and that more people will live longer and will have a better quality of life in their later years. But, I think we will find that everyone ages and deteriorates, that most of us really start to decline significantly after 85, that centenarians are uncommon (2 standard deviations), super-centenarians (110+) are quite rare (5 sd) and that there is a hard biological upper limit on our life spans of ~125 years.
As for myself. I am 74 and in basically good health. I just cleared the two most important cancer screenings. I feel that I have a good shot for ten more years, a punter's chance of 15, and would not wager even a small stake on 20 more years.
The more I read about humans wanting to live longer the less I like humans. The sooner the humans die off the better. I want bees or ants to be the future of this planet not ugly primates.
Note that if you care about passing on your DNA to the rest of the universe, the descendants of bees or ants may do a better job at passing on some of your DNA than do the descendants of apes. Of maybe the descendants of ferns, orchids or beetles will.
Does ANYONE explicitly cares about passing their genes? We are adaptation executers, not fitness maximizers, after all.
I've heard that some people want to have children in order to "continue themselves" or for the sake of some legacy. And it seems as close to caring about passing genes as possible. But, I wonder, is it actually about blood ties as a terminal value or rather an instrumental one?
>Does ANYONE explicitly care about passing their genes?
I wouldn't have thought so a decade ago, but how else to explain why so many people are concerned about X Risk?
One also sometimes hears arguments from far-rightists about wanting to help those with whom they share more genes despite those people being far outside their nuclear family-- a case they make explicitly. Perhaps those people are being insincere, but it can be hard to gauge the sincerity of others.
Bees and especially ants are also city-dwelling agriculturalists who devastate landscapes and go to war with chemical weapons. Aesthetically, a hymenopteran civilisation doesn't seem like it would be much of an improvement.
When I read posts like this, it makes me think of the bit in Manalive where the protagonist points a gun at people who say they want to kill themselves.
Disclaimer that I haven't read the book even if I read some of Sinclair's scientific output earlier, but to be absolutely clear resveratrol is absolutely not even close to bioavaliable enough in humans. We're talking about taking literal tons of tomatoes or wine or whatever for a biologically significant effect, whatever it is.
This paper https://pubmed.ncbi.nlm.nih.gov/27552971/ by Sinclair did a good work explaining how the mechanism for Sirtuin activating was elucidated and entablished to be related to a resveratrol-in vitro like mechanism against the skepticism of losers and haters (this is a narrow claim, I'm not saying his wider output always replicates). And it takes for granted we need synthetic sirtuin activating compounds for any significant effect. Does Sinclair mention this sort of stuff on the book? This is from 2016 and my quick check is that a lot of the late phase clinical trials in humans with these compounds are not done yet.
>It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
If I may add one anecdata point, in italy most resources are gobbled up by the state pension fund and we are suffering from quite bad youth unemployment rate so I would claim that this scenario is in fact happening nowadays - albeit without the dictatorship part.
Similar situation in Germany, and the elderly are more likely to vote, are quite numerous and there is an age restriction to voting, so raising the retirement age or cutting benefits is political suicide. They also hold more assets, the income on those assets has to come from the young as well, and tax rates for the young are higher inflation adjusted since the tax brackets have stayed pretty much the same since introduction of the income tax.
Probably a good time to remember the Adversarial Collaboration Contest entry from 2 years ago that looked at aging and concluded the evidence for calorie restriction in humans results in longer lifespan was less strong than e.g. animal studies would suggest: https://slatestarcodex.com/2019/12/12/acc-does-calorie-restriction-slow-aging/
Hi Scott! Great review! And, as the author of another book on aging biology (Ageless: The new science of getting older without getting old), I agree with both you and David on different things. In agreement with you, I think that solving aging is going to take more than just reversing epigenetic changes. In Ageless, I break things down into ten ‘hallmarks’ of the aging process of which I think we’ll need to solve a decent subset in order to make *really* significant progress against aging (though results from tackling individual hallmarks like cellular senescence and epigenetic reprogramming make it seem encouragingly as though we could get some decent gains without solving everything). Where I agree with David is that I’m nonetheless optimistic that if we did plow a decent amount of money into aging biology, we could make huge advances, and it might well be easier than curing cancer (cancer cells are constantly evolving to maximize replication; the changes that cause aging are largely accidental side-effects of evolution and aren’t actively trying to outwit your treatments).
And I’m going to be releasing a free, bonus chapter on the ethics of treating aging next month, so sign up here to be the first to hear about it! https://andrewsteele.substack.com/
> It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
You might want to look around.
But bitter jokes aside, I'm 100% on board with your train of thought. Unfortunately I lean towards the SENS model more than the Sinclair model, but if Sinclair is right, that's _such_ a low hanging fruit we need to exhaust that research direction anyway.
Anectodally, intermittent fasting makes you feel fantastic, actually heals muscle injuries (by downregulating inflammation, I guess?), keeps the weight off. Highly recommended even if it does not, in fact, make you an immortal space murine.
« Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself? Or more to the point, since most drugs act by flipping biological “switches”, why does your body have a switch set to the “be weak, slow, and dumb” position? »
Algernon's Law seems very real to me, but for aging, there is something that works strongly in our favor: natural selection heavily discount what happens at older ages, because in our evolutionary past, we were statistically dead after, say, 40 years. This means that a genetic variant producing a very small advantage in youth at a huge cost in later life was usually very advantageous and retained by natural selection. So it seems possible that, conversely, the cost of not aging could actually be very small. And besides, a relatively small number of organisms, some trees and turtles for example, do not seem to age, or at least we are not able to detect a decrease in capacity over time. So it seems possible for biology to make organisms that do not age, or at least age very very slowly.
I find the issue with many of these longevity arguments is in conflating lifespan vs healthspan (the duration of one's life in which you are healthy and disease-free). You could argue that many efforts of medical science over the past 100 years have focussed exclusively on lifespan, and this has caused a number of societal challenges with people who live longer, but are highly dependent upon support to carry out their activities of daily living.
So too with the summary of this book; if these theories bear out, then sure we can prevent cancer, or dementia, or any number of the other "Geriatric Giants", but this isn't (to my mind) going to prevent us losing muscle strength (which happens after age 50 despite exercise, even in retired olympic athletes), or to repair our knee cartilage, worn out from too much running. Without fixing these millions of tiny insults (as Scott says), we might be left with a retired generation who are biochemically healthy, and yet utterly unable to live independently.
To support this statement I would point to this good publication on healthspan[1] which states:
"The past century was a period of increasing life expectancy throughout the age range. This resulted in more people living to old age and to spending more years at the older ages"
and
" In recent decades, there have been some reductions in the prevalence of physical disability and dementia. At the same time, the prevalence of disease has increased markedly, in large part due to treatment which extends life for those with disease"
You might want to read the actual book, it goes at length discussing exactly this question and how all anti-aging research is about expanding healthspan (compared with fixing individual diseases, which only increases lifespan).
Sinclair is not trying to cure cancer or dementia, he wants to stop cells aging PER SE. If your cells do not age, or don't age as quickly, and there's no terrible side effects like 1000% increased cancer risk, then yes, your healthspan is necessarily going to increase.
PC Firefox also breaks down, I see "Uncaught TypeError: this is undefined expandToggleClicked comment.js:146" in browser console so Substack has broken code in production.
Someone may let them know or wait until they notice.
It's not pretty but it works. Probably the next feature I'll work on is either collapsing comments or a killfile (which Pycea's extension has had for a long time).
> But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
We evolved and are tuned to lifestyle involving massive amount of exercise and much wilder swings of temperature and far less plentiful food.
It seems plausible to me that modern lifestyle is a massive health problem. We life longer because it was outweighed by reduction of diseases and starvation, but still sitting still in front of screen is extremely unhealthy.
It is not surprising that our body gets out of whack if we sit still, look at colored plate 50cm away and eat piles of food.
People of the past had much more physically demanding lives, but usually had less cognitively demanding lives unless they were part of a tiny priesthood/aristocracy. Being in a permanent state of brain-fog from hunger is miserable, but a hunter-gatherer or medieval peasant could be miserable in that way and still get through life. It's more debilitating for modern anorexics/bulimics, people with female-athlete-triad, stimulant addicts with suppressed appetite, etc. They may well be in similar caloric deficits, but are expected, at bare minimum, to be literate, numerate, and able to plan their lives further than the next week. I don't think modern life is healthy either, but I don't think living as most humans have in the past is necessarily the best way when conditions have changed.
I am not convinced that "usually had less cognitively demanding lives" is really true.
Hunter-gatherer definitely needs plenty of attention/vigilance and people put enormous effort, also intellectual into that. And what minimal experience I had with similar things - I really doubt that it was less mentally challenging that typical intellectual work in a modern world (to say nothing about working in factories).
A hunter-gatherer life where you don't spend any time reading or writing (let alone, most of your working life reading), very little time planning more than a short distance into the future, knowing only at most maybe 150 people and rarely meeting and having to cooperate with total strangers, rarely dealing with novel, abstract ideas, learning completely new skills as an adult, etc. seems a lot less cognitively demanding life than a typical professional office worker in a large city, at the very least.
> But if you transfer the skin cell DNA to an egg, inseminate the egg, and turn it into a baby, that baby is just as young as all the other babies. So DNA damage can’t be the whole story.
Is it possible that this process filters out any damaged cells? As in, more damaged cells will not succeed and we just look at successful ones?
So one mostly end with failed growth or (usually) healthy new organism?
Lets say that growing baby is a tricky process where any unhealthy/damaged cells will die. Would it be consistent with success rate of cloning?
Still, reproduction requires producing less burdened cells so likely there is some repair - but maybe it is for some reason of another very costly to do or rarely successful?
Yes, as the clone embryo develops it will filter out a lot of damaged cells. In general, during early pre-implantation development embryos can kick out cells that are "wrong" in favor of cells that are "right", but it's not a perfect process by any means, obviously we get non-cloned babies in all species that spontaneously abort or are born with defects.
Also this seems like a fine spot to say a bit about cloning:
If you transfer a skin cell nucleus to an enucleated egg, then you don't inseminate it. It already has a full set of DNA. You're making a clone not doing sexual reproduction. The resulting one cell embryo does need to be chemically activated, which is something that is usually triggered by insemination.
To say that baby is just as young as others is not *necessarily* true. Developmentally, it's true. But the DNA could be retaining marks of its age in a few ways.
1. As some people have mentioned, telomere length. Telomeres should be extended after genomic activation in an embryo (at first, an embryo isn't making any of its own gene products...it's using up maternal resources in the oocyte) but this doesn't happen perfectly or reliably in clones.
2. Mutations. If there are replication errors in DNA sequence, cloning won't fix that.
3. During embryonic and fetal development there are a couple of waves of demethylation and methylation that theoretically would reprogram the methylation patterns in the transferred DNA to be exactly as they should be at that developmental stage, but again in practice that isn't always the case.
Clones can be healthy but they also can be extremely unhealthy. They also have higher than normal rates of sudden death due to no apparent cause.
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
I am surprised anyone would make this kind of argument. There were quite a lot of other changes in health and nutrition and everything confounding the life expectancy changes. For example, industrial revolution kicked off an extreme population growth event, and until recently there (in general) was more kids and young people than old people (discounting mortality effects from world wars).
Immortality is also different than extended lifespan. Extended lifespan for one individual still ends, which obviously results in kids and grandkids of the said individual getting the inheritance. (Maybe it could be good for economy that people have time to collect more net worth and then pass it around.) It is quite different from true immortality (it is no longer making sense to save money for retirement, instead it makes sense to build continuous equally immortal income streams to fund on-going immortality treatments and all the fun stuff you want to do).
Also greatly expanded lifespan is different than slightly expanded lifespan. The first change was that lifespans were more equal: more people had a chance of live into so old age where they could be grandparents and maybe great-grandparent, but there were such people even before. The future where the super rich / all 1st world people / everyone gets to live until they are 120 or 200 with young person's body (if not immortal) would be more drastic change.
There are two things here: first, extended (or not) lifespan, but we don't suffer the ill-effects of aging so you naturally die at 80-100 but you are healthy and vigorous up until then.
Second, the Struldbruggs of Jonathan Swift's "Gulliver's Travels", who continue to age over their long lifespan, and are subject to civil penalties from the age of 80 onwards in order to prevent this entire problem of an immortal clique monopolising all assets:
After this preface, he gave me a particular account of the struldbrugs among them. He said, “they commonly acted like mortals till about thirty years old; after which, by degrees, they grew melancholy and dejected, increasing in both till they came to fourscore. This he learned from their own confession: for otherwise, there not being above two or three of that species born in an age, they were too few to form a general observation by. When they came to fourscore years, which is reckoned the extremity of living in this country, they had not only all the follies and infirmities of other old men, but many more which arose from the dreadful prospect of never dying. They were not only opinionative, peevish, covetous, morose, vain, talkative, but incapable of friendship, and dead to all natural affection, which never descended below their grandchildren. Envy and impotent desires are their prevailing passions. But those objects against which their envy seems principally directed, are the vices of the younger sort and the deaths of the old. By reflecting on the former, they find themselves cut off from all possibility of pleasure; and whenever they see a funeral, they lament and repine that others have gone to a harbour of rest to which they themselves never can hope to arrive. They have no remembrance of anything but what they learned and observed in their youth and middle-age, and even that is very imperfect; and for the truth or particulars of any fact, it is safer to depend on common tradition, than upon their best recollections. The least miserable among them appear to be those who turn to dotage, and entirely lose their memories; these meet with more pity and assistance, because they want many bad qualities which abound in others.
“If a struldbrug happen to marry one of his own kind, the marriage is dissolved of course, by the courtesy of the kingdom, as soon as the younger of the two comes to be fourscore; for the law thinks it a reasonable indulgence, that those who are condemned, without any fault of their own, to a perpetual continuance in the world, should not have their misery doubled by the load of a wife.
“As soon as they have completed the term of eighty years, they are looked on as dead in law; their heirs immediately succeed to their estates; only a small pittance is reserved for their support; and the poor ones are maintained at the public charge. After that period, they are held incapable of any employment of trust or profit; they cannot purchase lands, or take leases; neither are they allowed to be witnesses in any cause, either civil or criminal, not even for the decision of meers and bounds.
“At ninety, they lose their teeth and hair; they have at that age no distinction of taste, but eat and drink whatever they can get, without relish or appetite. The diseases they were subject to still continue, without increasing or diminishing. In talking, they forget the common appellation of things, and the names of persons, even of those who are their nearest friends and relations. For the same reason, they never can amuse themselves with reading, because their memory will not serve to carry them from the beginning of a sentence to the end; and by this defect, they are deprived of the only entertainment whereof they might otherwise be capable.
“The language of this country being always upon the flux, the struldbrugs of one age do not understand those of another; neither are they able, after two hundred years, to hold any conversation (farther than by a few general words) with their neighbours the mortals; and thus they lie under the disadvantage of living like foreigners in their own country.”
I think people would prefer the first instance to the second.
"Immortality is also different than extended lifespan. Extended lifespan for one individual still ends, which obviously results in kids and grandkids of the said individual getting the inheritance. "
Most people do not receive a significant inheritance, so this is not important.
"One unambitious - but still potentially true - counterargument to this is that a world where we conquered aging, then euthanized everyone when they hit 80, would still be infinitely better than the current world where we age to 80 the normal way"
Is it really? I think it is quite ambitious argument to make that it doesn't matter that in the universe A (current) we don't do anything we are not currently doing and in universe B (aging stops and people are euthanized) lots of people are killed. Sounds like an argument against universe B, because in universe B we are euthanizing a lot of healthy people.
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
Thomas Malthus would like to have a word here.
One of the arguments from the school of economics at the time of the Great Famine was precisely this - there were just Too Damn Many Irish, so the famine was in fact a great opportunity in disguise to clear out the surplus excess population (by emigration to Canada and the USA) and put agricultural practices on a profitable basis.
The problem with us Irish at the time was mainly sky-high birthrates, not a sudden and drastic increase in lifespan, though. (And of course the situation was exacerbated by landlord/tenant relations and cash crop export arrangements and so on, but that's another spiel.) Scott is correct that sky-high birthrates are still the main problem in the parts of the world that need to worry about overpopulation.
That said, I do think Scott's argument regarding medieval Europe in general is pretty poor- he's talking about a slow improvement in longevity that took place over, what, 800 years? That's hardly going to stop your population from turning over on a regular basis, given humans only live to 80. Alternatively, if he's talking about the massive gains in life expectancy that occurred just over the last century or so, it can be argued that the Boomers being the wealthiest generation in history (and perhaps locking younger generations out of positions of ownership and prestige) does in fact have something to do with them living so long. If our life expectancy goes up by a factor of 10 over the next 50 years (which might conceivably happen), the effects would be much more significant than life expectancy doubling on a timescale of centuries.
I just don't see any long-term escape from the a situation where a world without death either becomes a world without children or runs headlong into another malthusian wall at some point centuries from now. (Which, if I live forever, I might live to see.) The argument for space colonisation (A) assumes that space migration will be cheap and safe enough to be worthwhile and (B) that no legal and political barriers to mass migration offworld will be imposed. This is not an option that has trivially solved the malthusian crises of Africa, for example.
There will never be total immortality, as people will still die of accidents, rare diseases, murder and suicides. Birth rate can be kept low just so it replaces the people who die unexpectedly. Take trees for example. Many of them are biologically immortal but manage to die anyway, from diseases, competition, wind, lightning and whatnot. They are still in a Malthusian trap of course because of their crazy breeding speed - a million seeds by some successful individuals who manage to reach breeding age.
Keeping birthrates this low in the first place would be a major social engineering challenge, especially if you're working to keep accidents, disease, murder and suicide to a minimum (which we do, strenuously.)
Religious conservatives might be willing to shun life extension technology as 'tampering with nature'- can't meet your maker if you never die, after all- and they're also the group most likely to keep up their birthrates and resist child-licensing. So maaaaybe those factors will cancel out. But that doesn't seem like a super-reliable solution.
You could probably convince Christian fundamentalists to at least get the life expectancy up to 120.
Genesis 6:5: And the Lord said, “My Spirit shall not strive with man forever, for he is indeed flesh; yet his days shall be one hundred and twenty years.”
(note that this was a downgrade from pre-flood humans who seemed to be able to live as long as they wanted, over 900 years in some cases).
The previous explanation I've encountered for aging clashes with this. The way I've heard aging explained before is that genes do a bunch of different stuff (assumedly due to compression) and some of those things will be good/bad early/later in life (where early is before passing on genes via having children).
So a gene that's bad early gets evolution'd out of existence; leaving genes that are good early and good/bad later. The probability space of negative mutations is larger than positive mutations so most genes end up being beneficial early in life and bad later in life.
This logic feels compelling to me and precludes the idea that aging is simple enough to be easily cured. I admit to not really knowing much about the topic though.
Antagonistic pleiotropy is an evolutionary origin hypothesis (latest genomic data seems to support it as at least part of the story) but it doesn't imply much about ease of anti-aging interventions (except versus ageing as genetically programmed to control population size or whatever, which is *very* against consensus and considered close to an old rejected idea). All the stuff about why we age could be equated with "what bad things do genes do later in life" under that idea leaving all else unchanged.
Is part of the answer to the “algernon’s law” objection “because we aren’t evolved to be in this environment of plenty all the time?”
The people who are big on fasting argue you’ll feel more mentally alert and sharper when you’re hungry. This matches my experience as well: I have less energy after I’ve eaten a meal. My guess would be that we may be evolved for a specific long term average rate of mTOR activity, and most of us have it on too often, just like most of us are overweight.
He also argues in the book that there wouldn’t have been some evolutionary benefit for living for arbitrary periods of time in an environment that was chaotic and dangerous. So maybe there’s the answer: yes, you might take longer to heal from physical injuries with lower mTOR activation but this cost is outweight by having fewer senescent cells.
Also, maybe he looks super young in part because he’s so optimistic? Maybe it’s a mix of drugs and positive attitude.
Another point against it: in nature, there's always a high probably of a non-age related death (disease, flood, lion, murder, etc). This means reduced aging will have diminishing returns on actual life expectancy. So no matter how much adaptive advantage a higher life expectancy might provide, if there's any trade-off at all, evolution will never favor anti-ageing very much over alternative adaptations.
If my math is right: if ageing didn't exist but you had a 1% chance of death every year from all other causes (probably a low estimate for humans in nature), life expectancy would be ~69 years. Make it a 2% chance and its ~50. A 3% chance and it's ~23. Ageing would barely move these numbers, whereas an adaptation that reduces risk of death from other causes could make a big difference.
Isn't Algernon's law reconciliation well established for aging? Aging and dieing are good for evolution. We mature we reproduce we care for our offspring and when they are mature we age and die. In the malthusian environment all species evolved in, not competing with our young for resources makes the species more fit. So the trade off to solving aging is that our species is less fit 100000 years out. This could make the toggle easy, but it could also be hard, not because evolution couldn't figure out how not to age but it explicitly made it hard to avoid.
I gave up on true anti-aging when I read an ophthalmology textbook. It was *filled* with explanations of the changes to the eye that take place as you get older, and reversing/stopping those changes would require technology unrecognizable to us. Even if you found some way to get the rest of your body to live forever, you will eventually go blind.
I recently learned about this too, it's interesting to how the eye is built from the inside-out, and remains filled with long-lived proteins (LLPs) that are as old as you are. These proteins slowly degrade with time, and apparently this is a driving factor in the formation of cataracts with age.
It's also not clear to me after reading whether these ideas apply to permanent cells. Can a permanent neuron or a cardiac muscle cell really be induced back into a stem cell? Can a senescent cell?
It'll be hard for me to let go of the assumption that age is a combination of many factors, but I admit the epigenetic idea is interesting.
It's straightforward to do epigenetic mapping of cells, even down to the single-cell level. So: take an elderly mouse and a baby mouse, do the epigenetic mapping, see if there are systematic differences. Has he done this?
Agree with the distinction between lifespan and healthspan. Also skeptical that extending lifespan will be as simple as taking a pill and/or intermittent fasting. I think it's likely that average lifespan will continue to increase. But there is likely a natural limit (I've seen ~150 yrs mentioned before, but don't recall exactly what that's based on). Haven't read Sinclair's book yet. So not sure if he addresses it, but mitochondrial dysfunction plays a key role in aging. Mitochondria acquire mutations as we age due to ROS, etc. which leads to cellular malfunction. One potential therapy I haven't seen mentioned in this thread yet is mitochondrial transfer from healthy (young) cells to damaged cells. This has been shown to occur in vitro and in vivo. Nobody has quite figured out a way to harness this phenomenon for therapeutic use yet (lots of people claim they have, but evidence is lacking). The appeal of somatic cell nuclear transfer (SCNT) is that you can create genetically-matched cells for cell-based therapy that have young, healthy mitochondria from a donor oocyte/egg. This is also an advantage of embryonic stem cells over iPS-based cell therapies because those cells originate from an adult with already acquired mtDNA mutations (we've published on this). The challenges with therapeutic cloning of course is that donor oocytes are scarce (although maybe not for long if we can mass produce them in vitro) and delivery is an issue as with any form somatic gene therapy. Anyway, if you're a VC or philanthropist reading this post and want to support our research in this area (as the NIH currently does not fund human embryo research), hit me up. Paula Amato, MD at amatop@ohsu.edu.
> it would be weird if some drug could make you stronger, faster, and smarter.
Isn't that methamphetamine? Perhaps it has some negative side effects.
Regarding embryo's resetting the clock to zero . . .. Years ago, I watched one of those science shows (could have been NOVA), and the topic was cancer. The showed some results with chimeric mice. Start with a blastocyst from a white mouse, then inject a few cells from a black mouse. When the mouse pup is born, and grows, you can see where the black cells ended up -- all the black patches on the mouse.
Now the interesting bit. Now inject black cancer cells into a white blastocyst. In the experiment presented, they injected particularly nasty cancer cells, known to create a tumor wherever they land. The mouse pup is born, grows . . . and is cancer free. You can see where the black cancer cells ended up -- the black patches on the mouse -- but they are not cancerous.
Aging seems like an area where we might not expect Algernon's Law to apply. In my opinion, the evolutionary biology of aging is pretty solid:
From an evolutionary standpoint, organisms (probably) face tradeoffs between survival and reproduction--any given resource can either be invested in maintaining your current condition, or producing offspring, but not both.
Having offspring now is better than having offspring later, even if you have the same total number of offspring, because that means that your lineage fits more generations into the same time period as your competitors, and is thus more fit. Depending on the numbers, it will often be better to have fewer offspring quickly than more offspring over an extended period of time.
Put this together, and it means that basically all organisms should want to shorten their lifespan in order to reproduce more and more quickly. Even going from "infinite lifespan" to "finite lifespan" is going to be worth it for surprisingly small gains in reproductive rate.
"Aging" is just the molecular consequences of making that tradeoff. Stopping aging isn't about breaking a tradeoff (in which case Algernon's Rule would kick in), but just moving the tradeoff to an evolutionarily disadvantageous solution. This seems easier.
There's a very compelling series of essays on LW starting here: [1], detailing the non-adaptive explanation for aging. The summary is that regardless of aging, people will die anyways, to disease or predation or what have you. From an evolutionary standpoint, genome invested in preventing aging are wasted, because most people will be dead before it has any benefit. So most new mutations go towards helping young people stay fit, with the elderly falling to the wayside.
This explanation also reduces the applicability of algernon's law, since it supposes basically that there hasn't been much pressure to decrease aging. We know that there are species that, for all intents and purposes, can live forever. If sufficient pressure was applied, we could do the same. So aging isn't entirely impossible, like, say, building more efficient muscles would probably be.
But non-adaptive explanations are far less hopeful than adaptive ones. The adapative explanation supposes that there's basically a switch, and evolution can adjust it up or down based on how long it wants people to live. If we find the switch, we solve aging. Under the non-adaptive explanation, there is no such switch. There are probably tens of little switches we could adjust, but they are relatively hard to find, or else evolution would have found them. We are still incredibly poor at medicine, and nearly all of our treatments basically involve helping the bodies natural healing mechanisms. So if the body doesn't have a healing mechanism, with respect to aging, then we are very unlikely to solve it any time soon.
Good point--the "selective shadow" hypothesis you describe is another important evolutionary explanation. The only thing I would add is that to some (partial!) extent this *is* an adaptive hypothesis: discounting of future reproduction due to chance death is part of why trading off lifespan to get current reproduction is selectively advantaged.
OK, I'll add one more thing--it's important to note in this discussion, as Scott kinda did, that germline cells don't age. So there ARE switches to be manipulated (cough telomerases cough)--the questions are whether these are switches that are practical to manipulate, and whether manipulation of them has the desired effect at the tissue/organ level.
Chiming in as well to add my take on rapamycin: out of all of the longevity agents I am interested in and/or take myself, it is likely to be the one that I have the highest hope for in humans. We have a decent understanding of the mechanism (compared to many other things, at least), it works very consistently and strongly in several other organisms, and the mechanism of action is strongly evolutionarily conserved. As for safety concerns, it seems like if taken in a low dosage and infrequently enough, the safety profile improves significantly and it may be a net-plus in many areas (this may be related to mtorc1 vs mtorc2 activation depending on the dosage and timing (it does have a pretty long half-life!), which also makes it seem like it can be taken without actually suppressing one's immune system or causing some other undesirable effect categories).
Although I do know of many others that take rapamycin, I still don't suggest it to anyone myself, firstly because I don't offer medical advice of that nature regardless of my cost/benefit analysis (are there risks of potentially bad unknown side-effects with long-term usage? sure, but the risk of *not* taking longevity agents is also pretty large, and results in a much earlier likely death), and secondly because it is still likely to be higher risk than a lot of other simple things that I do often suggest to others, like glycine supplementation, which I see as close to zero risk (a few others on https://nearcyan.com/supplements/ if interested). I'd hope that anyone that takes it themselves has blood panels done (if not much more) to ensure they're not doing easily-observable harm to themselves as well. It's definitely a very interesting area of research either way; I can't stop myself from paying attention to stuff like this due to how large the potential impact on humanity is.
A few rapamycin links for those interested (more if you just search on pubmed!):
I enjoyed David Sinclair's book and some videos, but he is too good at hyping whatever he wants to. I trust his results published in good magazines, but he hasn't so far done anything in humans. He is a mouse guy.
Meanwhile, Greg Fahy has succeeded in reducing epigenetic age in humans by rejuvenation of the thymus (by a combination of HGH which rejuvenates the thymus + metformin and DHEA that prevent some bad side effects of HGH on insulin regulation). The trial was called TRIIM. He is now running an extended trial in humans again, called TRIIM-X, to find out how many measurable qualities improve as well. (Because we do not know how tight or loose the connection between epigenetic age and real state of the organism is). There was a recent interview in which he claimed that intermediate results are fairly good so far - for example, kidney function has improved, inflammation markers and PSA went down.
But Fahy is an unassuming kind of guy, almost shy, so he gets almost zero attention.
>Modern Europe is currently in crisis because it has too *few* people and has to import immigrants from elsewhere in the world.
It's not hard to imagine that in a society where people live to be 200, the fertility rate would plummet, particularly if you measured fertility based on the number of children women have for each year of their life, which might be a sensibility way to measure it if that denominator changes dramatically. And if the problem is not too few people, but too few workers, you could end up with a lot of old rich people living off many decades of capital gains. A shortage of workers could really become a problem in such a society.
But that's just speculation, and I agree with the point you make in the next paragraph:
>Would Europe be better off if the government killed every European the day they turned 45? If not, it seems like the experiment with extending life expectancy from 45 to 85 went pretty well. Why not try the experiment of extending life expectancy from 85 to 125, and see if that goes well too?
I suppose the notion of many old people being able to live many decades off capital gains is in conflict with the notion there would be a worker shortage. If there is a great worker shortage, there wouldn't be much in the way of capital gains!
I like to imagine that longevity therapies that staved off death would also improve general mental and physical health, which aside from reducing burden on the health system might also allow the elderly to engage in some level of productive work. Depends on exactly how spry they feel, I suppose.
Even if physical and mental health grow proportionate with life expectancy, it seems like a lack of creative young minds would still hurt society a bit. OTOH, some scientists and engineers may benefit intellectually from being able to use knowledge gained over a hundred-year period. I wonder how many innovations we lose because one person can only be productive in their field for say 50 years instead of 100?
I'm haunted by Hanson's thesis that since for most of human existence most humans existed at subsistence levels, the best prediction for the long-term future is that most humans will exist at subsistence levels. Perhaps a massive increase in longevity combined with stagnant productivity increases will help us get to that future/return to that past.
But it in the long run we will all be dead. Or will we?
If we were able to revert everyone to a mid-20s state (presumably you can't go back to before the brain is fully developed), presumably everyone would have a creative young mind, only boosted by experience.
Hard to say. We lose cells as we age and a lot of synapses get pruned, but I supposed sufficiently-advanced rejuvenation treatments might be able to fix those problems as well.
It's not a great line (from Scott) because it implies the usual n00b mistake about life expectancy. A better way of putting it would be "Would Europe be better off if the government kill every other European in childhood and the other half lived to be 85?" Depending on how the government chose its victims, the answer to that might actually be "yes."
I would expect the fertility rate to increase, no decrease. If you increase a woman’s reproductive years from ~40 to ~140 then that gives her many more chances to reproduce. What’s more, many women fail to reproduce because they seek a career first and then find that their biological clock has run out: imagine if you had enough time to build a career and still had a hundred years to take time off to start a family? Right now leaving work to raise kids takes you out of the workplace about 10-15 years or so. Currently that’s about one third of your total working life, which is a big deal. If we live to 200 it would be more like one tenth or less, a much smaller sacrifice to make.
Finally, kids are an investment in well being. Up front they are a lot of work, but every year they live they are less work and yield higher dividends in life satisfaction. If you live three times as long then the potential return on the investment of having a child increases as well.
Anti-ageing therapies, in and of themselves, can't fix that problem (though of course with sufficiently advanced biotechnology you could just clone new egg cells or, for that matter, bioprint replicants on assembly lines.) Biologically speaking, a woman's optimal life strategy would be to have children in her early-to-mid 20s and pursue a full-time career once her kids are out of the home (or at least partly capable of fending for themselves.)
My favorite aging theory is the gradual dysfunction of proteosomes. Cells make a crapton of proteins all the time, and they really need to get rid of all the broken and dysfunctional ones, so my theory is the increasingly failure to do so as cells age is what makes them senescent. It also fits nicely with the starvation effect: presumably when your cells aren't getting enough fuel and nutrients they have some ways of boosting the efficiency of recycling.
Yes, and the type of immigrants its trying to prevent are those that have a strongly net negative fiscal impact (along with a slew of other strongly negative socio-economic impacts on average), which is to say, those that not only don't fix the economic issues associated with a higher dependency ratio due to an aging population, but actually make it much worse.
> calorie restriction hasn’t been around the hundred years it would take to see results in humans. A few very committed biohackers having been trying it for a few decades now, so I guess we’ll know if it works by the mid-21st century.
We should see results in reduced mortality rate soon.
> Why didn’t the body just evolve to secrete that drug itself?
Since only traits that are beneficial or neutral would have persisted, presumably keeping old people around beyond a certain point is not particularly beneficial. Older proto-humans had incentives to crush younger and healthier challengers to their power, which would inevitably weaken a species. Older genetics may also be more poorly adapted to changed environments.
Humans are now pretty adaptable to a wide range of different environments, and we have some cultural adaptations that could possibly mitigate the "threat" of immortal old people.
> The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
It's common sense that you would want a strong immune system, unless you get lupus. So maybe mTOR gets *overactive* as we age, and these compounds suppress it only where it's not really needed.
People in this thread keep saying that NMN is "cheap", but I don't see it. Sinclair recommends 15mg/kg/day, so that's 1g/day for me. Most capsules I see on Amazon look to have 150mg and a bottle of 120 capsules is over $100 (CAD). That's $5.50 per dose, per day. That's not really that cheap given its speculative benefits.
Even the bulk supplier I'm aware of sell 500mg bags for over $1,600 (CAD), which is at least cheaper at $3.20 per dose, but still not cheap. If the benefits were more certain then maybe it'd be worth it.
I'd love if we could make some progress against aging, but I'm highly skeptical of nearly every claim made about its underlying causes and how to control it. Call me part of the camp that believes the problem is a death by a thousand cuts issue, where aging isn't just one or two problems that can be solved by 'fixing' DNA damage or epigenetic drift.
Speaking of DNA damage: it just doesn't fit. If accumulating mutations naturally caused aging, then why don't successive generations live shorter and shorter lives? We shouldn't have a situation where lifespan (controlled for infant/infectious disease mortality) is LONGER today than at any time in the past. Presumably the gametes are still dividing, just not as much as the kidney cells, so the same mechanism is at play there. So the same mechanism of DNA damage accumulation will happen, just more slowly over generations instead of over a single lifespan. In other words, this mechanism seems to suggest humans would have died of old age long before they ever evolved as a species.
Same argument for mtDNA damage accumulations.
Same argument for epigenetic drift. Why aren't we seeing epigenetic drift in the gametes? Are egg cells special in that they don't have epigenetic drift? Shouldn't we expect that there will be none left in a few generations - same as other cell types? Why not?
Meanwhile, there are all the normal mechanisms of aging that just don't feel like they're adequately explained by these ideas. They feel like a lot of hand-waving about how a general mechanism will lead to downstream effects, without ever having to connect the dots. For example, why does this accumulation of genetic/epigenetic changes lead specifically to memory B-cell depletion? And why is that mechanism both consistent, and gradual? If this were random drift, we'd expect to see more variation among individuals. A natural mechanistic explanation would better explain a phenomenon that is consistent and gradual.
For example, not everyone gets malignant cancers, and yet we all accumulate stochastic mutations over our lives. And even among those who get cancer, there's massive variation in which cell types are most affected, and how that manifests. Yet for aging, we always see arterial wall hardening, skin changes, etc. Why such consistency if we're working from a random mechanism? It doesn't fit our other experiences with stochastic biological mechanisms.
Is there a good word for slowing aging? Even if none of the theories are complete, maybe making use of all of them buys an extra 50 years in decent health.
Deleterious mutations get selected out. This works because you are able to mate with somebody who doesn't have those mutations. Sometimes this selection pressure on a species weakens and you get mutational meltdown or an extinction vortex. I suspect this is the main reason why sexual reporduction exists.
I'm still unconvinced by this hypothesis. The idea is that all your cells are accumulating mutations all the time. Some more than others, okay, but then why does aging happen so consistently at the tissue level if it's so inconsistent at the cellular level? This does not match what we observe in other diseases.
And if we're accumulating mutations throughout our lives, but it manifests as 'aging' only after the first few decades, then we should STILL expect to see a gradual aging at the population level, regardless of the effects of the sexual selection mechanism. Accumulated mutations can't always and forever be happening somewhere else. Mutation isn't a directed process, so some cells are going to capture some of those age-related mutations (or epigenetic drift, or whatever) yet still be viable. It's just the next generation will need less to get the organism past the threshold, i.e. aging will be quicker with each successive generation.
Sexual selection has a major cost: 1/2 of all the organism's genetic material. Yet it persists, because it allows for genetic admixture within the population in a way that asexual reproduction cannot match (not even by passing plasmids around). It is beneficial to reproduce because you create more copies of your genes. It is beneficial to reproduce sexually because you get genetic change more quickly that way. Many nematodes can switch between asexual and sexual reproduction. In times of low stress, they preproduce asexually, keeping all their genes. In times of stress, they switch to sexual reproduction, which drives greater genetic diversity/change.
No matter how you splice it, an organism has to get its genetic material into the next generation, keeping the vital mechanisms of life as intact as possible in the process. I just don't buy the argument that these very mechanisms are in a state of constant decay because of accidental, stochastic processes that only ever manifest in the very old but are accumulating throughout our lives everywhere but in the gonads.
I feel like a lot of the signaling pathways game misses the complexity of the system. We talk about "mTOR" as if it were a hormone like insulin that we can track, or that your body turns on and off. But mTOR is an intracellular signaling molecule. And intracellular signaling molecules don't work in PATHWAYS so much as they work as parts of NETWORKS. The complicated-looking diagram Scott showed is probably right for some cells, where other cells might have a different set of signaling molecules expressed. Thus activation (or suppression) of mTOR will have a different effect, depending on what else is being expressed in the cell at the time.
To say cell signaling is complex doesn't begin to describe the situation. I remember learning about promiscuous signaling molecules back in undergrad, and thinking, "Okay, now I know how NFkappaB works", or "so that's what ras is doing." Then I'd learn that NFkB wasn't just a single protein, it was made up of subunits, and each of those subunits had different splice variants which would do different things, and some scaffolding proteins changed which subunits came together in the protein complex, and post-translational modifications could also alter each protein subunit, and all the same were true of ras, and ... eventually I gave up.
I realized that the easiest thing in the world is to say that "signaling molecule X is the key to this whole operation". That's like telling a patient, "The reason you're having difficulty breathing is because of your lungs." Great. That's not really interesting or helpful.
It's the illusion of knowledge about the root cause of the situation without any actual understanding of time, place, and manner. Saying things like "we just need to turn off mTOR" is about as useful as saying, "you wouldn't have these breathing problems if we just shut off your lungs. No more breathing, no more problems." Or the seemingly more sophisticated, "we can solve your aging problems through better regulation of mTOR" which is functionally equivalent to, "we can solve your breathing problems through better regulation of your lungs."
What we should really be saying is, "It looks like mTOR is involved in this process, but we honestly don't know how or why. We're unclear how we might use the mTOR information to solve the problem. We're looking into it, but don't get too excited because until we understand the root cause of the issue we won't even begin to know how to solve it." Not as much hype that way, though.
> And the increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
Didn't most of the life expectancy increase between medieval and modern occur in the 20th century? And aren't most developed nations right now trying to cope with an abnormally large wave of increasingly long-lived people (e.g. boomers). And isn't the current zeitgeist that millennials have nothing while their parents/grandparents have everything? Saturday Night Live did a music video sketch about boomers not that long ago that contains this sentiment (paraphrasing) "they took all the money and they took all the jobs and they won't ever die!".
It's not a good reason to ban immortality, of course. And perhaps in the long-run steady-state, this would just work out OK, but people don't live in the long-run steady state - the first "old" generation to get the immortality pill is going to receive some truly vicious hate from the younger generations of the time.
Here's a somewhat plausible modest goal. There are people who live into their 90s in good health and then die fairly quickly. It runs in families, so presumably hereditary. The best news I've heard is that these people don't lack deleterious genes, they have more (better?) protective genes, so there might be something which can be bottled.
The massive challenge for any sort of longevity is that we might not have the tools we need yet. More math! But which math? Better tools! But which tools?
Living into the 90s in good health and then dying quickly sounds ideal. Seems modern morals go against the dying quickly part, however. I mean, few people are against figuring out how to make us live longer, yet I suspect many would be against research into how we could die quicker after living longer.
"Finally, a friend wasn’t impressed with Sinclair’s clone argument. They point out: suppose aging is DNA damage, and it happens to every tenth cell. Having a tenth of your cells damaged is pretty bad, especially if they become senescent. “Senescent cells”, common in elderly people, have sustained so much damage that they can’t even die properly, and just sort of sit around being hopelessly confused and secreting random chemicals which freak out all the other cells around them. Everyone agrees these are an important part of aging, even if they’re not sure about the specifics. But if 1/10 of your cells are like this, then you have a 90% chance of grabbing a healthy cell for cloning. And even if you get a bad cell, no cloning process works every time, so you’ll just shrug and try again."
Couldn't you decipher an old person's original, undamaged genome by sequencing the genomes of ten of their cells, and the creating a composite genome that excluded any base pairs that were different in a minority of the ten?
For example, assume there's a gene made of six nucleotides. I extract ten cells from the same person, and the sequences for that particular gene are:
Cell A genome: AGGCTA
Cell B genome: AGGCTC
Cell C genome: AGGCTA
Cell D genome: AGGCTA
Cell E genome: AGGCTA
Cell F genome: AGGCTA
Cell G genome: AGGCTA
Cell H genome: AGGCTA
Cell I genome: AGGCTA
Cell J genome: AGGCTA
Cell B is the senescent cell, and so is the only one that is different. I throw out its results and conclude that the correct sequence for the gene is AGGCTA.
It's probably way more expensive and way more complicated. First of all, you need to sequence the entire genome in each cell. The costs for that have fallen spectacularly, from $300 million in 2000 to $20 million in 2006 to probably ~$1000 today. But it's not super cheap, and if you need a lot of them, which seems likely, the costs add up.
Don't forget you will also probably need many copies to correct the errors you make in sequencing. The human genome is ~3 billion letters long, and the chances that you get *all* of them right in each attempt at sequencing are miniscule. So you'll need to do more sequences, to try to fix the errors in your sequencing, and of course these will get mixed up with the natural mutations, too -- I'm not sure how you would easily distinguish between them, which you clearly must if you're going to try to identify natural mutations to correct.
Finally, the harmful mutations that are most likely to happen are probably not random point mutations, like those you describe, but cases where extra DNA has been inserted (perhaps only a nucleotide or two), or some DNA has been lost, or a section has been transposed from one place to another. In all of these cases you can get very long stretches of DNA that don't match from transcript to transcript, because the "reading frame" has shifted, which I think makes identifying the correct sequence in a brute-force way (i.e. without knowing the function of all the DNA sequences) much harder.
One part of the definition of biological life, I think, is that it dies. Another implicit part of the definition, I think, is that it is unique, an individual entity. Are there cases where biological life as "an individual entity" are blurred?
Us fellow humans tend to view a bee hive as a composite entity, not life itself but composed of many individual biological entities. Part of the reason is the physical separation between one bee and another. Another part of the bigotry I mean bias I mean logical reasoning is that a particularly bee hive could last forever and not die like an individual primate is destined to in under 120 years.
Is it not a central reason that life can't become immortal because we define life as mortal?
Trees are immortal life forms. Unless you cut one down, but "immortal except in cases of violence or accident" is probably the closest you'll get without literal magic.
Does anyone seriously think that any anti-aging intervention we are likely to make in the next 10 years will be remotely applicable to people who are 70+ right now? Seems to me like preservation is the only way to help these people.
I didn't know that cloning works well, I remember being said that clones have shorter lifespans. So cloning works ok? Why can't we have hundreds of clones of Neumann then?
Will we be able to grow human skin tissue in vitro indefinitely soon?
To my limited knowledge, the issues with cloning humans are ethical, not scientific. Experimenting with human cloning means you're creating a person every time you give it a try, and that's a fraught decision even before you introduce the risk that your new von Neumann dies tragically young because of technical problems.
(Also, von Neumann died 70 years ago and I don't think we have any of his cells lying around.)
Google tells me that cloned skin for burn patients is a real thing that's done rarely - the two articles I found say it was because the burns were so large there wasn't enough skin left for traditional grafts. So we can do it, it's just a practical problem now - there aren't that many applications for human skin outside medical emergencies, and simply taking skin from elsewhere on the patient's body is usually easier.
I suspect the ethical issue is driven by blank slatists who maintain that cloning Neumanns, even if succeeds, would be useless, and mount scientific defense to (nearly) blank slatism.
So... I guess in the end this supposed "cure for aging" would really only be a significant-but-not-orders-of-magnitude slowing of aging? If so, surely none of the usual arguments against preventing aging/death apply?
My first thought is that aging isn't just about DNA or generalized metabolism. There are all sorts of structural things going on. The body can repair itself, but the repairs rarely leave the body in the same shape as its original structure. There are all sorts of scarring, restructuring, and work arounds. You can reduce to damage by providing better medical care. You can induce repairs. You just can't eliminate the structural changes.
For example, there is work on inducing heart cells to reproduce to repair heart attack damage. It might even work, but how much growth can be induced and how much scarring endured without compromise.
Still, I'm optimistic. Every time scientists agree that we've reached some maximum age limit, new ideas and treatments come up and we move past it.
> The increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps
Except it actually does -feel- that way. (Sorry I don't have any resources to back this up but my own experience). If you grow up in Italy you're definitely confronted with a political and economic system where older and powerful actors hoard resources and prevent younger dynamic forces to destabilise them. No wonder Italian researchers/workers/entrepreneurs do so well when they emigrate: the latent potential is there (they're educated in a modern, beautiful, powerful country) but they lack the opportunity to express their talents.
So yeah, maybe reversing again does have negative consequences to the economy.
Good enough for science fiction: energetic young people keep discovering new areas for their ambitions. I have no idea whether the older people eventually manage to lock all possibilities down, nor what structure of ageing and death would be best, in some sense, for the species.
Energetic young people in these countries will probably find out it's easier to emigrate somewhere else rather than trying to change things around them. So things don't actually change because there's an easy way out. Which is great for those that can escape but not so great for those who can't for a variety of reasons.
I finished this book 1 or 2 days ago. The end has a lot of discussion of political issues and I felt like it was a lot less enjoyable to read his analysis of the political issues related to aging and his progressive viewpoint on certain things.
On the off chance that anyone will ever read this, I want to comment on Scott’s skepticism that sirtuins (or some other protein) can figure out the “correct” epigenetic state of a gene, esp because it differs for the same gene in different cell types.
One epigenetic modification is cytosine methylation when it is followed by a guanine, called CpG, to distinguish it from the CG base pair. One might notice that if one strand has 5’CpG3’ then the complementary strand also has CpG at that point (read the opposite direction - the strands are antiparallel. When CpG cytosines are methylated, they are methylated on both strands.
So, if somehow the methylation is lost in one strand, a hemimethylase could check the other strand. If it’s methylated, then methylate the first strand. Incidentally, methylation tells the cell which strand is old when DNA is replicated. If there is a mismatch, the unmethylated strand is wrong. It’s imaginable that breaking methylation ups the mutation rate, though probably only slightly.
There is also a possibility that the transcription factor(s) for being one cell type can suppress transcription from other sorts of promoters. Maybe that’s how a muscle cell knows to be muscular? Maybe that process breaks down when an animal is well-fed?
That said, I think epigenetic dysregulation is an interesting theory of aging. Probably wrong, but very interesting.
Bats would be super-interesting to study for aging research. There are lots of species, so cross-species comparisons are more reasonable than mouse <--> man. If two bats species have similar size, diet, and metabolic rate, but much different lifespans in captivity, then physiological differences might be causing slower aging. Some bats are roughly mouse-sized but live a lot longer.
On cancer and telomerase, the protein p53 checks for DNA damage and arrests the cell cycle/leads to apoptosis (cell death). It’s mutated or missing in half of cancers. Elephants have many more copies of the gene and much lower cancer rates. Upping p53 in all a person’s cells through germline or currently magical somatic cell genetic engineering would give them a lot more headroom for other changes that would increase cellular regeneration but increase cancer risk,
Then, it could well be possible to reverse this process quite easily by giving cells the signal(s) opposite to the pro-aging one(s). Katcher has essentially done it even more impressively than Sinclair in rats.
Also, are you aware that Sinclair's lab managed to make old mice regrow their optic nerves using Yamanaka factors? That's just one tissue but it's an amazing boost. And the cancer problem was solved because they removed one of the five factors which turned out to be cancerogenic.
The anti-cancer effects sounds fascinating (I dimly recall bumping into some article on the topic on reddit at some point) but it does raise the question why that biological programming evolved in the first place.
There have recently been controversies about Sinclair's work on resveratrol and sirtuins; video summary, from Lifespan News, here: https://www.youtube.com/watch?v=eBxw6_8PivA.
My favourite pop science book on aging is Andrew Steele's "Ageless" (2019); it's broader and less focused on one guy's theories. My goodreads review of it is here: https://www.goodreads.com/book/show/52954648-ageless
It's really not.
I believe the conventional wisdom is that, at least in humans, living longer has been selected for. See the Grandmother hypothesis. Because infant and children humans are so much weaker and fragile than infants of other species, we have adapted to live longer to provide support to our children as they rear their own children.
I don't think there's a clear answer, this hypothesis was developed to help explain why human beings lived significantly past the age of menopause. Though I am by no means an expert in this field. That being said, given the number of genes you share with each subsequent chain of your lineage exponentially decays, I would expect the fitness benefits of aging longer to rapidly dwindle.
I think it is important for people to become weaker and infertile as they grow old, because otherwise they would be competing with their own offspring for status, resources and mates. That kind of cross-generational strife would be terrific for tearing apart families, tribes and societies. Perhaps we evolved to age as we do because those proto-humans that did not tore each other to pieces?
I believe there is a strong difference between selection for lifespan and the grandmother hypothesis, which is really needed not because of long life, but because of long (well, relatively long) life past menopause, where you really needs some special kin selection (advantage not on yourself, but on multiple individuals sharing part of your genes.) because normal selection predict the fitness after reproduction to be 0, by definition. So only indirect effects are present, in the form of helping (GM hypothesis) or hurting (consuming their resources).
For the reproduction lifespan, it should always be a positive in term of fitness, because living longer allows to produce more offspring, trivially....Kin selection may interfere, indeed, but for it to select shorter life there should be a pretty big hit on fitness of many offsprings (1/2 of your genes) or grand-offsprings (1/4) just by your existence. I do not think this is a likely explanation, because your own consumption of resource is no greater than the one of your competitors, so I thing dying off to let your used resource go to your kin does not work out mathematically. It does only makes sense in group selection, but group selection is not considered a valid explanation anymore. The only example I see where dying off is directly selected because of kin selection is some animals dying off to feed off their (very numerous) offsprings. This happen in some spiders iirc (sometimes with a twist, where the male feed off the female some of the time), and there I can see how death pays off in term of amount of offsprings succesfully reaching reproduction age, so in term of fitness....
The "short" lifespan is mostly explained (and I think this is a very convincing explanation) by tradeoff of extended lifespan vs other things, like added fitness at young age (faster growth, or other short-term advantage at the price of lifespan), because there is always a time preference linked to "accidental" death: the biological lifespan is longer than the actual one, because of all the non-age-related deathcauses (sickness, predation, accident). So a long biological life always have diminishing return in term of fitness, which means any tradeoff will defavor immortality. The equilibrium (average biological life expectancy) depends on the actual set of tradeoffs in a particular organism (I guess it depends on general organisation, so past evolution, which often put a lot of contraints on future possinble adaptations), but also on the rate of "accidental" death and offspring production rate: low offspring production rate and/or low accidental death rate means longer life. This is one explanation for the longer lifespan of flying creatures, compared to non-flying ones with similar size. Less accidental death rate because flying is a very efficient escape mechanism, maybe lower offspring production rate (because flying usually take more time, as half-flying may be dangerous) -> longer lifespan. The prime example is Bats vs non-flying small mammals.
Humans have quite low offspring production rate and accidental death compared to similar-sized mammals (and, but it's far less clear, compared to close apes). We also have longer lifespan, but not hugely so (compared to chimps)...So it kind of make sense. This also makes me believe there will likely be tradeoffs linked to "easy" anti-aging drugs, because the current lifespan is already a tradeoff...
It seems like evolution _should_ select for a thousand years and pumping out a baby every year. But instead we cease to be able to reproduce decades before we actually die.
One theory I've heard is that it's parasite-related and the same reason that most complex organisms reproduce sexually rather than asexually. If you live long enough with the same DNA then eventually parasites will become very good at targeting you, specifically. Better for your genes to keep swapping around as much as possible to stay a moving target.
I'm not convinced that this quite makes sense.
Women cease being able to reproduce after menopause. Men can reproduce at very advanced ages.
Women stop being able to reproduce because of aging. The female reproductive system has to function better than the male one in order to bring a viable fetus to term, and it also is much more dangerous to the woman when it malfunctions. women die from reproductive tract issues more frequently than men do for a reason.
>Women stop being able to reproduce because of aging.
You sure about that? Isn't it still controversial if women are born with all the ovuli for their entire life or they keep producing it every month?
There were a handful of papers at one point that suggested adult female mice might be capable of neo-oogenesis but that didn’t pan out. We do appear to be born with as many oocytes as we will ever have.
Does menopause also exist for other long-lived species like elephants or tortoises?
I’m not sure this is precisely correct. A woman’s body could stop aging and she’d still reach an end to her reproductive lifespan at some point. Women can’t make more eggs, so once you run out of what you were born with, that’s the end. Technologically this might change at some point and we might be able to make more oocytes for someone in vitro, but naturally we have what we have.
If that were the case, we don't grow old and keep pumping out babies until we die, we would probably not live much longer than we already do - especially prior to modern medicine. As others have mentioned, dying in childbirth is a real thing and a real problem. Having thousands of babies would simply increase the death rate to a point where it's certain what (barring something else happening sooner) women would die from in their lives. Once women consistently lived to the point where they died in childbirth, there would be no point in women having any greater lifespan at all. Therefore, evolution should prioritize what gets a reasonable number of births per woman, and then prioritize other things (like the grandmother hypothesis or whatever).
Are humans actually a good example to look at when considering the general question of the evolutionary value of longevity and reproductive windows? I could be mistaken of course but I thought that a confluence of strange selective pressures resulted in the rather extreme difficulty of reproduction for human women and that the vast majority of mammals have a much easier go of it.
I think that just raises the question to another level - why do humans die in childbirth? For lack of a better alternative explanation, we are presuming that there is a tradeoff involved that selected for what we have now, and that by going a different direction we would have lost out on some other metric.
That does presume that rabbits (or name your highly fertile mammal) wouldn't hit the same wall we are talking about with humans. Most mammals in the wild have very high likelihood of dying to various non-birth causes. If those other causes went away, maybe more would die in childbirth as well. Meaning, it would be more advantageous for them to get better at basic survival than to continue increasing their ability to procreate.
A lot of variation in natural lifespan seems to be based on "how good is this creature at avoiding being killed and eaten?"
Creatures that are bad at that generally have a short lifespan.
Creatures that are good at that tend to live significantly longer.
This suggests that living a longer period of time is beneficial, all other things being equal, but it can't be selected on if you aren't living that long.
So mice don't live very long at all because they all get killed and eaten.
Humans notably have extremely long lifespans for creatures their size, and indeed, in general, which suggests living longer has a significant biological advantage for them.
Indeed. You just have to add some biological tradeoff between decreased aging, and increased fitness/unit of time to see that in case of many non-age related deaths, increased fitness/unit of time will be selected against decreased aging. And such tradeoffs are easy to find: scars heal wounds faster but prevent perfect regeneration, faster growth to reproductive age vs more controlled growth, increased energy efficiency vs better waste cleaning, better immune response vs more autoimmune problems,....
extremely long lifespans, well, it depends. Compared to the other apes, we live longer, but not crazily longer. Longest living chimps reached 65-70 years in captivity....and they weight 50 kg. So we are not that special compared to our nearest cousins. the bodysize->lifespan scaling seems to be 0.15-0.3, so if humans are 75 kg, chimps 50, and lives 65y, taking a 0.2 exponent you expect a human to live 65*(75/50)^0.2=70.5. I guess with the relatively small chimp sample, and captivity conditions, humans would be recorded having a 75-85 max lifespan. Maybe about 15% than you would expect...
I fear that we won't get to find out promptly (read: while I could benefit) because of the FDA's stubborn insistance that aging itself isn't a disease (making it harder to meet ethical critera are a were).
More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
I'm a fan of exploring these ideas but it's not cool when bio-ethicists work to justify our emotional impulses rather than working to correct them when they disagree with our best rational reconstructions of morals.
Nir Barzilai, the scientific director of the American Federation for Aging Research (AFAR), seems to be much more optimistic about FDA support. He is currently leading the TAME trial, whose end goal is to get the FDA to approve aging as a treatment indication. He and Jamie Justice said in an interview with the Foresight Institute that the FDA had been very helpful in establishing trial guidelines that would lead to this goal.
I just interviewed Nir Barzilai for my Live Longer World podcast! And yep he mentioned how the TAME trial is meant to serve as a template to get the FDA to approve drugs to target the biology of aging itself.
Goddammit, she's got italics.
"More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously."
I'm less harsh on this intellectual habit than I used to be, given that tinkering with human biology and social relations in particular can have long-term side-effects that no-one predicted. e.g, contraception and abortion paradoxically made it easier for men to keep mistresses, which led married women to retaliate with 2nd-wave feminism in the 60s/70s and was most likely a huge contributor to the soaring divorce/illegitimacy rates we've been seeing ever since.
The consequences of our currently rapidly ageing population and shrinking birthrates (most especially in the developed world and China but rapidly becoming a global issue) are so potentially terrible that I'm not going to turn down anything that helps offset those problems, but I think it's naive to imagine that radical longevity won't have significant long-term drawbacks as well, even if we can't logically nail them down right now (and a few plausible downsides have already been proposed.) A lot of the time, these conservative instincts are actually right.
(To be clear, I'm not suggesting the pill and abortion-access had no benefits or that it would be practicable to roll them back- that genie is out of the bottle and it's quite possible the net benefits to human well-being outweighed the erosion of marriage norms. But I don't think the people who were/are worried about the social consequences had no valid perspective, even if they couldn't quite nail down the why beforehand.)
I would like a citation on the idea that 2nd wave feminists where primarily motivated by an increase of misstress having.
Maybe using Eugenics as an example would've been better, since it is more obviously bad.
Perhaps... but I honestly consider the stigma surrounding eugenics to be fuelled entirely by selective remembering and double-standards (20,000 lobotomies in the US alone prior to the 1960s didn't cause us to ban psychiatry or spend most of a century insisting that the brain was not the seat of intelligence.)
While I agree that eugenics as concept probably didn't deserve to be tossed out wholesale by the post-WWII world order, the idea that the stigma is fueled "entirely" by selective memory strikes me as a bit fatuous. Likewise, comparing the ill-effects of popularized and politically charged eugenics to those of early psychiatry is...well, disproportionate in the extreme is probably the polite way to put it. Practical eugenics has been a major factor in the biggest genocides and the nastiest caste systems of the last couple of centuries. Literally some of the worst things that have happened to humanity in recent memory.
So the scope of the atrocities in question (psychiatric motivated vs. eugenics motivated) is out of whack. Additionally, the comparison of the rejection of eugenics to "insisting that the brain was not the seat of intelligence" doesn't fit. This would only make sense if the anti-eugenics contingent insisted that genes don't play a role in life outcomes (granted, some people do make this argument, but most don't). The more common and, I think, more serious argument against eugenics is this: while genes have a huge impact on life outcomes, we aren't at a point yet as a species where we can confidently say whether certain genetic traits are desirable or not (excluding those which cause disease, obviously). And if we were to start identifying particular genes as desirable or undesirable, our social structures may not be secure enough to prevent our species from sliding towards a genetically homogenous Gattaca-style dystopia.
Anyway, with all that said, I more or less agree with your point.
"This would only make sense if the anti-eugenics contingent insisted that genes don't play a role in life outcomes"
This was more-or-less the practical position of the academy for most of the last century whenever any specific divergence in gender, class or racial outcomes was discussed, and it is effectively an assumption that most of our social policy regarding education and welfare is still predicated on. To this day, any politician suggesting a moderate and humane version of a eugenics program, such as paying meth addicts to use long-term birth control, altering tax structure to favour middle-class fertility, or subsidising access to embryo selection or sperm banks, would be committing career suicide- certainly if he or she explicitly justified this on genetic grounds.
"...comparing the ill-effects of popularized and politically charged eugenics to those of early psychiatry is...well, disproportionate in the extreme is probably the polite way to put it."
I don't accept that charge. Roughly 70,000 people were forcibly sterilised under eugenics programs in the united states. Lobotomisation is arguably worse than sterilisation, and when you add in other therapies such as early forms of electroshock, insulin shock or heroin medication, I think one can make a completely plausible argument that psychiatry destroyed as many lives as formal eugenics movements in the US and most of the developed world.
Comparisons with 20th century genocidal regimes- most obviously the Nazis, Imperial Japan and the like- also fall under the heading of double standards. If we had reacted to Trofim Lysenko and the Holodomor, or the Killing Fields and Great Leap Forward, in the same way as Mengele and Auschwitz, we would have spent most of century insisting that class did not exist, banning all public policy based on the idea that people are shaped by their environment, and demonising the notion that the rich might be exploiting the poor. I have no idea why the left gets to impose these lunatic double-standards on the conversation.
I would also point out that genocidal regimes have been as frequently motivated by resentment of a more-successful ethnic group as by the demonisation of a less-successful ethnicity, precisely based on the idea that- in the absence of genetic ability differences- the more-successful group must owe their pre-eminence to conspiracy or exploitation. The Nazis disowned IQ tests (a separate but not totally unrelated concept) precisely because the data from such tests kept contradicting their notions of jewish and slavic inferiority. If a belief in genetic advantage can lead to atrocity, and the *absence* of belief in genetic advantage can lead to atrocity, what exactly is the risk-free belief system we are supposed to adopt?
Lastly, while historical caste systems can certainly be nasty and much of the data here remains unclear, there is the outside possibility that some of the religiously-motivated marriage practices and sexual mores of pre-modern human societies effectively functioned as a kind of 'soft' eugenics program, and may even have helped make the Great Divergence possible. I don't want to jump to conclusions, and I'm not saying we don't have more liberal alternatives for tweaking the gene pool today, but it can't be dismissed on technical grounds either.
"Anyway, with all that said, I more or less agree with your point."
I appreciate that, and I don't mean to jump down your throat. It's just that I really think our society has a screw loose on this topic.
" And if we were to start identifying particular genes as desirable or undesirable, our social structures may not be secure enough to prevent our species from sliding towards a genetically homogenous Gattaca-style dystopia"
Sorry, missed this part, but I have a few extra comments here- there seems to be a common assumption that the use of embryo selection or gene-editing would lead to higher genetic uniformity, and I want to push back on this in three ways.
1. If we were to identify every locus in the genome where a minor allele was beneficial or a major allele was harmful, it would in some sense be mathematically trivial to flip the frequencies around- 'make every common bad gene rare and every rare good gene common.' The result? Identical genetic diversity. Massive gains in fitness.
2. Most genetic diversity is either useless or bad. This follows from the simple observation that 80% of our DNA is junk and most mutations that affect function are harmful (absent other selection pressures, entropy always increases.) There are certain kinds of *phenotypic* diversity we want- a diversity of talents and personalities to solve different economic and social problems, and perhaps a diversity of skin tone, hair colour and body types for either aesthetic reasons or to adapt to different climates (which is why they evolved in the first place.) We don't particularly want a diversity of crimes or a diversity of cancers.
3. In principle, exotic options like horizontal transfer or designing genes from scratch could allow humans to add brand new material to their gene pool- either borrowed from elsewhere in the kingdom of life or synthesised from first principles. (This could potentially be useful when colonising places like Mars, so that colonists can tolerate higher CO2 levels, radiation, or perchlorate contamination. Just a thought.)
In other words, I think these concerns about 'loss of diversity' are overblown.
There is nothing wrong with Eugenics itself. What's bad is the methods. Yes, it's obviously bad to kill off / sterilize\* "wrong" kind of people (nevermind the criteria weren't even sensible). It's bad because it's murder.
That doesn't imply gene therapy, designer babies and such are bad "because this is Eugenics, which is bad". This reasoning doesn't make any sense.
\* On topic, IMO it'd make sense to make anti-aging drug conditional on giving up rights to unrestricted procreation in order to deal with population explosion - certainly a better solution than killing people, which is what opposition to anti-aging proposes, pretty much.
Also, some solution to balance political power. Because while Scott says it's not a problem... eh, it might be. Plenty of people today claim "boomers" control politics.
"Also, some solution to balance political power. Because while Scott says it's not a problem... eh, it might be. Plenty of people today claim "boomers" control politics."
Yes, I've made this point in another thread. Your suggestion for making immortality conditional on childlessness... I mean, in principle it could work, but I suspect the necessity of this measure won't become obvious until society is already close to some malthusian wall, and at that point it's probably too late. Unless our species gets a lot more rational over the coming centuries, which I suppose isn't impossible.
At 73 I've yet to find that Boomer Button that controls politics. Maybe I'm just not trying hard enough...or slept through that day in school....
Eh. I don't know if obtaining that level of evidential rigour is even possible in our current academic climate, but I think I first heard the idea put forward here.
https://www.youtube.com/watch?v=5wuBQa86nj0
By a citation I did not mean literally a Chicago style citation or something alike. Just evidence. It is possible that such evidence is present in the video you included but i fear I do not hve the time to watch 50 minutes of video just to be sure there is. Is there any way you could direct me to some direct evidence? Maybe a number of notable feminist claiming their motivation was misstress related for example. Or failing that could you summerise the point.
If you claim that the climate is so bad that you wouldn't be abble to give any evidence whatsover, that would be too convienient to be true at all I believe. That would imply your claims are unfalsefiable.
I'm struggling to try and dig up something more concrete, but I know this is a fairly widespread argument among conservatives and the theoretical arguments seem fairly sound. There's a specific rundown on the topic here coming from an academic thesis, if it's any help.
https://www.youtube.com/watch?v=EHNiBAjZq_0
I suppose it's possible I'm just wrong about this, but the odds that the pill and abortion-access had no impact on the general culture or that those cultural effects were purely good seem slim to me.
Seems like a product of advanced anal fact finding to me, but that's me...
Two quick counter-arguments against that line of reasoning:
1) For every new technology, there are dozens of "predictions" about negative side effects. It is extremely difficult, even impossible, to determine which of those predictions will come true, and to what extent. That general argument could have been used to suppress all beneficial changes and progress in the history of humankind. Just think of all the negative long-term side-effects that this new-fangled bipedalism could bring!
2) The societal benefits from contraception and, to a lesser degree, abortion, are so much higher than the supposed drawbacks from more men keeping mistresses, that I can't even call this a "tradeoff" with a straight face. So even if this negative effect would have been reliably predicted, it was worth it.
Besides: Is the proportion of men "keeping mistresses" really higher than, say, 100 years ago?
I'm fairly sure the incidence of adultery and illegitimacy is indeed higher, and one of the negative side effects of the breakdown in marriage (or at least a coincident trend) has been a collapse in birthrates below sustainable levels. The side-effects of the latter could be potentially catastrophic over the next few decades (which is part of the reason why I'm tentatively in favour of anti-ageing therapies to try and offset the other side of the demographic equation.)
https://www.youtube.com/watch?v=b1IJ9kqBilE
https://youtu.be/UkEwHQTv9IY?t=972
I realise all technologies carry risks as well as rewards- even things like the printing and social media, which might have seemed likely purely technical engineering developments at the time, have had seismic ramifications on the social fabric. It's tough to draw the line. I'm just saying that blind optimism is a little unwarranted.
> one of the negative side effects of the breakdown in marriage (or at least a coincident trend) has been a collapse in birthrates below sustainable levels
Countries' fertility rates going negative is a cross-cultural phenomenon that is seen in pretty every single developed country worldwide, and is most highly correlated with decreased infant mortality and economic opportunities. Basically, people have more interests than just popping out babies which detract from those interests, and they don't need to have a lot of kids they no longer die before they reach maturity.
"Countries' fertility rates going negative is a cross-cultural phenomenon that is seen in pretty every single developed country worldwide"
Yes? And which of these countries have not seen increasing divorce and illegitimacy?
"...they don't need to have a lot of kids that no longer die before they reach maturity"
As I have already pointed out and videos I linked to explain in excruciating detail, these birthrates have gone way below replacement fertility, and there are reasons to expect this to result in economic stagnation at best and catastrophic social collapse at worst.
> Yes? And which of these countries have not seen increasing divorce and illegitimacy?
Plenty. Italy and Malta, for example. Below mean divorce rate, extremely low fertility rates (near 1). Plenty of representatives among developed nations, including Ireland, Greece. Compare for yourself:
https://worldpopulationreview.com/country-rankings/divorce-rates-by-country
https://worldpopulationreview.com/country-rankings/total-fertility-rate
> these birthrates have gone way below replacement fertility, and there are reasons to expect this to result in economic stagnation at best and catastrophic social collapse at worst.
Maybe. Social security depends on growing populations, but immigration can make up the difference for now. At some point we may have to reckon with the fertility rate issue, but I still don't see a significant causal association between the breakdown of marriage and the collapse of fertility rates, which is the only point I was disputing.
> given that tinkering with human biology and social relations in particular can have long-term side-effects that no-one predicted
Yes, large changes have consequences. Still, last 200 years or so should make us want changes rather than stagnation.
"which led married women to retaliate with 2nd-wave feminism in the 60s/70s"
The Female on Male spousal homicide rate decreased sharply in the US over that period.
"The consequences of our currently rapidly ageing population and shrinking birthrates are so potentially terrible"
I don't follow. Is the global population supposed to increase forever? Unless space travel and energy become very cheap, that sounds like it could have a problematic end. A lot of human problems go away if the population is smaller. And that will be even more true as automation replaces the need for manual labor.
"The Female on Male spousal homicide rate decreased sharply in the US over that period"
Homicide rates in general decreased over this period, but this was coincident with large increases in incarceration and also improvements in medical technology (which turn a lot of potential murders into aggravated assaults.) One can plausibly argue that present-day homicide rates would be much higher otherwise.
"I don't follow. Is the global population supposed to increase forever?"
I think you misunderstand. Birth rates are far below replacement levels across much of the developed world at present. (Conversely, if death rates drop to near-zero due to perfect anti-ageing therapies, this actually will cause global population to increase forever unless birth rates drop to near-zero, which will create some of the problems you mention.)
I already mentioned some of the problems with ageing demographics in a previous post, but there's a video on the topic here. Automation can address some of these issues but not others, and relying heavily on automation will arguable exacerbate problems like income inequality and unemployment (moving a shrinking workforce into high-skilled professions assumes that all your workforce can be retrained to do high-skilled jobs, which is rarely true.)
https://www.youtube.com/watch?v=b1IJ9kqBilE
Yes homicide rates decreased in general, but I'm pointing to a trend in spousal homicides apart from that. (Though charts which break out victims by race as well as gender seem to show a different trend, so I'm not certain exactly what's going on.)
http://1.bp.blogspot.com/__cLfPbhhwmw/SfHO8f_AfxI/AAAAAAAAB08/RQY5iaDd4zY/s1600-h/00+Intimate+Homicide.jpg
Do you have a link to the full article? Male intimate homicides declining faster than women's is interesting, but I'm not seeing a comparison with homicide more generally.
I believe this is the original source (results from the National Crime Victimization Survey.) I have not had time to read it, admittedly.
https://bjs.ojp.gov/content/pub/pdf/ipv.pdf
Wow! That's a really interesting statistic. Do you have any theories about what might have caused that?
The obvious explanation is that the new easy availability of divorce meant that women could more easily escape abusive marriages and so weren't driven to kill their husbands in self-defense. (The majority of wife-on-husband homicides are at least claimed to be cases of self-defense against abuse.)
This would match up with the significant decline in suicides by married women in states that liberalized divorce laws.
But the very surprising result that husband-on-wife homicides *didn't* significantly decline to remotely the same extent would seem to argue against this.
Maybe the fact that abused wives are most likely to be murdered *when they attempt to leave* meant that more divorces exerted a counteracting pressure which increased the husband-on-wife homicide rate?
But in that case you would also expect the wife-on-husband homicide rate to increase, if there were an increased number of attempted lethal attacks on wives thwarted by wives killing husbands in self-defense.
It does seem, though, that most cases of abused-wife-on-abusive husband homicide that I've read about aren't self-defense in the narrow sense of fighting off an immediate lethal attack, but more attempts to escape a generally unbearable situation by attacking when the husband is off-guard.
And then one has to consider the striking fact that America is the only country on earth where wives kill (or at least *used* to kill, before the recent divergence you pointed out) husbands at a rate remotely comparable to the rate at which husbands kill wives. The obvious explanation here is that America has more guns and "God made man and woman, Colonel Colt made them equal"--but this utterly unique gender similarity applies even to non-firearm homicides.
Given that societies where wives are proportionately much less likely to kill husbands include both those that are equally or more gender-egalitarian than the US (NW Europe, the rest of the Anglosphere) and those that are less gender-egalitarian (everywhere else), as well as both societies that are less violent overall (Western Europe, the rest of the Anglosphere, East Asia) and those that are more violent overall (Latin America), it seems really hard to come up with a cultural explanation for this.
I don't have that much more to contribute in terms of understanding root causes, except that It seems there's a stark divergence between trends as they apply to black men and caucasian men. Black men saw a decrease in homicide victimization at least comparable to women. With black men removed from the picture, the caucasian male victimization rate is nearly constant from 1976 to 2002, if smoothed out.
https://www.researchgate.net/profile/Susan-Sorenson/publication/7102593/figure/fig1/AS:667181570334750@1536079890729/Intimate-Partner-Homicide-Victims-by-Sex-and-Race-United-States-1976-2002-SOURCE-US.png
None of this is what I would have predicted, so I hesitate to speculate.
Of course, the two graphs give different total victimization rates, such that the two studies must have different definitions of what constitutes 'intimate partner violence.'
I'm not sure I can comment on these trends in more detail, but I will point out there is a mountain of evidence for gender symmetry in domestic violence (despite predominant aggressor policies that assume the opposite and can make it quite risky for men to call police to deal with violent women.)
I think "the problem without a name" -- educated women expected and expecting to be content with running households-- was a major driver behind second wave feminism.
Oh, absolutely! The 1950s was particularly rigid, recovering from WWII, and prompted a backlash. And with appliances and industry replacing a fair bit of housework (who darns their socks these days?) and educated women having fewer children then... yeah. Means, motive, and opportunity. ;-)
There may have been a kind of tipping point, also. Housewives live better lives if there are other stay-at-home parents for them to work and socialize with. Working women do better in the workforce if women working in the workforce is common and some women are in management. So there are probably some collective interests at play as well which could develop to critical mass.
There are perfectly reasonable arguments to be made that some recalibration of gender roles was both feasible and desirable in the wake of the medical and labour-saving innovations of the early-to-mid 20th century, but women's life-satisfaction peaked in the 1970s and has declined steadily ever since despite enormous legislative and economic changes in women's favour.
Feminists have predictably ascribed this to 'increasing awareness of patriarchy' and dismissed a mountain of evidence that, on the average, conservative women, married women, and part-time-working or stay-at-home mothers are happier than liberal, unmarried or full-time-working women. But 80% of women preferring less workforce participation doesn't make GDP go up in the next fiscal quarter.
Source for married women being happier?
I've always heard that, according to surveys, marriage made men happier but women less happy.
Reasonable summary here. I'd expect the picture changes somewhat if you look at how women feel about it at 25 vs. how they feel about it at 60- it's more of a long-term investment strategy than instantly hedonic- and there could be various selection effects going on.
https://ifstudies.org/blog/are-married-people-still-happier
There are some women who just aren't cut out for marriage and kids and conversely there are some women who positively love kids from day 1, but that doesn't mean you can't formulate policy based on averages.
>I'm less harsh on this intellectual habit than I used to be, given that tinkering with human biology and social relations in particular can have long-term side-effects that no-one predicted. e.g, contraception and abortion paradoxically made it easier for men to keep mistresses, which led married women to retaliate with 2nd-wave feminism in the 60s/70s and was most likely a huge contributor to the soaring divorce/illegitimacy rates we've been seeing ever since.
I'm not certain what caused stage 2 feminism, but it's conspicuous that it caused the 2 income trap. This indicates that the leaders may have not been powerful women, but rather corporations seeking to cheapen labor.
At any rate, to whatever degree birth control contributed to the ideas of powerful people, you have left elitism out of the analysis. It didn't happen because of middle class housewives being unhappy or something.
The two-income-trap is something I have mixed feelings about, since it's probably a real effect and there's no question that short-sighted economic minmaxing pressures have a huge effect here (aside from supplying corporate labour, women also contribute much more to luxury goods consumption than men do.) At the same time, the only way around those pressures is to bar women from the workforce, which feels a bit procrustean.
I think Nancy Lebovitz pointed out in a nearby comment that educated women wanting to have some career outside the household was probably another factor once infant mortality reductions and labor-saving devices made it practicable. It's just that Moloch keeps eating our fertility to make GDP go up.
Yes, that was me.
_Sex and Destiny_ by Germaine Greer may be of interest. It's about Family-centered cultures compared to commercial cultures, and part of her point was that commercial cultures pull labor out of families.
She spent some time among Italian peasants and was very favorably impressed. If you read with attention, you'll find some drawbacks to Family cultures. If your Family is bad, you have no alternatives. Barren women are badly treated.
Still, I'm wondering whether part of what's happening in the modern world is damaging institutions which work well some of the time to protect people against the failure modes of their institutions.
No system is perfect, but I think the modern welfare state and some attention to individual variation would compensate for the drawbacks you mention. But I think it's pretty hard to refute the idea that some reversion to family norms is going to be needed to keep our societies sustainable, unless those anti-ageing therapies kick in in a big way.
The welfare state is based on the premise that systems are better than personal loyalty. Is this sustainable for the long haul? Damned if I know.
"This indicates that the leaders may have not been powerful women, but rather corporations seeking to cheapen labor. "
Why not both? Movements are a confluence of interests. There were plenty of midwestern housewives who wanted careers and independence. It's not like 2nd wave feminists don't exist. I've talked to them. Haven't you? The fact that some of their interests matched up with corporate interests likely made the movement much more likely to succeed.
Results and intentions are different things, in any case. I don't think that we can say "because the War on Drugs was disproportionately harmful to African Americans then that means no powerful African Americans advocated for it." African American leaders did support the War on Drugs and then saw their communities bitten by that movement.
My impression is that the war on drugs as it pertains to afro-american neighbourhoods is one of those problems where you have to dig through multiple levels of cynical obfuscation to get at anything like the truth, but roughly, it's a chicken-and-egg situation where residents who mistrust and fear the police (and/or can be intimidated by local drug gangs- "snitches get stitches") refuse to cooperate with the justice system, which makes the justice system malfunction, which in turn prompts the police to get creative about securing arrests and convictions (in which respect the somewhat flexible application of US drug law is, ah, helpful.) And around it goes.
This particularly generates mistrust when residents see people being locked up over relatively minor drug offences while murder and rape cases go unsolved. (In reality, many of the perps being put away for drug offences are in fact responsible for murders and rapes, and the police often have reasonable evidence to this effect, but it's easier to make a drug charge stick than a murder charge, and the former can get perps off the streets long enough to break up criminal orgs and buy a few months of peace before some other drug gang emerges to fill the gap in the market.)
Liberals often complain that these drug laws were formulated in order to artificially increase arrest rates in black neighbourhoods and that black americans are much more likely to be put away for drug offences despite similar levels of drug use compared with whites- in a sense this is true, but it glosses over the fact that whites can sell drugs to eachother without committing murder at 5 times the national average (even in desperately poor areas like white appalachia.) The squeaky wheel gets the grease.
Another popular suggestion is to just legalise drugs entirely, but the truth is that the social effects this change in legislation would have are deeply uncertain. No-one really knows what percentage of violent crimes are prevented by using drug laws to periodically sweep gang members off the streets vs. what percentage of violent crime would be prevented if the black-market drug trade didn't funnel so much money in the direction of criminals. The results could be net positive, net negative, or a complete wash (setting aside the possible effects of drugs themselves being more easily available.)
Failing that, your options are (A) massively improve equipment, training and manpower available to police, and focus on both street presence, witness protection and prosecuting murders and other serious crimes, which will probably require federal funding since a lot of these cities are skint broke, (B) identify individuals with a high risk of violence (i.e, psychopaths) early in life and use some combination of diagnosis and monitoring to minimise their criminal entanglements, (C) create stable, respectably-paying jobs that don't require advanced academic skills so that non-psychopaths are less tempted by the money in crime and less like to use drugs to self-medicate depression, and (D) start taking anti-dysgenic policies seriously, because that's likely to be an accumulating problems over multiple generations (gene therapies, sperm banks, project prevention, middle-to-upper-class fertility incentives, et cetera.)
But of course, none of this will happen as long as the right's only acceptable response is By Your Bootstraps and the left's only acceptable response is Education Conquers All.
> so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
This is how the trolley problem worked for self-driving cars. Something that would hardly ever come up in the real world, and if it did there was an obvious solution[1], but millions of man-hours wasted on it.
[1] the solution is "hit the brakes and hope for the best"
Yeah, so far as self-driving cars are concerned I'd agree. "Drive slowly enough to not hit people in the first place" is what they'll effectively be obliged to do regardless.
bonus "don't make vehicles that are so heavy that they can kill people on impact".
Well that's a total non-starter, it's not like the mass of cars is ballast, it's necessary for them to function. Altering bonnet shapes to make pedestrian collisions less fatal is definitely an area worth investigating thoroughly, though.
You could make cars lighter. Particularly if there were regulations requiring cars to be lighter, so that you didn't try to be extra heavy to protect your occupants from the even heavier other vehicles ramming into you.
> "Drive slowly enough to not hit people in the first place" is what they'll effectively be obliged to do regardless.
I doubt it. If we cared enough about that outcome, we'd already be requiring people to do it. The speed limit shows the places we do care: school zones have very low speed limits comparatively.
I think the current default is sensible in principle - cars are required to drive slowly and cautiously near pedestrian crossings, and pedestrians are otherwise assumed to stay out of the road. Children can't be assumed to behave sensibly, and so roads with many children expected have lower limits.
Now, as to the actual detail, car braking technology has improved dramatically over the last decades but speed limits have tended to go down, and (at least where I live) speeding fines are a substantial source of revenue for the state government... One begins to suspect that safety is no longer the sole or even primary motivator.
> More generally, I'm furious at the many bio-ethicists who are complicit in the game where something bothers ppl in the population but it doesn't seem like a coherent worry so the bio-ethicists compete to see who can offer a theory of why that worry should be taken seriously.
I think anti-aging people should be silent about their focus on curing aging, and instead point to the symptoms directly. Population is... bad... enough to be anti-anti-aging once there's hope of actually solving the problem IMO.
Bioethicists are downstream from that common-meme bullshit.
> fear that we won't get to find out promptly (read: while I could benefit)
The National Lampoon did a bit in 1970 about Science being on the verge of solving all the ills of aging. Not in time for their readers - presumably teens and twenty somethings - of course.
I guess that satirical prediction didn’t pan out.
I've never understood this argument. A cure for aging would cure all aging related diseases and would be approved easily. Statins had an easy path to approval for just putting a small dent in one aging related disease. The FDA is terrible, but it's not the bottleneck in curing aging.
There is something repellent about the idea of professional ethicists, bio- or otherwise. A biologist who cares a lot about being ethical ? -- sure, I love that guy. But someone who calls himself a bio-ethicist? Seems like making a career out of claiming the moral high ground. Prigs.
Bioethics is just a name for a particular kind of philosophical ethics concerned primarily with the human body, medicine, and biology.
Mostly, they’re not claiming any moral high ground. Like all ethicists, they’re just trying to think through difficult moral dilemma’s and determine the optimal outcome.
We all engage in bioethics. Abortion is a bioethical debate. So is human experimentation, or the FDA approval process, or the COVID vaccine.
I think bio-ethicists specialize in "this why people shouldn't have what they want" without considering that what people want might have some good points.
Longer healthy lives, threat or menace?
I think it's spelled "resveratrol."
Yes!
Fix it, Scott, before it spreads! :P "Resveratrol"!
Yup
'Reservatrol' is my new app for helping social media celebs find a better class of troll 👹😅
That weirdly sounds like a viable idea, although recruiting high-quality trolls might be challenging (how do you know they're not trolling you with their applications?).
This is clearly the first hurdle in the interview process. Seems like a winning strategy is to let all the extreme ones through.
Amazon is reputable. They can have MTroll. It'll be an easy spinoff of MTurk
https://www.mturk.com/
> using what template?
Show me a hundred copies of a string with a random error and I tell you the original.
Hmmm, Hamming codes (et al) for the genome... coding theory could be valuable for anti-aging, if this shakes out. Shame I don't really know any.
Look, you just take the most common DNA letter at every place. If there were enough random errors to make that come out wrong you'd be a puddle of goo.
But there's no mechanism that allows a hundred cells to pool all their DNA together and compare them. How does a cell know what to repair when the nearest reference copies are locked behind two layers of membranes?
My original comment was a reply to the "using what template?" in the section about DNA.
I'm vaguely aware of methods to allow far fewer checks than one might expect to obtain very good accuracy. Of course, that does nothing about the *physical* problem
Stem cell potential declines with age even with induced pluripotent stem cells. The right thing to do if you're paranoid about this is freeze some of yours ASAP, like some people do with umbilical cord, and then take the most common DNA on a base pair basis *there*
If you're going to be paranoid about what parts of yourself are irretrievably lost to time, don't freeze cells that can be deduced later, keep a diary.
You take a hundred samples from the patient, sequence a hundred DNAs, and custom-synthesize your treatment to restore that template.
This essentially already how your cells repair their own dna damage.
I have a lot to respond here, but don't have time to write a full response tonight, so here's a shorter one. I might revisit this later.
David Sinclair is definitely a hype machine, but some of what he's hyping might actually work. Resveratrol is not one of those things (pharmacologically it sucks), but partial epigenetic reprogramming (with OCT4/SOX2/KLF4 or other transcription factors) is. In particular there was a very cool paper recently about restoring vision in aged mice: https://www.nature.com/articles/s41586-020-2975-4
Anyway, I'll believe he can reverse aging when he shows me a 5 year old mouse.
Also, messing with mTOR is generally not worth the side effects.
I think messing with mTOR will be necessary, but not by simply down-regulating it. Rather, we need to strategically break links in the entangling of the mTOR and FOXO3a networks, and add ways we can turn subsets of both networks on and off ourselves.
The mTOR network activates mostly things that take lots of energy, like growing, reproducing, and fighting off disease. The FOXO network activates mostly defensive things. It's very hard for genes deep inside your body to know what's going on outside, and evolution likes to accrete things onto existing systems, and bistable switching systems are simpler and more stable than tristable or multiple switches. So we have dozens of major functions whose activation have all been dumbed down to "energy high => mTOR active" vs "energy low => FOXO3 active". We have to turn on all the energy-wasting, damage-producing mTOR systems every time we need any one of them, AND to turn off lots of repair and stress-resistance systems. And we have to turn off fun things like growth and libido every time we need to activate any FOXO3 system. It's a dumb design. We'd probably win a lot of lifespan if we could switch some things on and off ourselves, say by ingesting a chemical that will flip a genetically-engineered regulator on or off, instead of flip-flopping the whole network.
Thoughts on NMN?
It's very safe (unlike rapamycin), but benefits (if any) are likely small.
I get the impression that mice are really weird, and most of the things that work on mice don't work on large mammals. Is anyone trying these things on animals which are a closer analogue to humans? (I realise of course that sitting around for fifty years waiting for chimpanzees to die of old age isn't really a convenient experiment either.)
I mean, one obvious problem with the mouse argument is that mice probably haven't evolved to have long lifespans to begin with, whereas humans have. So it's possible many of the things we "fix" in mice are things that are already fixed in humans.
Have we really evolved to have long lifespans? Or are we just better at not dying? Evolution didn't really fix us; we did that ourselves. We stopped dying from polio, fever, parasites, appendictitis, and even kidney failure, and no genes are responsible for that. The fact that we get decrepit and senile in our old age suggests that if anything, evolution *doesn't* want us to have a long life.
I think it's more likely that smaller animals are more vulnerable to aging. All the damage of aging accumulates in small bodies at the same rate as large bodies, so it catches up with them far sooner.
The natural, ancestral environment human lifespan is one of the longest lifespan in the animal kingdom, a record that stands even when compared to all now-extinct life. Most animals do not live to 30. Hunter gatherers frequently lived to 70.
Considering our children are not capable of caring for themselves till multiple generations of mice have died, I think we can say we've evolved to live long.
Note also that people happily lived the best part of a century throughout history (and got senile). It was less frequent due to illnesses but the underlying point that a human who stays healthy to that point can easily live over three quarters of a century suggests we did evolve to allow long lives. Evolution probably optimised surviving to a younger age (past childhood, to the grandparent stage maybe) but it therefore allowed a long lifetime.
As for senility, elderly dogs and cats get this, at a much younger age than humans (including the breeds of dog that are as large as people), which suggests it's a common late-life failure mode in mammals living beyond their prime. It's probably not evolved so much as not been evolved away as so few mammals at that stage of life have children that there's no real evolutionary driver to not be senile.
I thought our children aren't capable of caring for themselves because if they gestated to when they would be, they'd no longer fit through the birth canal. We've evolved to have unusally long childhoods, sure, but I don't think that's the same thing as evolving an unusually long lifespan.
Senility in large dogs is a fair point, but I'm more curious to aging in similar primates. Chimps live to 50-60 years in captivity, with the oldest living chimp being about 77, which is not that much different from humans. Did the same evolutionary pressures apply to them, or did we further evolve to get that 10-20 years extra?
According to project chimps, for chimpanzees in captivity the mean life expectancy is only 32.5 years for males and 40.1 years for females.
Apparently, chimpanzees have a pattern of mortality that's distinctly younger than that of all human hunter-gatherer populations except for Pygmies.
This paper argues that abnormally short average lifespans in Pygmies--closer to those seen in chimpanzees than in any other hunter-gatherer group--is what lies behind the selection they faced for early puberty, which in turn led them to stop growing early.
Now, this paper attributes high Pygmy mortality to the greater dangers of their jungle environment--high disease burden and poor nutrition--rather than to any genetic tendency to early senility.
Reading it, I was very curious to learn if Pygmies taken out of the jungle and given a modern Western standard of health care and nutrition would still age faster and die younger than other humans, but they said nothing about that possibility.
Also, Pygmy life expactancies, while much lower than for other hunter-gatherer groups, actually seem pretty comparable to the life expectancies of some pre-modern agricultural populations that faced extremely poor nutrition and high disease burdens--and yet none of these populations underwent anything like the same selection for early puberty.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2154411/
As I understand it, larger dogs don't live as long as smaller dogs. I don't know about lifespans for different sizes of wild canines.
I believe part of the extended lifespan for children is grandmothers (perhaps especially maternal grandmothers) helping to care for children.
Longer lives are associated with not resembling a prey animal. Large size, communal living, poison, armor, and flight correlate with longevity. Bats are very long-lived for small rodents.
You can't combine all of the longevity factors, but I wouldn't mind some sf about about long-lived flying poisonous communal turtles, maybe on a low gravity planet.
Considering how little care (most?) turtles show their young, could they be communal? Although I have read about a sci-fi amphibian race who like frogs lay and fertilise eggs without sex, and therefore with minimal concern for parenting. They aren't portrayed as having families but rather select factions to join, and I think are suggested to have high childhood mortality. Christopher Nuttall's Ark Royal saga from memory. Do I suppose alternative models of community might apply.
Mammals with a long maturation period tend to have long life spans, because the parents need to be around to raise their offspring long after they're born. Humans have one of the longest maturation periods of any animal out there, if not the longest, hence, we also have evolved to have relatively long lifespans.
It's been tried in monkeys for calorie restriction (less cumbersome than primates but still lots of trouble) https://www.nature.com/articles/ncomms14063 you will notice the effects are much more noticeable for healthspan (morbidiy curve) than lifespan but sample is anyway small
Even if we did manage to avoid people raising fake ethical concerns the problem is that there aren't that many compared to mice, specially when you get to actual primates. We'd have to get everyone to agree on the best experiment (epigenetic? stell cell reprogramming? organ replacing?) and then if something goes wrong and we get a fake conclusion because of some quirk or incomplete experiment that could anchor us away from potentially good solutions
Mammal lifespan is very much a factor of mammal size, plot age and size on a graph and the results are uncanny. All mammals are basically the same system scaled to a different size, at the extremes limited by elements of the circulatory system. Shrews couldn't be any smaller because a heart can only be so small and still be viable; if blue whales were any larger, their aorta couldn't handle the pressure required to maintain bloodflow. Yet both of them (and us humans) over the duration of our lives experience on average the same number of heartbeats!
Is there an actual scientific proof of this? I've vaguely accepted it as true for much of my life, but it is such a just-so fact that I think I'd like to have my willingness to accept the idea bolstered by some actual evidence.
Here's a site that crowdsources people digging through biological documents to verify this. They have 175 species plotted, and humans are by far the biggest outlier.
http://robdunnlab.com/projects/beats-per-life/
I get the impression that mice are peculiarly susceptible to dying of cancer, such that "curing cancer" and "extending lifespan" correspond much more closely in mice than in humans.
A five-year old mouse is still short of reversing aging though it's going in the right direction.
I'd want to see a decrepit 2 year old mouse eventually become a healthy 5 year old. Yes, I know, good security to prevent substitution.
Why did you use 40 and 70 in "If a 70 year old man marries a 40 year old woman.."? I think I'm missing the point and would like to understand.
Oh! Did you mean woman who was not very young either, but still able to have babies?
A 70 year old man plus a 40 year old woman is just about the oldest combination of humans that could plausibly have a baby.
I believe in the book when Sinclair was talking about the Yamanaka factors, he asked the reader to imagine that you start getting into your 40s or 50s and are diagnosed with age. You go in to a clinic for treatment and they use the Yamanaka factors until you become 20 again and you do this over and over. I'm not sure that is possible but that idea got me really excited when reading this book.
I'm interested in taking resveratrol and NMN but I don't really know about this stuff and it seems so speculative. How badly can you hurt yourself with these?
>How badly can you hurt yourself with these?
Resveratrol and NMN are quite safe. Resveratrol doesn't do anything though so I don't recommend it. NMN might so you can take it if you want.
Stay away from rapamycin though, its side effects are too dangerous.
Thank you!
Low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him.
@metaclesus is right. Resveratrol doesn't do much. NMN is safe but upside may be overblow, at least for younger folks. There is only one study that shows lifespan benefits with NR. Some people report feeling anecdotally better on NMN, but it's mostly older folks and could be placebo. You can get a good number of NAD benefits by exercising & fasting instead of taking NMN. It's expensive. That being said, if you wish to experiment with it, it's safe!
Oh and metformin is the other drug that is safe and has healthspan benefits. However, it can blunt increases in muscle mass, not muscle strength, if taking it with exercise.
Isn't it mainly effective for people with metabolic problems? Apart from it being a diabetes drug originally, I've read that the published effects mix a big effect for unhealthy people with minimal effect for the metabolically healthy.
This is based on an n=1 sample, but I take high-dose metformin (2000mg/day) for its alleged lifespan benefits and although I can't make any claims about its effectiveness in that regard, it definitely has some dramatic effects. I've gone down a belt notch without any intentional change in diet and my blood sugar is near the bottom of the normal range, which I think is where you want it to be.
I don't do intermittent fasting but I think if you wanted to, metformin would also make it a lot easier, since you'd get fewer hunger cravings.
It's most commonly used as a Type 2 diabetes drug! The studies that have been done are people above 65 and they showed that those who took metformin had 17% less mortality than healthy people not taking metformin. That being said, it's possible that the healthy 65 year olds could have benefited from it maybe because they weren't as metabolically healthy as a younger person (even though they were "healthy" for their age).
It is an open question whether metformin will be beneficial for people in their 20s, 30s, or 40s specially if they are exercising & metabolically healthy. That being said, I don't think it has side effects, except for blunted gains in muscle mass, not muscle strength!
My next podcast will be with Nir Barzilai who researches on metformin if you're interested in learning more :)
It doesn't seem to be safe for everyone. Digestive problems, I think.
I read Sinclair's book last year, did a bit of research, and started taking NMN daily in sublingual powder form - it's quite cheap and at least harmless. I'm 54, pretty healthy and active, and can report feeling anecdotally better, though that could be a placebo and obviously it will be another few decades before any major positive effects on my mitochondria kick in.
Good to know, Patrick! Yes sounds like a lot of people above 50 seem to anecdotally report more energy on taking NMN. I'm in my 20s and I was taking it, but didn't notice a difference, but who knows! Agreed with you that it's harmless and placebo effect is still strong, so if it's having a benefit that way, so be it :)
I'd be curious to see more studies being done though because so far there is very little data except one study that shows minor lifespan benefits with NR in mice
How much do you take?
> And finally, what’s the worst that could happen? An overly literal friend has a habit of always answering that question with “everyone in the world dies horribly”. But in this case, that’s what happens if we don’t do it. Seems like we have nowhere to go but up!
I am always surprised that there isn't much, much more support for anti-aging research. I'd figure that everyone expects to age and no one wants to. So the government/billionaires/whatever should be showering the research with money. Yet that doesn't seem to be the case.
>billionaires/whatever should be showering the research with money. Yet that doesn't seem to be the case.
It is. https://www.technologyreview.com/2021/09/04/1034364/altos-labs-silicon-valleys-jeff-bezos-milner-bet-living-forever/
I suppose that depends on what you define as 'shower'... For perspective, Jeff Bezos alone is probably spending ~3.7x more per year (~$1b) on 'make rocket go boom' than Altos has raised total ($270m). Or to put it another way, Altos's capital of $0.27b is 0.01% of Jeff Bezos's net worth ($205b?).
That's 0.1%, not 0.01%, though still small!
I think the key issue is that we know how to make rockets go to space, but so far are pretty iffy on anti-aging (and cancer, for that matter.) One could reasonably assume that we are not close to the "shower money on it and it will happen faster" state for those things yet. Medicine, at least, seems to be one of those fields where you can't spent 9x as much and get results 9x faster.
Perhaps it doesn't look like it as much from the outside, but as a cancer researcher, I would say that not only do we know a lot about cancer, but we've used that information to dramatically improve treatment (and in many cases cures) for cancer over the past half-century. Despite a public perception that there's nothing happening in cancer, we've been making steady progress.
I agree that 9x more spending is probably not going to result in 9x more results, but we are seeing some progress for all the effort we've been putting into the problem. From where I sit, I fully expect that my children will not understand why the idea of cancer was such a scary thing for previous generations.
I don't doubt that you are right. I wonder though how much advancement is a question of more money and more researchers and how much it is just a question of time. The diminishing returns for adding additional researchers (what I assume is happening with more money) seems to have gotten steep, such that adding another researcher is nearly zero value add when it comes to speeding along research. That seems to be the case in just about all fields at the moment, at least on average, but of course that leaves a lot of room for specific fields having a lot better return.
I am just pessimistic on where we are on the "spend money -> get results faster" curve in general when it comes to science, or at least the science that gets funded by NHS, NIH, etc. The quality of research in general is so low that I think money spent realigning incentives is more useful, but then again fixing the incentives in science is probably well beyond what a few really rich people can do.
I agree that basic research needs a complete overhaul. The dilemma you face as a researcher is:
1. Work in an obscure field nobody cares about until you win a Nobel or get kicked out for never doing anything 'important'.
2. Work on the new 'hot topic' and rush to publish.
With strategy (1) you can take your time and do the research right, but you'll never have the money to do so. With strategy (2) taking your time to do the research right will never pay off, because someone will scoop you and get their work published first, or if it was wrong all you'll be able to do is publish a controversial 'corrective' paper that people will be annoyed at you with until they finally accept your careful work demonstrating that people were rushing to judgement. Meanwhile, the person who was willing to rush publication will get accolades and advancement whichever direction the research went. And since the 'careful research' direction isn't viable anyway, they can keep rushing publications for a whole career so that the errors that would have been corrected with careful research just get subsumed into the general morass of the 'replication crisis'.
Not sure what the solution is, but throwing more money at the system isn't likely to fix it. It'll probably just make it worse.
As someone who works on the clinical development side (from a small pharma perspective) I have to say that a lot of the research we might otherwise want to rely on is sloppy at best. Still, there's a lot of careful research being done downstream in the clinic. But clinical development takes years before you get data on each expensive trial. While benchwork gets results much faster at a fraction of the price. If we wanted to accelerate clinical development across the board, we would set high standards for academic research so less bad science got into the clinic before it was corrected.
For $XXX you can make a rocket go to space, and know that it will happen. How much does anti-aging cost? We don't know, because we haven't got anti-aging and the "best" stuff we have is highly speculative and often falls into hype like the author here. If you were 60 years old and had infinite money, how would you spend it on anti-aging? Lots and lots of baseline research projects, I would suppose, but they aren't likely to pan out for many years, if ever. Bezos will likely be dead or too far gone by the time this research (realistically) gets anywhere. If he wants to throw some money into pet projects, which he is, on the off chance that we get a sudden breakthrough, then he's already covered on that. Throwing more money into it at this stage of research is probably just throwing money away.
The rocket analogy to anti-aging would probably be something more like this - For a billion dollars you can take away one year of aging, so a 60 year old can become 20 again by spending $40 billion up front and then $1 billion per year after that (or alternately, remain at a stable age for $1 billion a year but not reverse aging). If such a technology existed, I would bet Bezos would be using it.
Maybe they are, in secret...
I think most Americans oppose anti-aging research. Western religions are based on the fear of death, and we've spent over 2000 years convincing each other that death is good and life is bad, and that society would be ungovernable if people didn't have a life after death to be both hopeful and fearful about. Many important Western philosophers, for instance Plato's Socrates, Jesus, Schopenhauer, Freud, Baudrillard, and Foucault, thought that death is good or desirable. A larger number, plus Buddhism, claim that death is better than life (because life is nothing but suffering).
(Oddly, most Americans also oppose the right to die.)
The NIH and FDA both explicitly oppose anti-aging work. The FDA says aging is not a disease and hence drugs against it can't be approved. The NIH refuses to fund research that targets aging rather than one particular disease of aging (although the National Institute of Aging recently floated these general aging research topics: https://www.nia.nih.gov/research/blog/2021/09/check-out-nias-new-cleared-concepts-aging-research ).
The FDA has approved treatment for Progeria. They don't have any problem with treating aging diseases, you just need to actually be able to define what you're treating.
To define something as a disease, you'd have to actually define what that thing actually is. Aging is ill-defined and may not be one thing; in fact, a lot of theories of aging suggest it is actually many things. This would also explain why trying to fix one thing doesn't result in immortal mice; even if you fix one thing that kills mice, the other thing will kill them instead. You'd have to fix all the things to get an immortal mouse.
I suspect that aging is DNA damage AND epigenetic damage AND fault accumulation AND probably numerous other things added together.
It's not one thing, it's all the things, so you're not going to be able to make a single "anti-aging" treatment, you have to treat each of the parts of it.
If someone developed a drug that, say, greatly reduced harmful mutations, thus acting as preventative for cancer and various other aging-related genetic diseases, I don't think that the FDA would have any problem with approving that; it's no different than a vaccine, in the end.
I am also skeptical of the idea that most Americans would oppose anti-aging research, given how successful various types of fake anti-aging products are financially, and how most Americans are in favor of living longer, healthier lives.
Assuming it doesn't involve eating less french fries, anyway, because really, if it does, what is the point? :V
I'd agree with this. I'm actually moderately optimistic that effective anti-ageing therapies will be developed over the next couple of decades, given that the incentives are so enormous.
The FDA considers progeria a disease, but not aging. It seems likely that a drug which reduced aging would also delay progeria, and thus the drug could be approved for progeria, and legally prescribed for anyone. But it also seems that the chance of your doctor writing you a prescription for that drug to reduce your normal aging would be similar to the chance of your doctor writing you a prescription for a muscular dystrophy drug to help with your bodybuilding, i.e., none.
Well, at that point it depends on your doctor - it's perfectly legal to script a drug off-label.
Re. "I am also skeptical of the idea that most Americans would oppose anti-aging research, given how successful various types of fake anti-aging products are financially, and how most Americans are in favor of living longer, healthier lives."
Well, I'm more confident that most philosophers and bioethicists oppose anti-aging research, and that most people who would be politically activated by a potential cure for aging would be against it.
Recall the book that President Bush 2's "President's Council for Bioethics" published, which mostly warned against trying to improve humans, as being an affront to "human dignity". A country that elected a president that selected a council so firmly opposed to life-enhancement tech can't be very enthusiastic about extending lifespan.
What's amusing to me is the never-addressed glaring contradiction between thinking that life is bad, and having children is one of the loftiest acts of virtue. The one in which you condemn the person you're supposed to care about the most to a lifetime of suffering.
It's not a glaring contradiction at all. Most people who have children (me among them) think life is worth living on net, or at least lives similar to our own, but only *conditional on it having an end*.
There's no more contradiction in this than "I like movies, which tell a coherent story that ends, more than Spider-Man comics, which have decades long incoherent serial nonsense".
You may not agree, and that's fine, but it's not a hard position to understand, or contradictory or even obviously wrong. It is a *preference* for a certain kind of life story.
I don't disagree in the sense that involuntary immortality would be much worse than inevitability of death. However, being able to determine its time and the manner without the certainty of eventual decrepitude would be much preferable to me (and to the vast majority of people I'm pretty sure). Of course, all evidence points to the universe not caring about our preferences whatsoever, and the prospects of this changing remain dim.
Your summary of the religious position is too simplistic, so you're missing why the nuance can exist and the contradictions aren't contradictions.
Life includes suffering, and inevitably will. If you stopped aging, you would still die in car crashes and have heart attacks from high cholesterol. Living forever (and still enjoying life, rather than living in a bubble for safety) is a worthless pipe dream and always will be. Hedonism offers no worthwhile benefit, only the appearance of worth on a short timeframe. People will get tired of hedonism the same way they get tired of anything else. By attempting to fulfill temporary and ultimately meaningless objectives, you only end up with false hope and growing frustration as you continue to seek out new and more exciting alternatives.
The only things that really matter and provide real value are our relationships with other people, and even more so with the eternal God. Death, and aging itself, are benefits because they encourage us to build those relationships and value the relationships over the material. Having children is a matter of creating social bonds and exemplifying the ideal of relationships. Never existing isn't a help, because there are real things that exist and that are good - those relationships. Material accumulation or hedonistic pleasure, on the other hand, are not ultimately beneficial. Growing older and dying are catalysts for us to pass along our knowledge, positions, and wealth to the new generations, building relationships with the new as we transition out of life. Take those things away, and there's no reason to interact with young people and create relationships (or have children), leading to an inevitable stagnation and endless hedonistic pursuits that will never actually solve our problems or bring us peace. We'll become more and more frustrated by the pains we still experience, losing the calmness and peace that comes from accepting our inevitable death and living a life that promotes others instead of running that hedonistic treadmill.
I wasn't summarizing "the religious position". I listed specific philosophers and one specific religion, which all specifically said death is better than life, or death is desirable. As in repeatedly writing "All life is suffering", and telling people the greatest thing they could possibly hope for is real death, as Buddhism does, and as many Western philosophers have done. I think I could have listed all the existentialists as well, but I didn't because I haven't recorded specific quotes by them on the topic.
(In the case of Jesus, death is better than life only for /some/ people. Although actually it's difficult to know now when he was talking about an afterlife, and when he was talking about a kingdom on Earth. He, or his followers, weren't interested in differentiating the two.)
> Life includes suffering, and inevitably will.
Sure, but there can be more suffering or less suffering, and less suffering is better. Without this assumption, many things we do would not make sense, for example medicine in general.
> People will get tired of hedonism the same way they get tired of anything else.
Then I'd leave it for them to find a hobby, or perhaps kill themselves.
> our relationships with other people
Which are sometimes interrupted by those people dying.
If death is so good, why don't we make a law to kill everyone when they get 30? (Enough time to have kids and keep the humanity existing. Unless perhaps extinction is also good.) This would be even more awesome than what we have now, wouldn't it?
Those 20 something people could then tell each other wisely sounding scary stories about the horrors of their ancestors living to their 50s or 80s leading utterly meaningless lives full of material accumulation and hedonism.
Logan's Run would be the most famous fictional example of that society, it's an idea that has certainly been explored before. Good point that it's a useful analogy here, much as reading Flatworld helps understand the implications of a 4th dimension
This may be a stupid question: If the FDA doesn't consider aging a disease, couldn't a "dietary supplement" claim to "cure/prevent/slow aging" without needing to be regulated as a drug? That seems better, at least for availability-after-development, although maybe not for getting research funding or profits.
It's a good question. I don't know what chemicals qualify as "dietary supplements", but they do all seem to be natural products. I don't think a chemical not occurring in nature could be sold as a dietary supplement, but I don't know. I do recall a case about 25 years ago, when a wrinkle-removing cosmetic was taken off the market by the FDA with the argument that it must be a drug, not a cosmetic, because it actually removed wrinkles, and therefore was a drug, and therefore had to formally prove to the FDA that it removed wrinkles. I wish I remembered more specifics, but I don't.
Here is a vague FDA policy and a list of dozens of actions against cosmetics:
"if a product is intended to make lines and wrinkles less noticeable, simply by moisturizing the skin, it’s a cosmetic...if a product is intended, for example, to remove wrinkles or increase the skin’s production of collagen, it’s a drug or a medical device."
https://www.fda.gov/cosmetics/cosmetic-products/wrinkle-treatments-and-other-anti-aging-products
https://www.fda.gov/cosmetics/warning-letters-related-cosmetics/warning-letters-address-drug-claims-made-products-marketed-cosmetics
Thanks!
So the FDA guarantees that any wrinkle-removing product we can buy, won't work.
Judaism is clearly in favor of living in a way that Christianity isn't, though Christianity isn't simply pro-death. It's complicated and I don't have all the details.
I read an account of a bio-ethics and longevity conference (probably can't find the link), and the only person in favor was a rabbi.
Christianity thinks of itself as not-anti-life because it's contrasting itself with Manichaeism, purer Platonism, Gnosticism, and other popular philosophies of the 3rd century which said that all physical reality is inherently evil. St. Augustine concluded that physical reality must be *capable* of perfection, because God was incarnated physically. Christian theologians make a big deal of this, but really, the difference between "matter is corrupt 100% of the time" and "there was this one bit of matter 2000 years ago that wasn't corrupt" is not that big.
There's also the "people are fundamentally bad because they want sex" part. This makes the vast majority fundamentally bad.
I really think the primary thing is expectations management. I think people get really upset (or think they will get really upset) if they get their hopes up and end up being disappointed. And so people learn this psychological defense mechanisms to avoid letting their hopes get up in the first place. And this is a problem because if we believe we can't do this thing, we'll never try and so we never will.
The medium matters for the message. A lot of the anti-aging people are social misfits who have blown all their weirdness points already and keep going on about how bad the people who don't support them are.
And normies see them and think "the first people to be immortal are going to be *those* people??"
Some good PR firms would really help with messaging. The major problem is that it involves a lot of the current crew sitting down and being quiet.
Your perspective deeply confuses me.
>A lot of the anti-aging people are social misfits who have blown all their weirdness points already and keep going on about how bad the people who don't support them are.
I don't know anyone like this. Certainly Sinclair isn't like this, he seems extremely normal and I haven't observed an ounce of victim complex from him. The other big name is Aubrey de Gray, who is certainly eccentric and weird but I also haven't observed a victim complex from him.
What I could understand your "going on about how bad the people who don't support them are" could be about, is the criticism that they have for people who don't support anti-aging research at modest levels compared to research into other diseases which have broad support.
>The major problem is that it involves a lot of the current crew sitting down and being quiet.
Again I'm not sure who you are referring to as the "current crew" but again I emphatically don't believe this is the problem. I think the main problem is that most people do not conceive of life extension to be remotely within the realm of realistic scientific progress within our lifetime.
Most anti-aging stuff is a scam. People are rightfully leery of it. Doubly so because we don't actually know what aging is, and my guess is that aging is probably many things.
Billionaires don't have *that* much money to spend. The real money is in the middle class, which has far less money individually, but who number in the hundreds of millions, as opposed to ten to twenty or so.
As it happens, people have a fairly short time horizon on death. When they are actually suffering from a fatal disease -- after the first heart attack, say, or when cancer is diagnosed -- then they will indeed spend a large fraction of their income on trying not to die. So the money available to treat active disease that will predictably lead to death shortly is substantial.
On the other hand, ask your generic 25-year-old whether he would donate 25% of his before tax-income to longevity research -- or have his taxes rise by 50-75% to pay for it -- which is what it would take, not milions but billions of dollars -- and he would laugh. Maybe 0.5-1%, sure. But that won't cut it.
You could certain siphon off a few billions from free daycare or community college, "infrastructure" or refundable tax credits, or any of the other massive wealth-transfer programs the Federal government runs that add up to a trillion or so per year, but I rather suspect the political pushback would be fatal.
>25% of his before tax-income to longevity research -- or have his taxes rise by 50-75% to pay for it -- which is what it would take, not milions but billions of dollars -- and he would laugh. Maybe 0.5-1%, sure. But that won't cut it.
Where does your intuition on these numbers come from? https://www.statista.com/statistics/216928/us-government-revenues-by-category/ says that the US gov collects 1.6T in personal income taxes a year. This https://taxfoundation.org/publications/latest-federal-income-tax-data/ claims that the average tax rate per person is 13.3% of their income. This is shoddy math but hopefully within an order of magnitude correct: 1% additional tax on the average person's income should raise total take by 1/13th, or 7.5%, or $120B.
Let's halve that as a conservative estimate for my lazy math, you don't think $60B a year wouldn't dramatically increase our odds of making good advancement in longevity research (specifically, something like a 25% increase in life expectancy for people with access to such healthcare)?
My impression is that 1% of 13% is 0.13%, so if you raise the average tax bill by 1% you get an extra 0.13% in revenue.
Anyway, if you want 7.5% more revenue, it follows the average tax bill has to rise by 7.5% and yes I rather suspect a lot of people would get crabby about that. Supposedly the average Federal tax bill was around $15,000,so you're talking an extra $1100 a year. I would guess if you went on the hustings and said we're going to raise your taxes by $1000 a year to fund longevity research you might very well get a fair amount of pushback.
"as opposed to ten to twenty or so."
https://www.forbes.com/billionaires/ lists over 2600 billionaires.
This. I'm constantly surprised by how chilled almost everyone is about they fact that they and literally everybody they ever loved are going to die, most likely in pain.
The simplest answer to "Why doesn't the body already do this?" is anti-aging isn't free: it costs resources the body can use on other things, like manufacturing sperm or cogitation or even burning for warmth. Animal lifespan varies based on a lot of things but it tends to be shorter in animals that can expect to die by accident or predators because in those animals there is no evolutionary benefit to adaptations for increased lifespan beyond a certain point. Meanwhile, birds that are the same size as mammals that can be expected to live 3-5 years will live 80 years, because flight and their relative intelligence means birds are much less vulnerable to predators and accidents and local food shortages.
Personally I think Algernon's law is absurd and betrays a lack of attention to the natural world and the constraints of evolution.
I mean, this is just exactly one of the exceptions described here, right? https://www.gwern.net/Drug-heuristics#loopholes It falls under Gwern's exception 3, or Bostrom's exception 1 or 2.
Isn't there a big evolutionary advantage to shorter lifespans, at a point? Natural selection of best fitness works faster when people have a few kids and die, and then their kids select for suitability and have more kids, rather than the same people just popping out effectively the same evolutionary generation forever
There's an evolutionary advantage to having a short time to produce the next generation. There's no advantage to dying early.
Wouldn't having a short time to produce the next generation without dying early result in overpopulation
Overpopulation is a problem for species, not individual genes. Remember: group selection is bunk, scarce resources only makes individuals compete more desperately.
Chiding that we "remember" a progressive dogma? What an odd way to reason through a problem. The above-mentioned flaw in Algernon's Law is near trivially correct, but it will probably take Paige Harden-type gentle coaxing for the larger part of the polite establishment to recover its sense.
...what?
I have literally never heard of anyone say that group selection being bunk is 'progressive dogma'
What are you even referring to?
That's a group selection argument. When someone tried to select for animals that attempt to avoid overpopulation, the result was cannibalizing the children of others. https://www.overcomingbias.com/2007/11/group-selection.html
There's an advantage to not consuming resources past the point of being able to acquire them for your offspring.
People do consume less as they age and become less productive. https://www.econlib.org/archives/2009/10/was_having_kids.html
Evolution doesn't actually favor kids, it favors the more "you" there is around. Living longer effectively generates more "you" as well.
"Evolution doesn't favor kids" is true of individual evolution. It is not true of species evolution(competition among species). Species evolution favors kids in several conflicting ways.
Consider sexual vs. asexual reproduction. With asexual reproduction, the population doubles rapidly but you get less evolution (only from mutations) and less variation of the gene pool. Given two populations 1 reproducing sexually and the other asexually, the asexual one virtually always wins due to reproduction rate and finite resources.
Sexual reproduction is half as fast (2 gametes are needed to create 1), however there is far more genetic variation. This leaves the species more adaptable to changing conditions. Since both of these two reproduction methods coexist(millions of years later), it follows that each has benefits in different scenarios.
Yes but this really isn't "species evolution" though it looks like it to us. IIRC the correct term is "lineage selection." Sounds pedantic, but it is an important distinction.
Yes, I made that up. I guess I should have realized that it had to have an agreed-upon name.
Algernon's law is like the efficient markets hypothesis, where the real world answer is "yes, that's true, except when it's not."
Yes, both of them underestimate the difficulties of finding and trying something new.
It seems like the other relevant dimension here is that we're talking about aging. Evolutionary selection for slowing down aging seems… complicated.
Perhaps slowing down aging increases lifespan, but doesn't affect your younger years. In this case, you've already passed on your genes (or not) before having a longer lifespan matters.
Creatures that die early have little selective advantage in living longer - they're mostly going to die by age one anyway, so what's the point of a gene that helps you live from age 2 to 3?
Living longer is upside, but most creatures can't achieve that. Those that can often do.
Algernon's law is indeed as absurd as the novella that spawned it - a sentimental sci-fi about a dying mouse as I recall... plus Algernon is just a silly name (apologies to any actual Algernons here) hence Wilde
It's a short story, later developed into a novel, called "Flowers for Algernon". There is a mouse in it, but it is notable as the subject of a revolutionary surgical procedure to increase intelligence. The researchers need a human subject, and they find one in Charlie Gordon, a mentally retarded man. The operation works and vastly increases his intelligence, but things don't go well.
As the mouse begins to behave erratically and regress then dies, so Charlie realises the same will happen to him and he loses all his intelligence and ends up as he began.
https://en.wikipedia.org/wiki/Flowers_for_Algernon
Oh yes, it's coming back to me... so would you rather get vastly increased intelligence, but knowing you'll regress to a vegetable after a while, and a mouse will die for you, or continue in your current state of blissful ignorance?
As I recall, he didn't regress to a vegetable, he regressed to his early state of fairly severe retardation.
Precisely. No such thing as a free lunch, but calories are a hell of a lot cheaper than they used to be so there ought to be a lot of very nice lunches out there indeed that modern humans can now afford where once we couldn't.
Only ~1/2 way through. But you haven't mentioned my fav. aging idea. Aging is the response of a multi-cellular organism to cancer. (One cell going crazy and dividing forever.) There is a limit on the number of cell divisions for non-reproductive cells. (most of your body.) When you reach the limit, cells stop dividing and repairing and you get older. The limit stops cancer at least to first order...
aging and cancer are the two sides of the death coin. (in this view)
argh, have you never heard of telomers? I want to say it's hard to read about an idea, alternate from your own.
https://pubmed.ncbi.nlm.nih.gov/11909679/
Right, thanks for the link.
I'm going to be so, so, so upset if aging is conquered a few years after I die, or when I'm in my 80s and it's too late for me, or some such thing.
The cosmic unfairness of it! — I want to live forever (or at least "way longer than current human lifespans", and the same for those I love) more than *anyone else I've ever met*; and I live in a time when the spiritual sort of immortality looks more unlikely than it did when "I dunno; magic?" was the best answer available for "how does any of this work?", but the physical sort looks absolutely possible and likely to happen *someday*...
... and I end up one of the poor bastards trapped without the comfort of an eternal heaven waiting after death, *or* the exhilarating freedom of endless experience stretching out to the cosmic horizon? And the latter could possibly be mine, except we spend our time and resources on frivolities that don't matter at all if you don't have *time*? (— whereas solve aging, and you can have all the frivolity you want... literally! you *can't* have all of anything you want, now, because you're going to become decrepit and die!)
I forgot if I had a point. I think it's just that I'm upset. Interesting book review and I want more like it, though.
Have you considered cryonics?
Maybe being the generation that were born too late to be comforted by religion and too early for science to conquer death, is the way karma finally catches up with Boomers.
I take solace in watching the end of homo sapiens as designed by evolution.
Even if we were born too early, this is a fundamental, species-wide change that will never happen again, and have the front row seats - we can work on it, in fact!
Thanks, this is strangely uplifting. Especially coming from a real dog!
I can guarantee that you will not be upset if anti-aging comes along after you're dead.
It sounds more like you don't feel that you are using your life properly now, and are looking for ways to buy more time so that you can experience what you want while you still can. Might I suggest re-evaluating your life priorities, and how you spend your time now? As someone who you would call very religious, I can vouch for the spiritual lifestyle, even if there were no eternal heaven. There's a peace that comes from not pursuing pointless worldliness, and I would encourage you to check it out.
Unfortunately, no amount of re-evaluating your life priorities and living spiritually can give you extra 1000 years of time... unless anti-aging is somehow involved.
Yes, we should spend the time we have as well as we can, but that it not an argument against wanting more time.
I'm actually making two arguments.
1) You will not enjoy more time if you continue spending it the way you aren't enjoying now. 1a) If you cannot retire or otherwise stop doing what you are required to do now (work, etc.), then you can't change your life as you would want.
and
2) If you are truly happy in how you are living your life, you don't need 1,000 years in order to enjoy it. You can appreciate the days you have, rather than seeking out what you lack.
This doesn't even get into the utility value of Heaven or the reality that even "immortal" people that never age would still die frequently and often unexpectedly - meaning you can't count on that 1,000 years under any circumstances.
I’m not sure what your point is. Whether it’s early retirement or mindful meditation, anything good you can do in a short lifespan can literally be extended and multiplied a hundredfold given a longer lifespan. It doesn’t matter if it’s 10 more years or 100 or 1,000, it is a strict superset.
Conversely, won’t any valid argument that an un-extended life is just as desirable as an extended life, also mean that a life cut short by disease is just as desirable as a life that isn’t?
Yes. None of us live very long in terms of human history, let alone geological history. That someone might live a few more years than another person matters far less than the quality of their lives. A well-lived life to age 60 is far better than a poor life to 80. Adding 20 more years to that poor life probably makes things worse!
You might not be a big fan a patriotism, but many countries, the US heavily among them, celebrate the death of young soldiers - not because of the death, but because of the purpose of their lives. And this is not just Army propaganda garbage, but genuine grass roots feelings of individuals, including the relatives of people who died in military service. Death in self-sacrificial ways is often considered a major positive, even if the death itself is also considered sad.
There is a side concern about how human relationships are affected by an "early" death. Someone with small children and a spouse that depends on them dying is a different kind of situation than someone who lives alone (all else equal).
As someone who is truly happy with how ve is leading vis life right now: Yes, of course I would like to have more of it! Why wouldn't I?
Of course that doesn't diminish the fact I'm enjoying it now and it doesn't make it a "need", any more than someone who dies abruptly (e.g. due to a traffic accident) in their mid-teens and had a great childhood "needed" to reach adulthood, but it's still a shame to just... stop after a few decades, for no reason than that some decades have passed? It seems like a lot of wasted potential and a lot of unrealised happiness to me.
I'm fine with only giving longevity to people who want it and think it will help them, there's certainly no need to force it on anyone, but why withhold it altogether? The argument to me sounds like "it makes no sense for this subgroup to have it, so let's not have it at all", but you probably don't actually mean that - or do you?
(And this is completely side-stepping the part where aging itself is a really unpleasant process. I'm healthy and in my mid-thirties, but this is still qualitatively different from a decade and a half ago, and I'm not looking forward to the presently inevitable further deterioration.)
I guess my main thought is that we would not enjoy immortality very much at all, and would inevitably run into the same problems we have and just grow more discontent with it all. Some others have made comments in line with my thinking regarding fear of danger, lack of purpose, delayed maturity, and other issues.
I wouldn't try to keep anyone from taking a treatment that made them (potentially) live longer. I am trying to add a different perspective about life, and help people realize that the happiness they think they could get from immortality, but don't have now, is very unlikely to materialize. This seems even more important to me, given that there isn't an immortality option and I'm responding to someone (OP) that seems to think they need immortality in order to reach happiness. It isn't true, and he would be better off if he could find a more suitable path to his own goals on a timetable that actually works for him.
Thanks for the response. That's fair and an entirely reasonable position to have; apologies for misunderstanding the point you were trying to make. I do admittedly disagree with your first paragraph quite strongly (as in, I do think we would enjoy immortality - I don't think it would be a panacea for happiness, not at all, but I think it would be a very strong net gain even just to erase the suffering of aging), but I understand your position better now and thank you for going out of your way to explain it a little more.
There are things I think I would like about immortality-- one is getting better at things.
And let me tell you, aging is starting to have an effect and it's bad even though I don't have a very bad case of it.
You seem to be arguing against the idea that immortality will make life completely wonderful. I'm sure there are people who believe that, but you don't have to have any such delusions to want immortality.
Why do you think OP is not enjoying their life? "I want more of X, much more! - Oh, that just means you're not enjoying X you have" is exactly the opposite of how we reason about everything else.
I find contentment in my daily life, which is much more satisfying for me than when I sought endless earthly experiences. I used to daydream of being immortal a lot, and was very concerned with a feeling of dread about growing older and eventually dying. It caused me a lot of worry, similar to what the OP is saying. But I am getting older, and frankly that's okay. I can't say that all of the experiences of aging are super awesome, but they are no longer overwhelming, because my priorities no longer require that I live forever to meet some crazy expectations for my life. As I have come to accept the reality of life, I see much more clearly the futility of my previous perspective. Even if I were to stop aging or become 25 again, that doesn't solve any of the underlying issues - partly because there will always be problems and frustrations (including death) and partly because material pursuits are endless.
Well, never aspire to anything beyond what you already have is certainly one way to reduce negative emotions, but not everybody's ultimate goal in life is to minimize negative emotions.
And in any case I'm not sure how any of this answers my question, you seem to be just projecting your experiences on the OP.
I personally believe immortality to be overrated. Considering that one needs to constantly forget quite a bit to remain sane (we couldn't possibly remember every moment so vividly as to be able to relive them on demand and still be attached to the moment), our lives are a slow rolling cycle of rebirth anyways. Even so we accumulate mental clutter that weighs us down -- you're only young once.
I say it's better to do a hard reset every once in a while, and start from scratch, except with the added benefit of leaving behind all your worst qualities and replacing them with the best parts of the person you love even more than yourself. I think having kids is a preferrable alternative to living forever.
> leaving behind all your worst qualities and replacing them with the best parts of the person you love even more than yourself
This is romanticizing well past the point of misleading yourself. If this were the case, every generation would be significantly better than the generation previous.
Having children is great, I'm sure your kids bring you endless joy, but this kind of romanticism sounds like flinching away from the uncomfortable truth that without a bunch of technological progress you're going to die (literally, not figuratively) in just a few dozen years.
So if you could live to 150 would you make kids and off yourself at 80?
My favourite human biology fact, the most mind blowing to me, is the fact that if you live to be 100, your odds of surviving to 110 are 0.1% (source https://en.wikipedia.org/wiki/Supercentenarian) . Human bodies just disintegrate at that point. It's also amazing, when you think about, that the world's oldest woman only lived 1.5x as a long as the average woman in a developed country. Whatever one thinks about Sinclair, it's amazing how strong the barrier is to exceptionally long life and more people need to be studying this.
I'm always amazed by how people can like Ivan more than Dmitri!!
I'm okay with Team Alyosha, but Dmitri? Really??
No seriously, I remember Dmitri as a drunken lout Alyosha was always trying to clean up after. Meanwhile Ivan was above it all, having interesting conversations with Satan.
+1 team Ivan
I think I read the following somewhere: "when I was young, I thought I was like Ivan. However, the older I got, the more I realized how we all really are Dmitris". This rings true in many ways to me.
It's an interesting point, but almost why I don't like him. It's not that I think I'm Ivan per se, it's that Ivan, Alyosha and even Smerdyakov were each exceptional in some way while Dmitri was just a person of normal appetites and below average self-control. Hence he's the least memorable brother.
I chose the pseudonym partly just out of Russophilia, and partly because Ivan's propensity for intellectual exploration seemed right for this blog. Ivan would read ASX.
I think the main argument in favour of Dmitri is that he was living his life to the fullest in a certain sense.
That's true, and it seems to go very much against the "humans are like cars" idea. The lifespan distribution of cars looks totally unlike that of humans.
The lifetime distribution of humans looks more like the lifetime distribution of Oscars speeches. Some end awkwardly early, some end right on time, and a few go over time but are quickly cut off by the producers.
The start of the human death increase looks like a bell curve, it just has a much steeper slope on the far side. So it seems to be semi-normally distributed, but it's harder to go long than it is to go short.
One obvious reason for this is that only one thing has to actually kill you, so as you get older, the odds of having more than one potentially fatal problem goes up.
> My favourite human biology fact, the most mind blowing to me, is the fact that if you live to be 100, your odds of surviving to 110 are 0.1%
I wonder why, through. What's the barrier? We can mechanically replace many organs. Wouldn't it work to just keep supplying the brain with oxygenated blood with necessary nutrients? What causes death then, if you subtract rest of the organism away?
When in doubt, check the manual:
> And the Lord said, My spirit shall not always strive with man, for that he also is flesh: yet his days shall be an hundred and twenty years.
Genesis 6:3
Oldest human ever was over 122 years old.
The context in which this verse is given seems to make it clear that God is saying he will flood the earth in 120 years from that time, not that humans will only live to 120 years. So Noah had lots of time to prepare for the flood.
Even if that were true, I'd give a lot to be young and healthy until my 120th birthday, an age which practically no-one comes close to.
This is the key question to me on Sinclair's hypothesis. Surely the amount of epigenetic damage that people undergo varies widely by large factors and so there should be individuals who survive much longer than other individuals, but that's not what we see, most people die around the same age. And dogs for instance die much younger than us, but why would their epigenetic harm be so much more aggressive than ours? Their environment is very similar to ours. This to me is strong evidence that animals have an active system trying to kill them, like planned obsolesce rather than just wearing out. The most plausible theory as to why we have this I have heard is that it is about parasites. The longer you live the more parasites you attract. Eventually most of the soma is no longer about reproducing the original genes but supporting the replication of parasitic genes, which is obviously bad for the original genes. As evolution will work to prioritise the survival of genes, not the soma survival, the best approach is for the genes to be periodically placed in new, parasite free soma, and to kill off the previous soma to avoid competition for resources from that old soma which is now largely parasitic. As well as avoiding resource completion, this means the old soma parasites are also prevented from infecting the new soma. I think this might be why we see visible signs of ageing in older people, a signal to the young to avoid the icky parasites.
I believe the parasite theory is now largely accepted as to why there is sex, so definitely it can provide strong evolutionary pressures.
If it is true that we have a system activity trying to kill us because it is better for reproduction, this means Algernon's law doesn't apply to this situation. If we can turn it off then this is bad for new soma, but good for the old. I really don't care if after 200 years I can no longer reproduce my genes.
The basic concept of Algernon's law has always bothered me. I don't think it actually holds much water, at least, not in the way that it's commonly used. The human body may well be perfectly optimized for our hunter gatherer lifestyles of the past, but that has very little bearing on how well optimized it is for today. We used to have very real energy input constraints, and that meant the availability of food was a major factor in the objective function our bodies were optimizing for. That constraint is effectively gone today. There may be quite a few biochemical switches that are tuned for energy scarcity that we could easily dial way up/down without harm, and without any real contradiction to Algernon's law.
Similarly, aging and decay are potentially epiphenomena of gene progression. Nature isn't optimizing for immortality of individuals, its optimizing for immortality *of genes*, which it achieves just fine by killing you after you've had your kids. There is no reason to think evolution tried and failed to make us immortal, and therefore no strong a priori reason to think that there shouldn't be low hanging fruit in that domain.
> Nature isn't optimizing for immortality of individuals, its optimizing for immortality *of genes*, which it achieves just fine by killing you after you've had your kids.
Interesting framing! I completely agree that genes ultimately only optimize for their own propagation, not necessarily the longevity of their carriers -- but the phrase "after you've had your kids" seems to smuggle in the assumption that there is necessarily a fertile period that stops at some point. Wouldn't you expect evolution to, all else equal, favor genes that encourage longer reproductive periods in their carriers?
Example: if a new allele slowed aging-related deterioration by 0.1% and had no downsides, its carriers would have more children than competing alleles', and it'd probably reach fixation. And this would keep happening until there were no more low-hanging, tradeoff-free longevity fruit to pick.
> but the phrase "after you've had your kids" seems to smuggle in the assumption that there is necessarily a fertile period that stops at some point. Wouldn't you expect evolution to, all else equal, favor genes that encourage longer reproductive periods in their carriers?
You're right, and I should have clarified this further. I think the fully spelled out logic goes something like this:
Let's say that the energy required to maintain perfect health is a linear function of age. This would mean that at a certain age the aggregate utility of an elderly person declines below that of their offspring. Under such a scenario, it's clear that under energy scarcity senescence makes sense.
It obviously doesn't even have to be as extreme as a linearly increasing function. It could even plateau at some point. Like, let's say the energy cost to live a normal human year is 100, but the energy cost to live that same year while also repairing any accumulated damage is 120. The evolutionarily optimal strategy is not necessarily to spend the 120, even if that 120 is available in the environment. The tribe that chooses to spend 20% extra energy hunting more, or fighting better is going to outcompete the immortal tribe*.
We can certainly imagine countervailing factors like accumulated knowledge operating in favor of the immortals. But that makes it then just a question of what the parameters of the model are, which is exactly the point. The point being that there are many parameterizations of the evolutionary function for which Algernon's law (as its used here) does not hold.
*That* being said, I do think there is a better version of Algernon's law that is legitimate. Which is that there should be no easy optimizations to the human body that don't consume more energy, or otherwise disrupt competitiveness in a primitive context.
Great comment. To add to it, I think that for human societies to function, and for the genes of the individuals who make up those groups to propagate, the "generational rhythm" is important. As the young come of age, the old must make way for them, or risk societal unrest which can pose an existential risk.
You can't have ambitious and energetic young people if you have adults that remain ambitious and energetic for many decades, long enough to breed multiple generations of more ambitious and energetic young people; you would end up with far too many pretenders for far too few crowns.
Human biology acts as a great stabilizing force: as our children grow up and start asserting themselves, we have aged enough to become just weary enough to be glad there's someone else to help shoulder the burden, instead of being threatened by them. The common theme of epic tragedies are parents who outlive their welcome, and children who grow old without the space to grow up.
> Which is that there should be no easy optimizations to the human body that don't consume more energy
Arguably, people would be in favour of this outcome because we're also in the midst of an obesity epidemic.
If the mTOR thing works as well as research suggests, if anything the _lack_ of food scarcity is working to our detriment.
Also, Algernon's Law is trivially defeated by examining the recurrent laryngeal nerve in humans, or if one is still not convinced, in giraffes.
"There is no reason to think evolution tried and failed to make us immortal, and therefore no strong a priori reason to think that there shouldn't be low hanging fruit in that domain."
I knew someone would've made this point in the comment section. Thank you for making it. :)
This was entertaining. But can we please get Mantic Mondays back?
Weren't there Mantic Mondays last monday (11/29) and two mondays prior (11/15)?
https://astralcodexten.substack.com/p/mm-omicron-variant
https://astralcodexten.substack.com/p/mantic-monday-1115
Ah I for some reason assumed it was a weekly thing, and not bi-weekly.
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant."
This seem incorrect, due to dosage effects. The doses that organ-transplant recipients use are much higher than those used for longevity purpose. There is even some evidence that rapamycin enhances immunity at lower doses. Here's some further discussion with references: https://peterattiamd.com/rapamycin-risks/
Agreed with you! Low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him.
Yes, in fact there was a human study where they used lower doses of rapamacyn (and some other mTOR inhibitor which is basically its analogue) to improve vaccine response in elderly people and it worked https://www.sciencealert.com/rapamycin-mtor-inhibitors-human-trial-boosts-immunity-elderly So rapamacyn can even improve immune response at some doses.
The other thing going on which kicks in after the 30-40% improvement is telomere shortening, making more and more cells senescent. This is also something which might have an easy fix once you solve the “all kinds of cancers” problem.
I want nanobots that go around removing senescent cells, cancer cells, arterial plaques, aggregates, unfriendly bacteria, etc. Like an artificial immune system that is way better than the natural one. That could extend lifespan by a lot, even before you program it to mess with Yamanaka factors.
Why not patch the existing fleet of nanobots instead?
"Cure aging, and the whole concept of life expectancy goes out the window" I am surprised at this comment - I would've thought it's obvious it doesn't. At 70, the probability of dying in the next year is slightly under 2% (albeit substantially higher for men than women). If you could stop aging at 70, then you'd have a 50-50 chance of living until 104. (0.98^34 is about 0.5) What if we could roll back aging to 21? 21 year olds have around a 0.08% chance of dying in a given year. That means you'd have a 50-50 chance of living to about 850 years old. (0.999167^950 is about 0.5) That's barely into the biblical lifespan territory. (Source of actuarial info: https://www.ssa.gov/oact/STATS/table4c6.html)
^950 should be ^830, sorry.
The distribution would have an expected value, but it would be a very different distribution--specifically, an exponential one. The self-similarity means that if your expected lifespan at birth was 1000, then your expected lifespan at age 500 would be 1500, and at 100 would be 2000, and at 2000 would be 3000, and so on. There wouldn't be the idea that "everyone dies by age X" anymore.
Even though the distribution is different, almost everyone would die by a certain age.
Your framing of the situation as "if you survive to X, you will expect to survive Y%
longer" is interesting. I imagine that life extension enthusiasts in general think of it
that way, but I see it as a cognitive distortion.
Being ageless is equated with being immortal, because accidents don't seem inevitable.
To me, though, they seem even more inevitable than aging.
I agree with an exponential model. My equation is simply "<years> = log <total survival rate> divided by log <one year survival rate>" - the latter being 99.9167%, give or take.
So, as I wrote, ageless people of the future might have a life expectancy at birth of
under 1,000 years.
After about 5,500 years, only 1% would still be alive.
After about 27,400 years, only one person out of 7.9 billion would be alive.
So people would live around 10 to 200 times as long as now.
Maybe that sounds fine, but to me, it means life wouldn't be fundamentally different. We wouldn't get to travel the galaxy at plausible speeds, and we wouldn't see Andromeda collide with the Milky Way, or the continents reshape, or the Sun become a red giant, and so on. If we were lucky enough to live much longer than average, then we'd see all the people we ever knew die before us, as people do now. Because of the distribution, more people would suffer that unhappy state, wouldn't they?
Ageless people might be risk averse, but if I could be 21 again, and in perfect health,
I would definitely spend more time enjoying alcohol and motorcycles than I do now.
> babies are very young [citation needed]
You are hella funny guy at times.
I love that it's both a joke and also literally a relevant question given the context.
To clarify, senescent cells are not exactly an unwelcome process in our body. Cells can become senescent to avoid malignant transformation into cancer cells - one of the characteristics of senescent cells is their lack of proliferation. It fits into a broader theme where aging and cancer are two sides of the same tradeoff, biologically speaking. Keep the cancer at bay, and you age faster. Suppress aging and you suffer from cancer. So in this paradigm aging is an in-built protection from cancer, and messing with it (injecting Yamanaka factors, extending telomeres) has a price.
From the publicity standpoint I think the easiest application of anti-aging research is improving the lifespan of our pets, turning cats and dogs into life-long companions. I can think of very few people who would object to that. The regulation in this area is probably much more lax, allowing biohackers to experiment with next-generation treatments and report the results.
However, I'm skeptical that the same anti-aging treatments that work on mice, cats and dogs would make a strong impact on humans. We still don't know why, mechanistically speaking, mouse tissues have a shorter "expiry date" than human tissues. Extending lifespan in animals could be as easy as identifying the mechanisms that keep humans from dying in their 20s and transferring these mechanisms to animals. To extend lifespan in humans we would need to either identify biological mechanisms that keep whales alive for 200+ years and steal those, or come up with the novel ideas ourselves.
Someone already had this idea.
https://loyalfordogs.com/
I don't understand why the cancer/ aging trade off isn't discussed more often.
Because it's a gross oversimplification based in decades old science.
Naked mole rats live basically forever and when one got cancer, it was such a big deal it got a paper written about it.
Perhaps senescense has a similar role in a macro view as well? Through aging, old humans are removed from the high rungs of the hierarchies so that societies can evolve. Old dogs loathe new tricks, so we need turnover to make sure our collective book of tricks corresponds to our changing environment. Old people still have great value, but it's better if they are not quite as sharp, energetic and ambitious as the young, so that they are willing to take a step back when the next generation is ready for the stage.
Are 200 year whales actually more longevity than 70 year humans? In terms of number of consecutive cell divisions?
Re: stem cells: Do stem cells always know what sort of cell to differentiate into? Would stem cells in the kidney always turn into kidney cells and not lung cells?
It depends what kind of chemical signals those cells receive, or rather what particular gradient of different signals, so in the kidney you would presumably be getting a lot more 'i-am-a-kidney' signals and a lot fewer 'i-am-a-lung' signals.
A separate issue would be tissue that's a heterologous mix of cells, like the pancreas, how do you get just the right number of islets vs. ductal cells for instance
I would be very interested in seeing a post on the relationship between cancer and ageing at a cellular mechanism level.
Cancer is a return to the unicellular world. Differentiated cells of multi-cellular organisms such as lung, liver, brain etc becomes dedifferentiated as cancer progresses. Cancer cells also use the significantly more inefficient pathway of anaerobic respiration, as opposed to aerobic or mitochondrial respiration, because the latter pathway was developed for an environment where efficient production of energy was desirable. Who else uses anaerobic respiration? Prokaryotes.
This has implications for us because when glucose is abundant, why care that aerobic respiration is 18x more efficient? Simply use anaerobic respiration, which is much faster and has the byproduct of generating lactic acid which can be used to kill neighboring cells for resources, just like bacteria and other unicellular organisms do. Rapamycin that Scott mentions, is a toxin secreted by a bacteria for this purpose. This is why obese people are significantly more likely to die of cancer. This is also where mTOR comes into the picture.
The other common way to get cancer is for cells to be exposed to chronic stress. If all your lung cells are abused by toxins in cigarettes, eventually they stop hoping that order will be restored, forget about the fact that they're supposed to be lung cells since it's getting impossible to function as one anyway, and revert back to their underlying programming of being a unicellular cell alone in this world, where cooperation no longer matters and survival must come at whatever cost.
At first glance, ageing and cancer seem to be two sides of the same coin. Cancers keep multiplying, just like bacteria, and are remarkable at survival because they are simply unicellular organisms that care only about their survival, to hell with everyone else. Most stay contained because our immune system is incredibly well suited to kill cells it doesn't recognize. But the war on cancer shows slow progress because we keep trying to find targeted ways to kill an organism that has undergone billions of years of evolution to survive. The organism simply evolves another way. Survival of the fittest.
Senescent cells help prevent cancer in a way, by dying off after their telomere cap is hit. Cancer cells aren't constrained by the telomere cap and can keep dividing. Increasing telomere length would reduce senescent cells, but that would increase the likelihood of cancer via cells gone rogue. But perhaps not, if the immune system could be kept healthy.
Jason Fung's The Cancer Code is a great intro to this paradigm.
Peto's Paradox (https://en.wikipedia.org/wiki/Peto%27s_paradox) would seem to indicate that there are ways to avoid this tradeoff.
This is actually something our host has written about before, albeit under a _very_ different context: https://slatestarcodex.com/2014/06/14/living-by-the-sword/
Actually cancer cells don't use anaerobic respiration, they use glycolysis. I think you may be conflating the two processes. Anaerobic respiration refers to respiration using something other than oxygen as the final electron acceptor and is common in bacteria. Glycolysis can happen regardless of oxygen and is common in many organisms and cell types (including cancer cells and in other highly proliferative normal healthy cell types in our bodies). Aerobic respiration is most efficient at producing ATP, but glycolysis has many other benefits that are favorable during proliferation. Metabolites from glycolysis are necessary for making several molecule types within the cell. If cells are growing and dividing, building materials for more DNA, proteins, fatty acids, etc are critical. Of course energy is also critical, but as you say, if glucose abundance isn't a limiting factor, then why use a method that does not make those other useful molecules and does cause oxidative stress and unnecessary breakdown of carbon skeletons?
I think this mechanism is fascinating in its own right. Take the skin, for example. You need to constantly renew the cells of the skin, so doesn't that mean you have a bunch of rapidly dividing cells that live forever? Yes and no. Yes, because you have a bunch of rapidly dividing cells, but they're not the same as the ones that live forever. This is due to the stem cell/progenitor cell system.
The adult stem cells at the basal lamina (the base of the skin) aren't restricted in their number of divisions, but they only divide about once a week. They're not restricted in their number of divisions, but they are severely restricted in their rate of division. When they do divide, they often give off a progenitor cell. (Except in the case of wound healing.)
These progenitor cells divide rapidly, but are only able to do so for a small number of times before their telomeres get too short and shut down further division. They get to go for about a week, creating all those cells you shed every day, but then they have to stop and die. These cells are limited in their number of divisions, but are not limited in their rate of division.
This system allows stem cells to look senescent most of the time, which avoids cancerous growths. It allows the proliferation to happen in a controlled, two-step manner. Rapid division is limited to cells that are going to die anyway.
Interestingly, there are a few schools of thought on where cancers can originate. Sometimes, cancer might originate from progenitor cells that either acquire the ability to extend their telomeres, or they just don't bother to care about genomic stability anymore. Those kinds of cancers would be rapidly dividing, and might be very susceptible to therapy that specifically targets rapid cell division.
Other types of cancers might arise from adult stem cells, though. These cells might still only divide infrequently, but give off cancerous progenitor cells that grow out the tumor. These cancer stem cells would be difficult to beat with traditional chemotherapy, since they're unlikely to all be dividing at the same time, no matter when you start chemo. Even if chemo worked, it would look like a complete ablation of the tumor, with no visible lesions left, but then surprisingly come back stronger the next time when it doesn't have to contend with the patient's immune system anymore.
The temptation to hit the patient harder and longer to 'get them all' would work in the case of progenitor cell cancers, but would exacerbate stem cell cancers. Hard to tell which you're dealing with from pathology alone.
Thank you, this is a great review and I'm glad you touch upon what "people who are not sinclair" think because some of the stuff in the book is hyped.
"Can you take rapamycin? Probably a bad idea, it’s a potent immunosuppressant. Organ recipients take it sometime to quiet their immune system down to the point where it stops rejecting the transplant, but it’s not a lot of fun."
^That point is not entirely correct. Rapamcycin gets a bad rep due to its history of being used as an organ transplant drug. But low dosage and once a week rapamycin may not be dangerous! In fact, it is one of the drugs that has consistently shown lifespan & healthspan benefits in mice. People in the industry like Matt Kaeberlein and Peter Attia take Rapamycin. I asked Matt about it in my podcast with him if people want to learn more on Rapamycin: https://youtu.be/BL67DhNepfg
Thread on the history & benefits of Rapamycin here: https://twitter.com/livelongerworld/status/1462538431091953668
"But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me."
^Yes there is a tradeoff because these activities like exercise & sauna are hormetic stressors. That means that a little bit of stress causes your cells to hunker down and extend lifespan. However, there is a limit where overdoing these hormetic stressors can lead to chronic stress. For example, if you are perpetually fasting, you will obviously die!
Similarly, exercise is in fact a stress to the body and causes low-level inflammation. But that's "good type of stress" where your cells learn to become resistant. Overdo exercise and you might be stressing your body more than what's good life lifespan and healthspan.
In other words, there is a sweet spot for these stressors!
Maybe I just see the most dystopian perspective on everything, but I have a bad feeling about the societal effects we would see from the development of immortality serum.
I don't imagine anyone being forced into immortality, but I can absolutely imagine life becoming impractical otherwise.
For example, increased lifespan means increased potential for labor extraction. More possible working years means greater debts could be repaid. Maybe the 100-year home mortgage becomes a thing, contingent on your compliance with anti-aging treatments, of course. Maybe then the price of houses scales to match what people can finance, just like we see with student loan availability and tuition fees rising.
Or on the other hand, suppose that people who are getting this serum are primarily those who have retired on their investments. How large of an ownership class can society bear?
In college, the frats that I knew the mortgages of had 40- or 50-year terms.
> Their heirs would still be a perpetual ownership class with even basic financial literacy.
Yet that very rarely happens. Out of thousands or tens of thousands of potential perpetual estates, the only one that looks to have survived 3+ generations is the Vanderbilts.
Your grandchildren will not share your personal finance ethics. But if the people who build the estates linger on for a long time, they can keep the fortune alive indefinitely.
On the other hand, "shirtsleeves to shirtsleeves in three generations."
The person who started poor and made a fortune is likely to be better at making more than his children and at not dissipating it than his grandchildren.
On the other hand, the fact that the grandparents are still alive when the grandchildren become adults means that the fortune is divided among more people, so less for each.
The thing is, it wouldn't fundamentally change the market for labor. A house costs a certain amount to build because that's what it costs to pay people to build it.
Immortality would completely destroy retirement, though. People might "retire" periodically but you'd almost always run out of money sooner or later.
While in principle it is true - 3% is quite optimistic.
Why do you think that 3% is optimistic? The SP500 has _averaged_ 10.9% yearly over the last 50 years. I have always seen 4% (of initial nut) as the safe spot. This is because 90%(citation needed) of the time a market wide investment (SP500) started at a random date in the last 50 years would have increased rather than decreased.
The reason for that caveat is that if a strong market decline coincides with your retirement date you can end up with an overall declining nest egg(due to the withdrawal of 4% of initial rather than current nut).
I don't know if we are just talking past each other here. I was trying to convey that 4% is fine in perpetuity, so long as you don't start your retirement at the beginning of a downswing. If SP500 is 10.9% average annually, your only risk is that you hit (something like) 3 down years and suddenly your 4% (of nut) is 12%(of current value). That would likely not be recoverable. (3 average years would result in 1% declines in current value)
On the other hand, if you had 3 up years then you are 30% up and your 4% withdrawals are effectively 2.7% + you have a 30% cushion.
Side note: median and average net worth are dramatically different for American net worth(e.g. >75 year olds $255k vs. $958k). Likely far more so for college grads(smaller pool), although I was not able to find that data.
> SP500
That is main blind spot! SP500 was very lucky compared to many indexes.
For example Nikkei 225 Index had 5% yearly over 50 years ( https://www.macrotrends.net/2593/nikkei-225-index-historical-chart-data (30/2.5)^(1/50) ), and is down over last 30 years.
And note that it is even worse! If you look at 50 year old index existing now you miss all that become gone completely.
The ideal solution, in my view, is that you retire from doing work you don't like doing, continue to do any work you do like doing. I'm retired — and continuing to spend fourteen hours a week on writing projects.
"A house costs a certain amount to build because that's what it costs to pay people to build it."
I thought main reason why houses cost a lot is that there is limited amount of space in areas where people want to live, and prices rise when more people want to live in same area, often with more (not less) room in their house.
That would be land cost, not the cost of building a house. Land costs way more in highly desirable areas.
In high-demand markets, that is the situation. Plus NIMBYs stopping new housing from being built.
But there are lots of places in the world, or even in the US, that are perfectly livable but not those areas.
>A house costs a certain amount to build because that's what it costs to pay people to build it.
Ricardo's law of rent beg to differ.
Ricardian rent was actually invented by Malthus (but Ricardo invented Marshallian quasi-rent, so it comes out even). And Ricardian rent explains the rent of agricultural land, which is in fixed supply, not of houses, which get built.
"agricultural land, which is in fixed supply," That may be what economists think. But it is only true in the short run. The Dutch would tell you that God made the world, but the Dutch made the Netherlands. Much of their best land used to be under the waves of the North Sea. Similarly in the US Midwest, there are hundreds of square miles of highly productive land that were unusable because of Malaria until they were drained. There is similar story about the Po River Valley in Italy.
> A house costs a certain amount to build because that's what it costs to pay people to build it.
You mean "because that's what people are willing to pay for it". We're now 3D printing houses, which is *substantially* cheaper, but I don't expect the full savings will be reflected in lower costs. The innovator keeps a heftier profit margin than his competitors.
In 2016 Sweden limited mortgage loans to 105 years.
> Swedish regulators calculated in 2013 that the average mortgage term was around 140 years.
> Nearly one-third of mortgages issued in 2014 allowed borrowers to repay only interest.
Sweden implements rent control, then wonders why there is no housing.
But I'm still astounded at your facts and am trying to figure out how things got there.
Well if those downsides come true and become unbearable, you'll still have an option of going back to the good old ways of non-existing at the age of 100, by killing yourself.
So does the insanity wolf perspective suggest I go buy 60 500mg pills of NMN for 27 bucks?
Yes, but take an ivermectin in case the NMN gives your worms immortality.
Im not going to address the entire review for the sake of brevity. But to the core of your question, I will try to argue for the anti-aging efforts and validity.
So, what could be an almost insurmountable problem for cells in a mature animal, but trivially vanishes when you clone a cell into an embryo?
In a few words; the consistency of unmethylated/methylated DNA. Meaning, the cells that grow from the clone are free of DNA methylation, because they have been pre-selected for healthy nucleuses, and therefore the complimentary DNA (cDNA) will be true to original form. The cDNA then goes through its regular processes in transcription then the many forms of RNA and respective processes of translation follow resulting in properly expressed proteins. So, not all cells or cell types are prone to DNA methylation at the same rate or even the same rates from the same hazards and it is because of this that cells progressively fail to transcribe and translate original DNA into proper proteins at high fidelity. As the cell health of the organism dwindles during senescence, proteins and growth factors alike are not being coded for at the rate needed and we see organ failure, cancer, etc. It only takes one serious break in the chain and we have big problems. That's what makes the biology so astonishingly robust and delicate at the same time.
Furthermore, as DNA is progressively compromised, cell division ceases to produce intact differentiated cells and those unsuccessful cells are destroyed by immune functions like those of macrophages. This is very similar to the destruction of an unviable fertilized egg in the blastocyst stage. Still there is no ultimate atavististic feature built into genetics... so once stem cell types have differentiated, that's the end form for potentiality. Although potentiality is limited by the number of viable daughter cells it is also governed by the expression of those cells.
Enter epigenetics. In epigenetics, this revision to a previous state is the goal of upregulating the sirtuins to a degree that all of the methylated DNA will be successfully cleaved back to its original unmethylated code. Not to be confused with changing or reversing cell type (genetics), but to keep the multipotent cells functioning efficiently. Granted I, too, have my doubts about the limit of sirtuin capabilities but remain optimistic about stem cell therapies and gene therapies.
Sirtuins are not the only way to regain optimal cell health from the DNA up. There are ways to shuttle in specific growth factors (to address your point about kidney cells or differentiated cell types more broadly) like engineered stem cells transfected with lentiviral vectors programmed to overexpress carefully selected growth factors that are specific to the target area. This is the area that I am focused on now, but the more communal-power focus on anti-aging the longer we may live to see our loved ones grow and the longer we may not weigh on them like a shadow of ourselves. Or better yet, the longer we will have to think of good solutions to difficult problems. Maybe we'll even get to relax after everything is patched up.
Anyway, I have applied for the ACX grant because a friend pointed me here. This is my first time on the board. I am currently a grad student in a related field but I need funding to complete my next course and hopefully do a PhD in neuroscience... support is warmly welcomed. So, too, would be an understanding PhD mentor, but alas.
The problem is that most clones actually fail. Only about 10% don't. This would be entirely consistent with the idea that cell damage is in fact quite common.
You are right. Most clones fail and cell damage is unavoidably part of life insofar as it is necessary before death. Species of clones is also going to greatly change the percentage of clones that survive and what age they survive to is also highly dependent on the species cloned at this point... and I don't know why half of my post is hidden from me... length restrictions? UI? substack newbie present
This is the case for mammals, but in the case of frogs it's higher (with some oddities like non-gamete donation from adult frog leads to tadpoles that don't turn into frogs)
https://www.sciencedirect.com/science/article/pii/001216066290043X and it was figured in the mid 20th century because it was way easier (for a while the argument was, sure, works on frogs but for mammals it will be impossible)
You either need a principled reason why amphibians would be much less bothered by DNA damage or accept mammal cloning is harder and we still botch it a lot and only get it right a few times by something like throwing darts and hitting bull's eye (which I think is the case). 10% for mammals seems to me like an optimistic number, https://www.karger.com/Article/Fulltext/452444#ref7 says ". Efficiency of SCNT is still rather low, with success rates of 0.3-1.7% per reconstructed oocyte and 3.4-13% per transferred SCNT embryo "
(One should also count, on the other direction, that most abortions are unintentional/non-induced, only like 30% of human zygotes can actually produce a healthy baby, most result in miscarriages, often before the woman is even aware she's pregnant. IIRC, shorted lived mammals aren't that bad at this. It remains unproven age-related damage of gametes is the cause, though it does go up with age)
Uh, the answer for the amphibians is that the ones that they cloned were all very young. From that paper, "transplantation of nuclei from endoderm cells of Xenopus laevis donors ranging from late blastulae to swimming tadpoles".
Sucess rate in mammals is still probably much lower controlling for relative age, but I'd need to see if someone has collected that data specifically for mice or other cloned mammals.
A comment on why it is harder to clone mammals than amphibians: some amphibian eggs can be 10,000 microns wide while human eggs are about 100 microns wide. This scale makes fertilization much more accessible for the frog eggs. Secondarily, amphibians may also be more resistant to DNA damage as well as easier to clone due to factors like oocyte size. On top of this, there is the complexity of the organism that increasingly provides places for a clone to fail with how many successive developmental steps that are need to be completed before maturation.
If we eliminate disease and aging, the only remaining causes of death are accidents, suicide, and murder. The chances of meeting a violent end become higher as those who favor suicide gradually eliminate themselves.
The stakes become higher for anything risky that you do. If you are 24 and have lived a third of your life already, jumping out of an airplane for your quarter-century birthday may seem a reasonable risk. But if you are 24 and have lived a tiny, tiny fraction of an unfathomably long life, then that risk, no matter how small, may seem terribly irresponsible. Leaving your house may seem terribly irresponsible, because there is so much to lose.
This may be the best reason for everyone choosing to live in the metaverse if we solve aging. If you jump out of a plane there and the parachute doesn't open, you just come back into the game as a new character. The stakes become reasonable again.
Even better, you can come back in as a new character and suppress your memories so you don't remember the previous incarnation. Then you get to experience novelty again!
You think it's a joke. I'm pretty sure that as my memory has gotten worse with age I enjoy rereading books more.
+1
Underrated comment right here. Freedom from aging without freedom from true danger will really take the fun out of the life. Do you want to live forever in the metaverse?
What is the punishment for murder now that its AYL is infinite? Do we have to make all reckless behavior severely punishable (drunk driving now is a murder charge regardless of outcome? ) as you're taking hundreds of years of life away?
Death is actually a pretty small component compared to physical and mental impairments from unsafe activities. Imagine blinding yourself doing something "stupid" at age 30, or losing an arm or a leg, or paralyzing yourself. Lots of activities have a fairly low chance of causing permanent damage, that over the course of 80 years may not be a big deal, but over 1,000+ years would be much more likely. That could include drinking and drugs, and a whole host of activities we now consider normal.
It's a common sci-fi trope that people who never age become amazingly risk-averse, and from what I've seen of humans, it's a completely accurate trope.
"The chances of meeting a violent end become higher as those who favor suicide gradually eliminate themselves."
Hang on. I don't see how that works. In a world where disease and ageing don't exist, perhaps death-by-violence will comprise a rising percentage of total deaths as suicidal people eliminate themselves (assuming we're not producing suicidally-inclined babies at replacement level). But how does that change the likelihood that *you* will die a violent death?
Seriously, is there any form of probability calculation that yields that result? I mean, I don't see how it causally makes sense.
Are you suggesting that, once the suicidal people are gone, there will be fewer total humans left over for the violent murderers to choose from, thereby raising your risk of being killed violently by an undiscriminating murderer for lack of alternatives?
Do suicidal people influence those around them to resist the urge to commit murder?
I'm really not prepared to raise my personal estimated-risk-of-violent-death each time I hear about someone in my community committing suicide.
> there will be fewer total humans left over for the violent murderers to choose from, thereby raising your risk of being killed violently by an undiscriminating murderer for lack of alternatives?
It's just the Monty Hall problem. You currently have 5 ways to die: disease, age, accident, murder, suicide. Per Fight Club, "on a long enough timeline, the survival rate of everyone drops to zero". If you eliminate disease and age, the probabilities of the other outcomes necessarily go up, since the probability you will die eventually must add up to 1.
Thanks. I figured it must be something along those lines.
This actually taps into some deeper features of probability estimation where I frequently get hung up. Perhaps there's a good source for teasing these things out?
To me, using the whole-population death statistics to determine your own chances of dying of x seems like using a large-scale framework with population-level information to solve a small-scale problem that necessarily involves using personalized information. I might reasonably population-level information as my prior for estimating the chances of dying of x, but I would feel like I was missing most of the information necessary for actually deciding my chances of dying of x, to the point of potentially misleading myself.
Example: say I'm a person who never drives and I have a heart condition. If cardiac arrest is totally eliminated from the rest of the population as a cause of death, you could look at that information and say my chances of dying by cardiac arrest have gone down and my chances of dying in a car accident have necessarily gone up. But that's nowhere near the truth. Even if you use population-level information as your prior, you're starting with a set of priors that are so far from reality, it seems to undermine the task of estimating relative death probabilities with any accuracy.
Is there a formal way to describe the phenomena I just touched on?
> Example: say I'm a person who never drives and I have a heart condition. If cardiac arrest is totally eliminated from the rest of the population as a cause of death, you could look at that information and say my chances of dying by cardiac arrest have gone down and my chances of dying in a car accident have necessarily gone up.
Yes, the statement is always with the implicit "all else being equal". But if you get better or more precise information such that all else is not equal, then you have to update the probabilities using Bayes' theorem.
https://en.wikipedia.org/wiki/Struldbrugg
"In Jonathan Swift's 1726 satirical novel Gulliver's Travels, the name struldbrugg (sometimes spelled struldbrug)is given to those humans in the nation of Luggnagg who are born seemingly normal, but are in fact immortal. Although struldbruggs do not die, they do continue aging. Swift's work depicts the evil of immortality without eternal youth.
They are easily recognized by a red dot above their left eyebrow. They are normal human beings until they reach the age of eighty, at which time they become dejected. Upon reaching the age of eighty they become legally dead, and suffer from many ailments including the loss of eyesight and the loss of hair.
Struldbruggs were forbidden to own property:
"As soon as they have completed the term of eighty years, they are looked on as dead in law; their heirs immediately succeed to their estates; only a small pittance is reserved for their support; and the poor ones are maintained at the public charge. After that period, they are held incapable of any employment of trust or profit; they cannot purchase lands, or take leases; neither are they allowed to be witnesses in any cause, either civil or criminal or economic, not even for the decision of meers (metes) and bounds."
Because:
"Otherwise, as avarice is the necessary consequence of old age, those immortals would in time become proprietors of the whole nation, and engross the civil power, which, for want of abilities to manage, must end in the ruin of the public."
Seems not really interesting? "do not die, they do continue aging" is badness of highest degree and noone really disputes it.
Even without blatant dystopia on top of that?
There is an origination called the Gerontology Research Group. one of their activities is tracking the oldest people in the world. Supercentenarians who are 110 years old and older. They take pains to validate their ages via government and private records. Here is a link to their table of living supercentenarians
https://grg.org/WSRL/TableE.aspx
There are 17 of them out of the ~7 billion living humans today. The oldest is will be 119 years on 2 Jan. 2022. She is older than any person they have tracked since Jean Calment of France who died 1997 at 122 years and 164 days. https://grg.org/SC/SCindex.html
I would posit that 125 years is a hard upper limit on human life spans. Some creatures, such a Galapagos tortoises and some whales live much longer than that. But, all living things grow old and die in their time.
Gen.47
[7] Then Joseph brought in Jacob his father, and set him before Pharaoh, and Jacob blessed Pharaoh.
[8] And Pharaoh said to Jacob, "How many are the days of the years of your life?"
[9] And Jacob said to Pharaoh, "The days of the years of my sojourning are a hundred and thirty years; few and evil have been the days of the years of my life, and they have not attained to the days of the years of the life of my fathers in the days of their sojourning."
No-no, not all living things have built-in senescence, are you forgetting perennial plants, most fungi, bacteria, and among animals, the legendary hydra?
You can be immortal, but you have to give up consciousness, identity, and sex. Not appealing.
"pterostilbene, a more bioavailable resveratrol relative. The other pill is nicotinamide riboside.
Those are the two ingredients in a product called "Basis" that I have been taking for many years. It's only a sample size of one but my biological age, as defined by whatever genetic markers Elysium, the company that makes Basis, uses, was measured a year or two back as about a decade lower than my chronological age.
But then my mother, who didn't take Basis, died at about a hundred and her brother at older than that, so I may just be lucky in my genes.
"you’d have to correct the DNA in every cell in the body (using what template? even if you’d saved a copy of your DNA from childhood, how do you get it into all 30 trillion cells?)"
The template problem is easy; you just take a majority vote of fifty cells. Unless they tend to all have the same mutations, that should get you back to the original.
The distribution problem is harder. In principle you do it with nanotech cell repair machines, but that is going to be quite a while. Possibly a tailored virus?
I really wanted to see more discussion of this. Which cells are breaking down, and how easily are they replaced?
Can I make myself a young-version-of-me liver, and then replace half of my liver with that one? (I'm not a biologist but I seem to recall from high school that the liver is fairly uniform as an organ.) What about my bone marrow, can I just inject some younger marrow in?
Replacing all my red blood cells with a young copy sounds easy enough. I have no idea how to do it with skin.
This is consistent with my understanding as well. Livers are supposedly able to completely regenerate from as little as 10%; if you have liver cancer, and it hasn't spread to anything else, a surgeon could (AFAIK) simply remove the cancerous part and let the rest regenerate on its own. (I imagine you'd have to also take reasonably good care of yourself while it does, including drinking no alcohol.)
Regeneration of all your blood cells is the basic goal of a bone marrow transplant, and we know those can work. (Fun fact: this can also completely change your blood type.)
Skin is regenerated with grafting from elsewhere on your body, but it takes a lot longer, won't look quite the same, and I'm pretty sure I'm just handwaving a great deal here. I think it's pretty hard.
“Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself?”
The reason this argument fails is that immortality isn’t actually evolutionary beneficial. Take two people, one of whom is immortal for biochemical reasons, and a regular human. The human, knowing their clock is ticking, is likely to have children quickly, stick around to help with the grandchildren, and then die. Whereas the immortal person seems like they wouldn’t in such a hurry to have kids, meaning they would be unlikely to pass on their genes as quickly. Consider how birth rates fall as life expectancy goes up, and you can understand why evolution would want to sabotage the body in some way, so that it doesn’t outlive its usefulness or waste time doing things besides copying its genes.
Given how difficult it was for humans to control their fertility for a long time, it seems unlikely to me that biological immortality would be in any way disadvantageous.
Not to mention the obvious fact that natural selection has caused humans to live abnormally long lifespans.
There are trees that can live an even longer amount of time. There's no advantage in dying early for them.
Trees have an advantage in living longer since they don’t grow infertile like humans do, and otherwise have a different reproductive strategy. I address why this is important in my response to Titanium dragon
Infertility is a side effect of aging. Menopause is caused by aging, and happens because female reproductive systems have to work much better than male ones to produce viable embryos. Male infertility is more obviously caused by aging a well, as many older men are still fertile.
But what would be the advantage in living longer from an evolutionary perspective? You’re infertile by this point, so there’s no chance in passing on your genes further, so I don’t get why it would be evolutionary advantageous to continue to live, consuming resources that could be better used by your children and grandchildren.
1) Infertility is a side effect of aging, so you wouldn't become infertile.
2) Per selfish gene theory, it doesn't actually matter how many children you have, what matters is how many of your genes are hanging around. Being immortal means your genes are always hanging around.
Brett Weinstein's argument seems to be that senescence isn't a bad outcome but a trade off. Immortality always converges on cancer (or IS cancer), so a universal max replication count (however fuzzy) avoids cancer (for the cancers that don't escape the mechanism), but guarantees aging and death. Aging is the body's answer to cancer.
Lab mice accidentally and systemically have been selected for long telomeres and are good at healing and live a long time, but tend to die a lot from cancer (even when we're not guaranteeing it).
+1, more on this view please.
I was going to mention the mice telomere thing as well, so I'm glad you saved me the trouble. It has serious implications about efficacy of drugs we test, and I haven't yet thought through what it implies for the claims Sinclair is making. (Bret discovered the issue by thinking about how telomeres and lab mice supply work, asked a breeder to confirm, and her response was along the lines of "holy cow, you might be right". There's an interesting YT video where Bret's older brother, Eric, calmly but angrily rips him a new one for not writing this up in enough detail to get the Nobel Prize Eric is 100% convinced Bret should have won.)
Bret seems to have a moral hangup about anti-aging research as well. In his opinion, people ought to accept the lifespans we currently have and just appreciate it as such.
That episode was interesting but very bizarre. Very bizarre how Eric acted toward Bret. They think that someone stole their work.
stole Bret's finding*
I think the best argument against making most of the population immortal today is that in a couple centuries, we will have engineered the entire population to be vastly more intelligent and fitter than they are today.
That said, even if we did achieve biological immortality, at present rates of accidental death, you'd probably make it to roughly 600 or so on average.
Bot sure how many people would agree to sacrifice their lives to give way to a better more intelligent species, but I myself am definitely in the "Nope" camp.
*Not
"Infinitely" seems obviously wrong. Not all the ills of the world consist of the aging process up to exactly the age of 80.
Has anyone ever looked at aging through the lens of a human/chimp comparison? We live decades longer than our closest relatives, which are themselves a long-lived mammal. What are the biological differences that makes that difference? If you figured that out, maybe you could crank up those differences.
You are assuming that you can crank them up, as opposed to them being basically fixes for things that we already have fixed.
Going to mention Kim Stanley Robinson's Mars trilogy (and his earlier novel Icehenge) here in case people are inclined to ctrl-F for his name like I was. As an exploration of the consequences of 500-plus-year lifespans I actually don't find the Mars books that interesting. That part of the science fiction is mostly a way to keep the same characters around through a several-hundred-year terraforming project. Robinson also exaggerates the Malthusian / environmental-risk / social-upheaval aspects of longevity, which is typical for him.
Icehenge mentions an interesting idea, though, which is that people seem to "peak" pretty young (physically in particular, but mentally too-- the example Robinson uses is chess champions), as in: soon after they mature. So even with strong anti-aging tech it seems likely that experience of the added years of life would be more like being 50 or 60 or 70 than, say, 30. There might be a feeling of decline and/or stagnation the whole time.
I think most of the decline in chess strength is due to aging (less physical energy) and lack of motivation (I've been at this for twenty years"). See e.g. Carlsen's remarks on the current World championship match. The first problem would be solved by curing aging. The second can not be solved, but if you live for ever you can just switch to a different activity when you get bored of the first one.
We're never, ever going to colonize space.
It is rather far. But our machines might do it.
Also, rather inhospitable. As per the topic of this post, we barely manage a few decades on the planet we have evolved for.
I would not be so sure. Even now it is possible (though mostly pointless)
The gating factor on colonization is not technological, it's commercial. Why would you use a ton of energy to get to another planet just to haul shit back that you could have found on earth? Europeans didn't sail the globe and establish colonies out of a sense of adventure, they did it to get rich or die trying. Any space colonization effort is going to need the former half of that equation; right now we just have the latter.
I think drawing parallels from European exploration can be misleading. European exploration was primarily commercial because people knew that they could make a staggering amount of money by directly importing spices from the Indies. The spices brought back by the one ship of Magellan's expedition that completed the first circumnavigation - and it was the smallest ship - more than paid for the cost of the entire 5 ship expedition. The funders of Drake's circumnavigation got a 5000% return on their investment. In these circumstances, financial incentives would naturally predominate - we'd already be on Mars if anything similar was realistically achievable.
But successful exploration and settlement can take place for predominantly non-commercial motives. Puritan settlement of New England, Cook's 18th century voyages and the subsequent settlement of Australia, Alexander the Great's explorations and settlements, Antarctica today, too many examples to list really, but overall I don't think that most historical exploration and colonisation has been undertaken primarily in order to make money for investors. It can happen even if there's no good financial reason to do it.
The idea of turning Mars into a prison colony has always been a popular way of getting permanent human settlement to work in sci-fi. Perhaps if some private prison contractor finds a way to persuade a compliant super-wealthy autocracy that deportation to Mars is preferable to Siberia, maybe you could make it work. But I still think you'd need to break the laws of physics for the economics to ever pencil out. Technoeconomics is still the gatekeeper between the possible and the actual.
Is there an SF story out there about humanity running into so much risk with various disease research that it ends up driving interplanetary colony research just so we can set up a giant cleanroom?
There was a post eight months ago on LessWrong where John S. Wentsworth, an "independent AI researcher" according to LinkedIn, gave a summary of his understanding of how aging worked:
https://www.lesswrong.com/posts/ui6mDLdqXkaXiDMJ5/core-pathways-of-aging
A summary (by me, a complete non-expert) would be:
The symptoms of aging (atherosclerosis, sarcopenia, etc.) are basically caused by too much inflammatory factors (SASP) and reactive oxygen species (ROS). Senescent cells release both.
SASP is released normally by senescent cells in order to tell the immune system to kill them.
ROS is generated by the normal action of mitochondria, and causes DNA damage. ROS goes up when the cell is in a DNA-repairing state - mitochondria become less efficient, producing less energy as part of the repair process, and therefore more ROS, which can in turn cause more damage.
Normally, cells have low levels of DNA damage and low levels of ROS. But after passing some threshold after enough stress has happened to the cell, the ROS damages the DNA faster than it can be repaired, and the cell becomes senescent.
The core cause of aging is suggested by the author to primarily be because of transposon proliferation. Transposons are genes that copy themselves; when they do this, they cause DNA damage. Most transposons in the genome are dead - no longer able to proliferate due to evolutionary accident; they make up about 50% of the genome.
Maybe 100 or so active transposons remain, and these are tightly controlled by epigenetics to prevent them from being expressed. However, as part of the DNA repair process, the epigenetic mechanisms (e.g. sirtuins) are drawn away from repressing them to go help fix the DNA. When that happens, they'll manage to copy themselves. These make future DNA repair attempts more inefficient, and a certain level of transposon proliferation represents the threshold beyond which DNA repair fails and the cell becomes overwhelmed by ROS damage. Transposons also make senescence permanent; once they've been given free reign to copy themselves due to the failure of the DNA repair system, they will proliferate and damage DNA until the genome is beyond recovery, even if the excess ROS were to be cleared away.
One particular thing about transposon proliferation is that it occurs in stem cells too; a stem cell that has a high level of transposon proliferation, but not enough to render it senescent, will cause the cells it forms to quickly become senescent themselves. So the ultimate cause might be said to be an overall increase in the rate of cells senescing, causing body-wide overexpression of SASP and ROS, due to more and more stem cells getting overloaded with transposons at sub-senescent levels.
As to why organisms don't get overloaded with transposons with each successive generation - someone in the comments mentioned that the gonads have very high levels of epigenetic control against the areas with active transposons; this has the side effect of hindering DNA expression overall (which maybe explains why fertility is so hard, and requires so many attempts to succeed).
I think it foolish for us to think we will live on past our time. We are not made out of incorruptible gold and adamant. We are dynamic balances between energy and entropy made out of water, sugar, oil, and protein, in an intricate pattern. We should appreciate the miracle of life and know that it is brief.
Thornton Wilder's novel The Bridge of San Luis Rey is a meditation on the meaning of life and random death. In it the Friar Brother Juniper witnesses the collapse of a bridge and the death of five travelers who were on it. He minutely investigates their lives and searches for the reason, if any, behind their deaths. The novel ends with the Abbess' observation: "There is a land of the living and a land of the dead and the bridge is love, the only survival, the only meaning."
Shakespeare The Tempest Act IV Prospero
Our revels now are ended. These our actors,
As I foretold you, were all spirits and
Are melted into air, into thin air:
And, like the baseless fabric of this vision,
The cloud-capp'd towers, the gorgeous palaces,
The solemn temples, the great globe itself,
Ye all which it inherit, shall dissolve
And, like this insubstantial pageant faded,
Leave not a rack behind. We are such stuff
As dreams are made on, and our little life
Is rounded with a sleep.
Gen. 3:
[17] And to Adam he said, ...
[19] In the sweat of your face you shall eat bread till you return to the ground, for out of it you were taken;
you are dust, and to dust you shall return."...
[22] Then the LORD God said, "Behold, the man has become like one of us, knowing good and evil; and now, lest he put forth his hand and take also of the tree of life, and eat, and live for ever"
[23] therefore the LORD God sent him forth from the garden of Eden, to till the ground from which he was taken.
[24] He drove out the man; and at the east of the garden of Eden he placed the cherubim, and a flaming sword which turned every way, to guard the way to the tree of life.
I sometimes send my students that quote after their exam.
Eternal life isn't about living past your time. It's about your time never ending.
We should appreciate our brief lives. And if we manage to make them less brief we should appreciate them even more. Lots of meaning and beauty can be extracted from our finitness. People have been doing it through out the history. This idea is very well explored. But don't you think, that we can explore other ideas as well?
Have you tried to imagine how much beauty and meaning can be extracted from a life that can last for thousands of years? Or one that truly never ends? Or one that can be ended only by your own volition? It's a completely new ground to explore and so much more new and beautiful things to say!
It seems, that in your mind eternal life would cost us all the beauty of Shakespeare and Thornton. It's a false trade off. These treasures of old will stay with us to experience and understand. However, we will also get many others.
Woody Allen wrote: “I don't want to achieve immortality through my work; I want to achieve immortality through not dying. I don't want to live on in the hearts of my countrymen; I want to live on in my apartment.”
"These treasures of old will stay with us to experience and understand. However, we will also get many others."
From whom? The same old guys are not going to invent new arts. If death disappears, so does new life.
Science, we are told, progresses one funeral at a time. If we live forever we will lose scientific progress. The arts are the same.
I love Mozart, but I also love the Beatles. I love Michelangelo, But Caravaggio knocks me out. And JMW Turner astounds me. Further, painting died some time after Van Gogh. Will something take its place? Not if the current generation does not depart the stage.
Fortunately, i am not worried about your scenario. It won't happen. There are hard upper limits on human life spans. Nobody has ever been verified to have lived more than 123 years.
"Science, we are told, progresses one funeral at a time. If we live forever we will lose scientific progress. The arts are the same."
There's no reason to expect this is true at least for science. New scientists tend to make the big breakthroughs and paradigm shifts, but what else could be the case? The old scientists stop making huge progress precisely because, you know, they AGE. They have less energy and their cognitive ability declines until they can no longer even work any more.
Imagine the greatest scientists alive today, imagine if they never aged. They could operate at their biological peak indefinitely and would continue accumulating knowledge and skills over time. This should be expected to produce great outcomes. Maybe novel minds create novel ideas, but great minds working indefinitely ought to produce more progress than billions of new mediocre people ever will. Imagine if John von Neumann and his greatest contemporaries had been able to live forever at peak health. Do you really think the novelty of new mathematicians would be worth sacrificing the greatest working indefinitely?
I can't help but think this "new people make new ideas" view is simply an artifact of a world in which old people are aged and lose energy and cognitive ability.
Sorry dude. your fantasy is nice. "it seems a crime that we should age" (Elton John "Friends"). But it is not the way the world is or that men are. We are limited beings. It is our tragedy and our glory. Get thee a heart of wisdom.
> I think it foolish for us to think we will live on past our time.
Modern humans live to be around 75..80 years old, on average. This is a pretty big jump from the historical average of 40..50. Are we living "past our time" ? Should we stop ? How do you decide what a person's appropriate "time" is, anyway ? Actually, who retired and made you Azrael ?
Don't confuse average life expectancies with the biological possibility of living a certain time. The 40.5 figure includes an enormous number of children who died quite young, an enormous number of young women who died in childbirth, and a very substantial number of men who died from war and violent attacks.
But, from great antiquity, men understood that our years stretched out farther than those horizons. Psalm 90, written ~25 centuries ago, famously says: [10] "The years of our life are threescore and ten, or even by reason of strength fourscore; yet their span is but toil and trouble; they are soon gone, and we fly away."
A few centuries later but still about 1700 years ago, the Sages wrote in the Mishna (Avot 5:21): "At thirty the peak of strength; At forty wisdom; At fifty able to give counsel; At sixty old age; At seventy fullness of years; At eighty the age of “strength”; At ninety a bent body; At one hundred, as good as dead and gone completely out of the world."
What our time is, is not for me to determine. I know, empirically, it is limited and, in comparison to human history it is brief, and in comparison to geological time, evanescent. I am not arguing or judging, just observing.
I am fond of the resolution of Ps. 90 [10] in [12]: "So teach us to number our days that we may get a heart of wisdom."
> The 40.5 figure includes an enormous number of children who died quite young, an enormous number of young women who died in childbirth...
This does not appear to be true; the average *adult* lifespan was around 40..50 years:
https://www.sarahwoodbury.com/life-expectancy-in-the-middle-ages/
> and a very substantial number of men who died from war and violent attacks.
It sounds like you might be splitting hairs at this point. Sure, that man might have lived to be 80, had he not gone to war. But this man here also could've lived to be 80, had he not died of gangrene, or pneumonia, or cancer. Where do you draw the line ? Should we stop treating pneumonia and cancer ?
> I know, empirically, it is limited and, in comparison to human history it is brief, and in comparison to geological time, evanescent.
Well, in that case, doubling our lifespan shouldn't make much of a dent, in the long scheme of things...
My point o averages vs. individual biological possibilities stands. Your Ms. Woodbury is a historian, not an actuary. And even as a historian she did not look at demographic data.
War and sub-war violence are not features of individual biology, they are features of society and politics, and so vary from time to time and place to place. Demographers and actuaries separate them out for purposes of analysis.
Perhaps there will be a revolution in science which raises life expectancy significantly for some. Likely there will be tradeoffs. Some will when, some will lose. My question is this: come such a revolution: do you feel lucky?
I feel certain that medicine will continue to advance and that more people will live longer and will have a better quality of life in their later years. But, I think we will find that everyone ages and deteriorates, that most of us really start to decline significantly after 85, that centenarians are uncommon (2 standard deviations), super-centenarians (110+) are quite rare (5 sd) and that there is a hard biological upper limit on our life spans of ~125 years.
As for myself. I am 74 and in basically good health. I just cleared the two most important cancer screenings. I feel that I have a good shot for ten more years, a punter's chance of 15, and would not wager even a small stake on 20 more years.
The more I read about humans wanting to live longer the less I like humans. The sooner the humans die off the better. I want bees or ants to be the future of this planet not ugly primates.
Note that if you care about passing on your DNA to the rest of the universe, the descendants of bees or ants may do a better job at passing on some of your DNA than do the descendants of apes. Of maybe the descendants of ferns, orchids or beetles will.
Does ANYONE explicitly cares about passing their genes? We are adaptation executers, not fitness maximizers, after all.
I've heard that some people want to have children in order to "continue themselves" or for the sake of some legacy. And it seems as close to caring about passing genes as possible. But, I wonder, is it actually about blood ties as a terminal value or rather an instrumental one?
>Does ANYONE explicitly care about passing their genes?
I wouldn't have thought so a decade ago, but how else to explain why so many people are concerned about X Risk?
One also sometimes hears arguments from far-rightists about wanting to help those with whom they share more genes despite those people being far outside their nuclear family-- a case they make explicitly. Perhaps those people are being insincere, but it can be hard to gauge the sincerity of others.
Are you a bee or an ant, or just in the pay of Big Hymenoptera?
I am a fellow human, bro.
Look, I'm as misanthropist as the next guy, but give me a break.
Bees and especially ants are also city-dwelling agriculturalists who devastate landscapes and go to war with chemical weapons. Aesthetically, a hymenopteran civilisation doesn't seem like it would be much of an improvement.
Reject spines. Retvrn to invertebracy.
If humans aren't around, how could it possibly matter if any other life exists or not?
Maybe all biological life shares the same soul?
When I read posts like this, it makes me think of the bit in Manalive where the protagonist points a gun at people who say they want to kill themselves.
Disclaimer that I haven't read the book even if I read some of Sinclair's scientific output earlier, but to be absolutely clear resveratrol is absolutely not even close to bioavaliable enough in humans. We're talking about taking literal tons of tomatoes or wine or whatever for a biologically significant effect, whatever it is.
This paper https://pubmed.ncbi.nlm.nih.gov/27552971/ by Sinclair did a good work explaining how the mechanism for Sirtuin activating was elucidated and entablished to be related to a resveratrol-in vitro like mechanism against the skepticism of losers and haters (this is a narrow claim, I'm not saying his wider output always replicates). And it takes for granted we need synthetic sirtuin activating compounds for any significant effect. Does Sinclair mention this sort of stuff on the book? This is from 2016 and my quick check is that a lot of the late phase clinical trials in humans with these compounds are not done yet.
>It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
If I may add one anecdata point, in italy most resources are gobbled up by the state pension fund and we are suffering from quite bad youth unemployment rate so I would claim that this scenario is in fact happening nowadays - albeit without the dictatorship part.
Similar situation in Germany, and the elderly are more likely to vote, are quite numerous and there is an age restriction to voting, so raising the retirement age or cutting benefits is political suicide. They also hold more assets, the income on those assets has to come from the young as well, and tax rates for the young are higher inflation adjusted since the tax brackets have stayed pretty much the same since introduction of the income tax.
Interesting, I didn't know that Angela Merkel committed political suicide in 2007 ;-)
https://www.spiegel.de/politik/deutschland/reformprojekt-bundestag-beschliesst-rente-mit-67-a-470794.html
Well she's out of office now well before the changes are in full effect in 2029 ;)
> in italy most resources are gobbled up by the state pension fund
Can you expand on this? At first glance it sounds like a late-stage-capitalism gripe about a fixed-size pie.
Probably a good time to remember the Adversarial Collaboration Contest entry from 2 years ago that looked at aging and concluded the evidence for calorie restriction in humans results in longer lifespan was less strong than e.g. animal studies would suggest: https://slatestarcodex.com/2019/12/12/acc-does-calorie-restriction-slow-aging/
Hi Scott! Great review! And, as the author of another book on aging biology (Ageless: The new science of getting older without getting old), I agree with both you and David on different things. In agreement with you, I think that solving aging is going to take more than just reversing epigenetic changes. In Ageless, I break things down into ten ‘hallmarks’ of the aging process of which I think we’ll need to solve a decent subset in order to make *really* significant progress against aging (though results from tackling individual hallmarks like cellular senescence and epigenetic reprogramming make it seem encouragingly as though we could get some decent gains without solving everything). Where I agree with David is that I’m nonetheless optimistic that if we did plow a decent amount of money into aging biology, we could make huge advances, and it might well be easier than curing cancer (cancer cells are constantly evolving to maximize replication; the changes that cause aging are largely accidental side-effects of evolution and aren’t actively trying to outwit your treatments).
If you’d like to find out more, check out https://ageless.link/
And I’m going to be releasing a free, bonus chapter on the ethics of treating aging next month, so sign up here to be the first to hear about it! https://andrewsteele.substack.com/
thanks Andrew - I'm interested in this area so just ordered your book and signed up for updates.
Thanks Patrick, hope you enjoy it! (And sorry for the slow reply, I only just saw this!)
> It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
You might want to look around.
But bitter jokes aside, I'm 100% on board with your train of thought. Unfortunately I lean towards the SENS model more than the Sinclair model, but if Sinclair is right, that's _such_ a low hanging fruit we need to exhaust that research direction anyway.
Anectodally, intermittent fasting makes you feel fantastic, actually heals muscle injuries (by downregulating inflammation, I guess?), keeps the weight off. Highly recommended even if it does not, in fact, make you an immortal space murine.
« Algernon’s Law says there shouldn’t be easy gains in biology. Your body is the product of millions of years of evolution - it would be weird if some drug could make you stronger, faster, and smarter. Why didn’t the body just evolve to secrete that drug itself? Or more to the point, since most drugs act by flipping biological “switches”, why does your body have a switch set to the “be weak, slow, and dumb” position? »
Algernon's Law seems very real to me, but for aging, there is something that works strongly in our favor: natural selection heavily discount what happens at older ages, because in our evolutionary past, we were statistically dead after, say, 40 years. This means that a genetic variant producing a very small advantage in youth at a huge cost in later life was usually very advantageous and retained by natural selection. So it seems possible that, conversely, the cost of not aging could actually be very small. And besides, a relatively small number of organisms, some trees and turtles for example, do not seem to age, or at least we are not able to detect a decrease in capacity over time. So it seems possible for biology to make organisms that do not age, or at least age very very slowly.
I find the issue with many of these longevity arguments is in conflating lifespan vs healthspan (the duration of one's life in which you are healthy and disease-free). You could argue that many efforts of medical science over the past 100 years have focussed exclusively on lifespan, and this has caused a number of societal challenges with people who live longer, but are highly dependent upon support to carry out their activities of daily living.
So too with the summary of this book; if these theories bear out, then sure we can prevent cancer, or dementia, or any number of the other "Geriatric Giants", but this isn't (to my mind) going to prevent us losing muscle strength (which happens after age 50 despite exercise, even in retired olympic athletes), or to repair our knee cartilage, worn out from too much running. Without fixing these millions of tiny insults (as Scott says), we might be left with a retired generation who are biochemically healthy, and yet utterly unable to live independently.
> You could argue that many efforts of medical science over the past 100 years have focussed exclusively on lifespan
This seems clearly untrue to me if by "many" you mean most. And if "many" you mean "many but still small part" it seems unrelevant.
Though https://slatestarcodex.com/2013/07/17/who-by-very-slow-decay/ is also relevant and may suggest that I am wrong.
To support this statement I would point to this good publication on healthspan[1] which states:
"The past century was a period of increasing life expectancy throughout the age range. This resulted in more people living to old age and to spending more years at the older ages"
and
" In recent decades, there have been some reductions in the prevalence of physical disability and dementia. At the same time, the prevalence of disease has increased markedly, in large part due to treatment which extends life for those with disease"
1. https://academic.oup.com/gerontologist/article/55/6/901/2605490?login=true
A low hanging fruit is to stop running, aka jogging. Walk, bike, or do anything else really. It makes your knees last longer.
You might want to read the actual book, it goes at length discussing exactly this question and how all anti-aging research is about expanding healthspan (compared with fixing individual diseases, which only increases lifespan).
Did you read the full summary?
Sinclair is not trying to cure cancer or dementia, he wants to stop cells aging PER SE. If your cells do not age, or don't age as quickly, and there's no terrible side effects like 1000% increased cancer risk, then yes, your healthspan is necessarily going to increase.
Is it just me or is 'expand full comment' broken for others too (fails both in mobile Firefox and mobile Edge for me)?
PC Firefox also breaks down, I see "Uncaught TypeError: this is undefined expandToggleClicked comment.js:146" in browser console so Substack has broken code in production.
Someone may let them know or wait until they notice.
Maybe they are fixing it already.
I guess I'll plug my own extension again.
https://github.com/EdwardScizorhands/ACX-simple
It completely replaces the Substack comment UI, so whenever Substack breaks their UI, I never notice.
The dist is way out of date, but the old one should still be functional. If you know how to clone/download a repo you can grab the latest.
And if you're used to Pycea's extension, mine is ugly, both visually and in the written code.
Hey, I got the releases working in Firefox. You should be able to go to https://github.com/EdwardScizorhands/ACX-simple/releases to install the signed .xpi file directly from github, and then go to https://astralcodexten.substack.com/p/book-review-lifespan/comments to use the comments on this page.
It's not pretty but it works. Probably the next feature I'll work on is either collapsing comments or a killfile (which Pycea's extension has had for a long time).
ALso broken for me, using Chrome on a PC.
Yeah me too,
Also broken for iPhone
> But when David Sinclair says that reservatrol or exercise or intermittent fasting or saunas act by “mimicking calorie restriction”, is he suggesting that they will make you weak and constantly tired? If not, why not? This sounds a denial of the fundamental mTOR tradeoff: less energy expenditure in exchange for worse performance. The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
We evolved and are tuned to lifestyle involving massive amount of exercise and much wilder swings of temperature and far less plentiful food.
It seems plausible to me that modern lifestyle is a massive health problem. We life longer because it was outweighed by reduction of diseases and starvation, but still sitting still in front of screen is extremely unhealthy.
It is not surprising that our body gets out of whack if we sit still, look at colored plate 50cm away and eat piles of food.
People of the past had much more physically demanding lives, but usually had less cognitively demanding lives unless they were part of a tiny priesthood/aristocracy. Being in a permanent state of brain-fog from hunger is miserable, but a hunter-gatherer or medieval peasant could be miserable in that way and still get through life. It's more debilitating for modern anorexics/bulimics, people with female-athlete-triad, stimulant addicts with suppressed appetite, etc. They may well be in similar caloric deficits, but are expected, at bare minimum, to be literate, numerate, and able to plan their lives further than the next week. I don't think modern life is healthy either, but I don't think living as most humans have in the past is necessarily the best way when conditions have changed.
I am not convinced that "usually had less cognitively demanding lives" is really true.
Hunter-gatherer definitely needs plenty of attention/vigilance and people put enormous effort, also intellectual into that. And what minimal experience I had with similar things - I really doubt that it was less mentally challenging that typical intellectual work in a modern world (to say nothing about working in factories).
A hunter-gatherer life where you don't spend any time reading or writing (let alone, most of your working life reading), very little time planning more than a short distance into the future, knowing only at most maybe 150 people and rarely meeting and having to cooperate with total strangers, rarely dealing with novel, abstract ideas, learning completely new skills as an adult, etc. seems a lot less cognitively demanding life than a typical professional office worker in a large city, at the very least.
> But if you transfer the skin cell DNA to an egg, inseminate the egg, and turn it into a baby, that baby is just as young as all the other babies. So DNA damage can’t be the whole story.
Is it possible that this process filters out any damaged cells? As in, more damaged cells will not succeed and we just look at successful ones?
So one mostly end with failed growth or (usually) healthy new organism?
Lets say that growing baby is a tricky process where any unhealthy/damaged cells will die. Would it be consistent with success rate of cloning?
Still, reproduction requires producing less burdened cells so likely there is some repair - but maybe it is for some reason of another very costly to do or rarely successful?
Yes, as the clone embryo develops it will filter out a lot of damaged cells. In general, during early pre-implantation development embryos can kick out cells that are "wrong" in favor of cells that are "right", but it's not a perfect process by any means, obviously we get non-cloned babies in all species that spontaneously abort or are born with defects.
Also this seems like a fine spot to say a bit about cloning:
If you transfer a skin cell nucleus to an enucleated egg, then you don't inseminate it. It already has a full set of DNA. You're making a clone not doing sexual reproduction. The resulting one cell embryo does need to be chemically activated, which is something that is usually triggered by insemination.
To say that baby is just as young as others is not *necessarily* true. Developmentally, it's true. But the DNA could be retaining marks of its age in a few ways.
1. As some people have mentioned, telomere length. Telomeres should be extended after genomic activation in an embryo (at first, an embryo isn't making any of its own gene products...it's using up maternal resources in the oocyte) but this doesn't happen perfectly or reliably in clones.
2. Mutations. If there are replication errors in DNA sequence, cloning won't fix that.
3. During embryonic and fetal development there are a couple of waves of demethylation and methylation that theoretically would reprogram the methylation patterns in the transferred DNA to be exactly as they should be at that developmental stage, but again in practice that isn't always the case.
Clones can be healthy but they also can be extremely unhealthy. They also have higher than normal rates of sudden death due to no apparent cause.
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
I am surprised anyone would make this kind of argument. There were quite a lot of other changes in health and nutrition and everything confounding the life expectancy changes. For example, industrial revolution kicked off an extreme population growth event, and until recently there (in general) was more kids and young people than old people (discounting mortality effects from world wars).
Immortality is also different than extended lifespan. Extended lifespan for one individual still ends, which obviously results in kids and grandkids of the said individual getting the inheritance. (Maybe it could be good for economy that people have time to collect more net worth and then pass it around.) It is quite different from true immortality (it is no longer making sense to save money for retirement, instead it makes sense to build continuous equally immortal income streams to fund on-going immortality treatments and all the fun stuff you want to do).
Also greatly expanded lifespan is different than slightly expanded lifespan. The first change was that lifespans were more equal: more people had a chance of live into so old age where they could be grandparents and maybe great-grandparent, but there were such people even before. The future where the super rich / all 1st world people / everyone gets to live until they are 120 or 200 with young person's body (if not immortal) would be more drastic change.
There are two things here: first, extended (or not) lifespan, but we don't suffer the ill-effects of aging so you naturally die at 80-100 but you are healthy and vigorous up until then.
Second, the Struldbruggs of Jonathan Swift's "Gulliver's Travels", who continue to age over their long lifespan, and are subject to civil penalties from the age of 80 onwards in order to prevent this entire problem of an immortal clique monopolising all assets:
https://en.wikipedia.org/wiki/Struldbrugg
After this preface, he gave me a particular account of the struldbrugs among them. He said, “they commonly acted like mortals till about thirty years old; after which, by degrees, they grew melancholy and dejected, increasing in both till they came to fourscore. This he learned from their own confession: for otherwise, there not being above two or three of that species born in an age, they were too few to form a general observation by. When they came to fourscore years, which is reckoned the extremity of living in this country, they had not only all the follies and infirmities of other old men, but many more which arose from the dreadful prospect of never dying. They were not only opinionative, peevish, covetous, morose, vain, talkative, but incapable of friendship, and dead to all natural affection, which never descended below their grandchildren. Envy and impotent desires are their prevailing passions. But those objects against which their envy seems principally directed, are the vices of the younger sort and the deaths of the old. By reflecting on the former, they find themselves cut off from all possibility of pleasure; and whenever they see a funeral, they lament and repine that others have gone to a harbour of rest to which they themselves never can hope to arrive. They have no remembrance of anything but what they learned and observed in their youth and middle-age, and even that is very imperfect; and for the truth or particulars of any fact, it is safer to depend on common tradition, than upon their best recollections. The least miserable among them appear to be those who turn to dotage, and entirely lose their memories; these meet with more pity and assistance, because they want many bad qualities which abound in others.
“If a struldbrug happen to marry one of his own kind, the marriage is dissolved of course, by the courtesy of the kingdom, as soon as the younger of the two comes to be fourscore; for the law thinks it a reasonable indulgence, that those who are condemned, without any fault of their own, to a perpetual continuance in the world, should not have their misery doubled by the load of a wife.
“As soon as they have completed the term of eighty years, they are looked on as dead in law; their heirs immediately succeed to their estates; only a small pittance is reserved for their support; and the poor ones are maintained at the public charge. After that period, they are held incapable of any employment of trust or profit; they cannot purchase lands, or take leases; neither are they allowed to be witnesses in any cause, either civil or criminal, not even for the decision of meers and bounds.
“At ninety, they lose their teeth and hair; they have at that age no distinction of taste, but eat and drink whatever they can get, without relish or appetite. The diseases they were subject to still continue, without increasing or diminishing. In talking, they forget the common appellation of things, and the names of persons, even of those who are their nearest friends and relations. For the same reason, they never can amuse themselves with reading, because their memory will not serve to carry them from the beginning of a sentence to the end; and by this defect, they are deprived of the only entertainment whereof they might otherwise be capable.
“The language of this country being always upon the flux, the struldbrugs of one age do not understand those of another; neither are they able, after two hundred years, to hold any conversation (farther than by a few general words) with their neighbours the mortals; and thus they lie under the disadvantage of living like foreigners in their own country.”
I think people would prefer the first instance to the second.
"Immortality is also different than extended lifespan. Extended lifespan for one individual still ends, which obviously results in kids and grandkids of the said individual getting the inheritance. "
Most people do not receive a significant inheritance, so this is not important.
"One unambitious - but still potentially true - counterargument to this is that a world where we conquered aging, then euthanized everyone when they hit 80, would still be infinitely better than the current world where we age to 80 the normal way"
Is it really? I think it is quite ambitious argument to make that it doesn't matter that in the universe A (current) we don't do anything we are not currently doing and in universe B (aging stops and people are euthanized) lots of people are killed. Sounds like an argument against universe B, because in universe B we are euthanizing a lot of healthy people.
"Second, life expectancy at age 10 (ie excluding infant mortality) went up from about 45 in medieval Europe to about 85 in modern Europe. What bad things happened because of this?"
Thomas Malthus would like to have a word here.
One of the arguments from the school of economics at the time of the Great Famine was precisely this - there were just Too Damn Many Irish, so the famine was in fact a great opportunity in disguise to clear out the surplus excess population (by emigration to Canada and the USA) and put agricultural practices on a profitable basis.
https://www.jstor.org/stable/2120439
https://www.jstor.org/stable/23040822
https://www.youtube.com/watch?v=7ai5sPkSDI8
The problem with us Irish at the time was mainly sky-high birthrates, not a sudden and drastic increase in lifespan, though. (And of course the situation was exacerbated by landlord/tenant relations and cash crop export arrangements and so on, but that's another spiel.) Scott is correct that sky-high birthrates are still the main problem in the parts of the world that need to worry about overpopulation.
That said, I do think Scott's argument regarding medieval Europe in general is pretty poor- he's talking about a slow improvement in longevity that took place over, what, 800 years? That's hardly going to stop your population from turning over on a regular basis, given humans only live to 80. Alternatively, if he's talking about the massive gains in life expectancy that occurred just over the last century or so, it can be argued that the Boomers being the wealthiest generation in history (and perhaps locking younger generations out of positions of ownership and prestige) does in fact have something to do with them living so long. If our life expectancy goes up by a factor of 10 over the next 50 years (which might conceivably happen), the effects would be much more significant than life expectancy doubling on a timescale of centuries.
I just don't see any long-term escape from the a situation where a world without death either becomes a world without children or runs headlong into another malthusian wall at some point centuries from now. (Which, if I live forever, I might live to see.) The argument for space colonisation (A) assumes that space migration will be cheap and safe enough to be worthwhile and (B) that no legal and political barriers to mass migration offworld will be imposed. This is not an option that has trivially solved the malthusian crises of Africa, for example.
There will never be total immortality, as people will still die of accidents, rare diseases, murder and suicides. Birth rate can be kept low just so it replaces the people who die unexpectedly. Take trees for example. Many of them are biologically immortal but manage to die anyway, from diseases, competition, wind, lightning and whatnot. They are still in a Malthusian trap of course because of their crazy breeding speed - a million seeds by some successful individuals who manage to reach breeding age.
Keeping birthrates this low in the first place would be a major social engineering challenge, especially if you're working to keep accidents, disease, murder and suicide to a minimum (which we do, strenuously.)
Religious conservatives might be willing to shun life extension technology as 'tampering with nature'- can't meet your maker if you never die, after all- and they're also the group most likely to keep up their birthrates and resist child-licensing. So maaaaybe those factors will cancel out. But that doesn't seem like a super-reliable solution.
You could probably convince Christian fundamentalists to at least get the life expectancy up to 120.
Genesis 6:5: And the Lord said, “My Spirit shall not strive with man forever, for he is indeed flesh; yet his days shall be one hundred and twenty years.”
(note that this was a downgrade from pre-flood humans who seemed to be able to live as long as they wanted, over 900 years in some cases).
I'd take 120 years in good health and say thank you, I suppose.
Deiseach, Deiseach... Tom miseryguts was right, there will always be just Too Damn Many Irish, and I'm also proud to be one of them 😁🍀
The previous explanation I've encountered for aging clashes with this. The way I've heard aging explained before is that genes do a bunch of different stuff (assumedly due to compression) and some of those things will be good/bad early/later in life (where early is before passing on genes via having children).
So a gene that's bad early gets evolution'd out of existence; leaving genes that are good early and good/bad later. The probability space of negative mutations is larger than positive mutations so most genes end up being beneficial early in life and bad later in life.
This logic feels compelling to me and precludes the idea that aging is simple enough to be easily cured. I admit to not really knowing much about the topic though.
I read about this in this book. https://en.wikipedia.org/wiki/Other_Minds:_The_Octopus,_the_Sea,_and_the_Deep_Origins_of_Consciousness
Antagonistic pleiotropy is an evolutionary origin hypothesis (latest genomic data seems to support it as at least part of the story) but it doesn't imply much about ease of anti-aging interventions (except versus ageing as genetically programmed to control population size or whatever, which is *very* against consensus and considered close to an old rejected idea). All the stuff about why we age could be equated with "what bad things do genes do later in life" under that idea leaving all else unchanged.
I'm amazed by people who long for eternity, when they don't know what to do on a rainy Sunday afternoon
I'd rather be dead than have nothing better to do than watch mediocre TV.
There are clearly people in both groups, but is there any serious overlap?
Do something interesting next Sunday afternoon, what's the rush?
I'm amazed by people wanting kids when they themselves don't know what to do on a rainy Sunday afternoon.
How many people interested in anti-aging find themselves bored often?
And think about how much harder it would be to become bored if you remained young, energetic and at full cognitive capacity.
"David Sinclair - ... celebrity biologist" Harsh!
"David Sinclair - Harvard professor" Harsher!
Reading this, and I cannot not make a connection to Robert Heinlein's Time Enough for Love. Read it in my 20s, a few decades back . . .
Is part of the answer to the “algernon’s law” objection “because we aren’t evolved to be in this environment of plenty all the time?”
The people who are big on fasting argue you’ll feel more mentally alert and sharper when you’re hungry. This matches my experience as well: I have less energy after I’ve eaten a meal. My guess would be that we may be evolved for a specific long term average rate of mTOR activity, and most of us have it on too often, just like most of us are overweight.
He also argues in the book that there wouldn’t have been some evolutionary benefit for living for arbitrary periods of time in an environment that was chaotic and dangerous. So maybe there’s the answer: yes, you might take longer to heal from physical injuries with lower mTOR activation but this cost is outweight by having fewer senescent cells.
Also, maybe he looks super young in part because he’s so optimistic? Maybe it’s a mix of drugs and positive attitude.
Against Algernon's Law: Evolution shaped us in a certain way under severe energy constraints.
Meaning, the most likely consequence of any improvement to intelligence or any other desirable trait is that you'd have to eat more to stay alive.
Which was catastrophic a couple hundred years ago, and a boon today.
Is that taken into account?
Another point against it: in nature, there's always a high probably of a non-age related death (disease, flood, lion, murder, etc). This means reduced aging will have diminishing returns on actual life expectancy. So no matter how much adaptive advantage a higher life expectancy might provide, if there's any trade-off at all, evolution will never favor anti-ageing very much over alternative adaptations.
If my math is right: if ageing didn't exist but you had a 1% chance of death every year from all other causes (probably a low estimate for humans in nature), life expectancy would be ~69 years. Make it a 2% chance and its ~50. A 3% chance and it's ~23. Ageing would barely move these numbers, whereas an adaptation that reduces risk of death from other causes could make a big difference.
Isn't Algernon's law reconciliation well established for aging? Aging and dieing are good for evolution. We mature we reproduce we care for our offspring and when they are mature we age and die. In the malthusian environment all species evolved in, not competing with our young for resources makes the species more fit. So the trade off to solving aging is that our species is less fit 100000 years out. This could make the toggle easy, but it could also be hard, not because evolution couldn't figure out how not to age but it explicitly made it hard to avoid.
> (using what template? even if you’d saved a copy of your DNA from childhood, how do you get it into all 30 trillion cells?)
One could just take the DNA from 100 or 1000 random cells and average it out. It'd be probably free of mutations... I think.
As for getting it into 30 trillion cells... yeah, that's an issue.
I gave up on true anti-aging when I read an ophthalmology textbook. It was *filled* with explanations of the changes to the eye that take place as you get older, and reversing/stopping those changes would require technology unrecognizable to us. Even if you found some way to get the rest of your body to live forever, you will eventually go blind.
I recently learned about this too, it's interesting to how the eye is built from the inside-out, and remains filled with long-lived proteins (LLPs) that are as old as you are. These proteins slowly degrade with time, and apparently this is a driving factor in the formation of cataracts with age.
It's also not clear to me after reading whether these ideas apply to permanent cells. Can a permanent neuron or a cardiac muscle cell really be induced back into a stem cell? Can a senescent cell?
It'll be hard for me to let go of the assumption that age is a combination of many factors, but I admit the epigenetic idea is interesting.
In such a scenario, I’m sure more research would be out into lab grown eyeballs and better eye transplants.
It's straightforward to do epigenetic mapping of cells, even down to the single-cell level. So: take an elderly mouse and a baby mouse, do the epigenetic mapping, see if there are systematic differences. Has he done this?
Sort of but not really, in a still un-peer-reviewed 2019 paper on biorxiv: https://www.biorxiv.org/content/biorxiv/early/2019/10/19/808642.full.pdf
Agree with the distinction between lifespan and healthspan. Also skeptical that extending lifespan will be as simple as taking a pill and/or intermittent fasting. I think it's likely that average lifespan will continue to increase. But there is likely a natural limit (I've seen ~150 yrs mentioned before, but don't recall exactly what that's based on). Haven't read Sinclair's book yet. So not sure if he addresses it, but mitochondrial dysfunction plays a key role in aging. Mitochondria acquire mutations as we age due to ROS, etc. which leads to cellular malfunction. One potential therapy I haven't seen mentioned in this thread yet is mitochondrial transfer from healthy (young) cells to damaged cells. This has been shown to occur in vitro and in vivo. Nobody has quite figured out a way to harness this phenomenon for therapeutic use yet (lots of people claim they have, but evidence is lacking). The appeal of somatic cell nuclear transfer (SCNT) is that you can create genetically-matched cells for cell-based therapy that have young, healthy mitochondria from a donor oocyte/egg. This is also an advantage of embryonic stem cells over iPS-based cell therapies because those cells originate from an adult with already acquired mtDNA mutations (we've published on this). The challenges with therapeutic cloning of course is that donor oocytes are scarce (although maybe not for long if we can mass produce them in vitro) and delivery is an issue as with any form somatic gene therapy. Anyway, if you're a VC or philanthropist reading this post and want to support our research in this area (as the NIH currently does not fund human embryo research), hit me up. Paula Amato, MD at amatop@ohsu.edu.
> it would be weird if some drug could make you stronger, faster, and smarter.
Isn't that methamphetamine? Perhaps it has some negative side effects.
Regarding embryo's resetting the clock to zero . . .. Years ago, I watched one of those science shows (could have been NOVA), and the topic was cancer. The showed some results with chimeric mice. Start with a blastocyst from a white mouse, then inject a few cells from a black mouse. When the mouse pup is born, and grows, you can see where the black cells ended up -- all the black patches on the mouse.
Now the interesting bit. Now inject black cancer cells into a white blastocyst. In the experiment presented, they injected particularly nasty cancer cells, known to create a tumor wherever they land. The mouse pup is born, grows . . . and is cancer free. You can see where the black cancer cells ended up -- the black patches on the mouse -- but they are not cancerous.
Aging seems like an area where we might not expect Algernon's Law to apply. In my opinion, the evolutionary biology of aging is pretty solid:
From an evolutionary standpoint, organisms (probably) face tradeoffs between survival and reproduction--any given resource can either be invested in maintaining your current condition, or producing offspring, but not both.
Having offspring now is better than having offspring later, even if you have the same total number of offspring, because that means that your lineage fits more generations into the same time period as your competitors, and is thus more fit. Depending on the numbers, it will often be better to have fewer offspring quickly than more offspring over an extended period of time.
Put this together, and it means that basically all organisms should want to shorten their lifespan in order to reproduce more and more quickly. Even going from "infinite lifespan" to "finite lifespan" is going to be worth it for surprisingly small gains in reproductive rate.
"Aging" is just the molecular consequences of making that tradeoff. Stopping aging isn't about breaking a tradeoff (in which case Algernon's Rule would kick in), but just moving the tradeoff to an evolutionarily disadvantageous solution. This seems easier.
There's a very compelling series of essays on LW starting here: [1], detailing the non-adaptive explanation for aging. The summary is that regardless of aging, people will die anyways, to disease or predation or what have you. From an evolutionary standpoint, genome invested in preventing aging are wasted, because most people will be dead before it has any benefit. So most new mutations go towards helping young people stay fit, with the elderly falling to the wayside.
[1]: https://www.lesswrong.com/posts/sbDuEdtkMEcs5zSrT/why-we-age-part-1-what-ageing-is-and-is-not
This explanation also reduces the applicability of algernon's law, since it supposes basically that there hasn't been much pressure to decrease aging. We know that there are species that, for all intents and purposes, can live forever. If sufficient pressure was applied, we could do the same. So aging isn't entirely impossible, like, say, building more efficient muscles would probably be.
But non-adaptive explanations are far less hopeful than adaptive ones. The adapative explanation supposes that there's basically a switch, and evolution can adjust it up or down based on how long it wants people to live. If we find the switch, we solve aging. Under the non-adaptive explanation, there is no such switch. There are probably tens of little switches we could adjust, but they are relatively hard to find, or else evolution would have found them. We are still incredibly poor at medicine, and nearly all of our treatments basically involve helping the bodies natural healing mechanisms. So if the body doesn't have a healing mechanism, with respect to aging, then we are very unlikely to solve it any time soon.
Good point--the "selective shadow" hypothesis you describe is another important evolutionary explanation. The only thing I would add is that to some (partial!) extent this *is* an adaptive hypothesis: discounting of future reproduction due to chance death is part of why trading off lifespan to get current reproduction is selectively advantaged.
OK, I'll add one more thing--it's important to note in this discussion, as Scott kinda did, that germline cells don't age. So there ARE switches to be manipulated (cough telomerases cough)--the questions are whether these are switches that are practical to manipulate, and whether manipulation of them has the desired effect at the tissue/organ level.
Chiming in as well to add my take on rapamycin: out of all of the longevity agents I am interested in and/or take myself, it is likely to be the one that I have the highest hope for in humans. We have a decent understanding of the mechanism (compared to many other things, at least), it works very consistently and strongly in several other organisms, and the mechanism of action is strongly evolutionarily conserved. As for safety concerns, it seems like if taken in a low dosage and infrequently enough, the safety profile improves significantly and it may be a net-plus in many areas (this may be related to mtorc1 vs mtorc2 activation depending on the dosage and timing (it does have a pretty long half-life!), which also makes it seem like it can be taken without actually suppressing one's immune system or causing some other undesirable effect categories).
Although I do know of many others that take rapamycin, I still don't suggest it to anyone myself, firstly because I don't offer medical advice of that nature regardless of my cost/benefit analysis (are there risks of potentially bad unknown side-effects with long-term usage? sure, but the risk of *not* taking longevity agents is also pretty large, and results in a much earlier likely death), and secondly because it is still likely to be higher risk than a lot of other simple things that I do often suggest to others, like glycine supplementation, which I see as close to zero risk (a few others on https://nearcyan.com/supplements/ if interested). I'd hope that anyone that takes it themselves has blood panels done (if not much more) to ensure they're not doing easily-observable harm to themselves as well. It's definitely a very interesting area of research either way; I can't stop myself from paying attention to stuff like this due to how large the potential impact on humanity is.
A few rapamycin links for those interested (more if you just search on pubmed!):
Rapamycin and aging: When, for how long, and how much: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401992/
Longevity, aging and rapamycin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207939/
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786175/
Rapamycin slows aging in mice: https://www.ncbi.nlm.nih.gov/pubmed/22587563
Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032600/
I enjoyed David Sinclair's book and some videos, but he is too good at hyping whatever he wants to. I trust his results published in good magazines, but he hasn't so far done anything in humans. He is a mouse guy.
Meanwhile, Greg Fahy has succeeded in reducing epigenetic age in humans by rejuvenation of the thymus (by a combination of HGH which rejuvenates the thymus + metformin and DHEA that prevent some bad side effects of HGH on insulin regulation). The trial was called TRIIM. He is now running an extended trial in humans again, called TRIIM-X, to find out how many measurable qualities improve as well. (Because we do not know how tight or loose the connection between epigenetic age and real state of the organism is). There was a recent interview in which he claimed that intermediate results are fairly good so far - for example, kidney function has improved, inflammation markers and PSA went down.
But Fahy is an unassuming kind of guy, almost shy, so he gets almost zero attention.
>Modern Europe is currently in crisis because it has too *few* people and has to import immigrants from elsewhere in the world.
It's not hard to imagine that in a society where people live to be 200, the fertility rate would plummet, particularly if you measured fertility based on the number of children women have for each year of their life, which might be a sensibility way to measure it if that denominator changes dramatically. And if the problem is not too few people, but too few workers, you could end up with a lot of old rich people living off many decades of capital gains. A shortage of workers could really become a problem in such a society.
But that's just speculation, and I agree with the point you make in the next paragraph:
>Would Europe be better off if the government killed every European the day they turned 45? If not, it seems like the experiment with extending life expectancy from 45 to 85 went pretty well. Why not try the experiment of extending life expectancy from 85 to 125, and see if that goes well too?
I suppose the notion of many old people being able to live many decades off capital gains is in conflict with the notion there would be a worker shortage. If there is a great worker shortage, there wouldn't be much in the way of capital gains!
I like to imagine that longevity therapies that staved off death would also improve general mental and physical health, which aside from reducing burden on the health system might also allow the elderly to engage in some level of productive work. Depends on exactly how spry they feel, I suppose.
Even if physical and mental health grow proportionate with life expectancy, it seems like a lack of creative young minds would still hurt society a bit. OTOH, some scientists and engineers may benefit intellectually from being able to use knowledge gained over a hundred-year period. I wonder how many innovations we lose because one person can only be productive in their field for say 50 years instead of 100?
I'm less concerned with maximising the pace of innovation and avoiding a general social collapse due to an inverted demographic pyramid.
I'm haunted by Hanson's thesis that since for most of human existence most humans existed at subsistence levels, the best prediction for the long-term future is that most humans will exist at subsistence levels. Perhaps a massive increase in longevity combined with stagnant productivity increases will help us get to that future/return to that past.
But it in the long run we will all be dead. Or will we?
"...the best prediction for the long-term future is that most humans will exist at subsistence levels..."
Yeah, that possibility worries me as well. None of us want to live in a 40K hive world.
The more innovation, the less workers that will be required.
If we were able to revert everyone to a mid-20s state (presumably you can't go back to before the brain is fully developed), presumably everyone would have a creative young mind, only boosted by experience.
Hard to say. We lose cells as we age and a lot of synapses get pruned, but I supposed sufficiently-advanced rejuvenation treatments might be able to fix those problems as well.
It's not a great line (from Scott) because it implies the usual n00b mistake about life expectancy. A better way of putting it would be "Would Europe be better off if the government kill every other European in childhood and the other half lived to be 85?" Depending on how the government chose its victims, the answer to that might actually be "yes."
I would expect the fertility rate to increase, no decrease. If you increase a woman’s reproductive years from ~40 to ~140 then that gives her many more chances to reproduce. What’s more, many women fail to reproduce because they seek a career first and then find that their biological clock has run out: imagine if you had enough time to build a career and still had a hundred years to take time off to start a family? Right now leaving work to raise kids takes you out of the workplace about 10-15 years or so. Currently that’s about one third of your total working life, which is a big deal. If we live to 200 it would be more like one tenth or less, a much smaller sacrifice to make.
Finally, kids are an investment in well being. Up front they are a lot of work, but every year they live they are less work and yield higher dividends in life satisfaction. If you live three times as long then the potential return on the investment of having a child increases as well.
Menopause occurs because women run out of eggs, because egg cells are produced prenatally.
https://www.sciencealert.com/why-women-s-eggs-run-out-and-what-can-be-done-about-it
Anti-ageing therapies, in and of themselves, can't fix that problem (though of course with sufficiently advanced biotechnology you could just clone new egg cells or, for that matter, bioprint replicants on assembly lines.) Biologically speaking, a woman's optimal life strategy would be to have children in her early-to-mid 20s and pursue a full-time career once her kids are out of the home (or at least partly capable of fending for themselves.)
Well, women might be more apt to postpone college if they knew they’d get a hundred more years after raising a family to have a career. Maybe.
Perhaps, if rational cost/benefit evaluation was the main consideration.
My favorite aging theory is the gradual dysfunction of proteosomes. Cells make a crapton of proteins all the time, and they really need to get rid of all the broken and dysfunctional ones, so my theory is the increasingly failure to do so as cells age is what makes them senescent. It also fits nicely with the starvation effect: presumably when your cells aren't getting enough fuel and nutrients they have some ways of boosting the efficiency of recycling.
"Modern Europe is currently in crisis because it has too few people and has to import immigrants from elsewhere in the world."
Much of Modern Europe is currently desperately trying to prevent immigration.
Yes, and the type of immigrants its trying to prevent are those that have a strongly net negative fiscal impact (along with a slew of other strongly negative socio-economic impacts on average), which is to say, those that not only don't fix the economic issues associated with a higher dependency ratio due to an aging population, but actually make it much worse.
> Kidney cells go from definitely-kidney-cells to mostly kidney cells but also a little lung cell and maybe some heart cell in there too.
I'm not a biologist... but isn't this a testable claim?
The "expand full comment" link isn't working for me. Anyone else have this problem?
See https://astralcodexten.substack.com/p/book-review-lifespan/comment/3835749
"Expand full comment" still isn't working on this post, but it's working on earlier and later posts (at least some of them.)
"Expand full comment" is working here now.
> calorie restriction hasn’t been around the hundred years it would take to see results in humans. A few very committed biohackers having been trying it for a few decades now, so I guess we’ll know if it works by the mid-21st century.
We should see results in reduced mortality rate soon.
> Why didn’t the body just evolve to secrete that drug itself?
Since only traits that are beneficial or neutral would have persisted, presumably keeping old people around beyond a certain point is not particularly beneficial. Older proto-humans had incentives to crush younger and healthier challengers to their power, which would inevitably weaken a species. Older genetics may also be more poorly adapted to changed environments.
Humans are now pretty adaptable to a wide range of different environments, and we have some cultural adaptations that could possibly mitigate the "threat" of immortal old people.
> The impression I get from Lifespan is that all of these things will both make you live longer and make you healthier. That doesn’t really make sense to me.
It's common sense that you would want a strong immune system, unless you get lupus. So maybe mTOR gets *overactive* as we age, and these compounds suppress it only where it's not really needed.
People in this thread keep saying that NMN is "cheap", but I don't see it. Sinclair recommends 15mg/kg/day, so that's 1g/day for me. Most capsules I see on Amazon look to have 150mg and a bottle of 120 capsules is over $100 (CAD). That's $5.50 per dose, per day. That's not really that cheap given its speculative benefits.
Even the bulk supplier I'm aware of sell 500mg bags for over $1,600 (CAD), which is at least cheaper at $3.20 per dose, but still not cheap. If the benefits were more certain then maybe it'd be worth it.
I'd love if we could make some progress against aging, but I'm highly skeptical of nearly every claim made about its underlying causes and how to control it. Call me part of the camp that believes the problem is a death by a thousand cuts issue, where aging isn't just one or two problems that can be solved by 'fixing' DNA damage or epigenetic drift.
Speaking of DNA damage: it just doesn't fit. If accumulating mutations naturally caused aging, then why don't successive generations live shorter and shorter lives? We shouldn't have a situation where lifespan (controlled for infant/infectious disease mortality) is LONGER today than at any time in the past. Presumably the gametes are still dividing, just not as much as the kidney cells, so the same mechanism is at play there. So the same mechanism of DNA damage accumulation will happen, just more slowly over generations instead of over a single lifespan. In other words, this mechanism seems to suggest humans would have died of old age long before they ever evolved as a species.
Same argument for mtDNA damage accumulations.
Same argument for epigenetic drift. Why aren't we seeing epigenetic drift in the gametes? Are egg cells special in that they don't have epigenetic drift? Shouldn't we expect that there will be none left in a few generations - same as other cell types? Why not?
Meanwhile, there are all the normal mechanisms of aging that just don't feel like they're adequately explained by these ideas. They feel like a lot of hand-waving about how a general mechanism will lead to downstream effects, without ever having to connect the dots. For example, why does this accumulation of genetic/epigenetic changes lead specifically to memory B-cell depletion? And why is that mechanism both consistent, and gradual? If this were random drift, we'd expect to see more variation among individuals. A natural mechanistic explanation would better explain a phenomenon that is consistent and gradual.
For example, not everyone gets malignant cancers, and yet we all accumulate stochastic mutations over our lives. And even among those who get cancer, there's massive variation in which cell types are most affected, and how that manifests. Yet for aging, we always see arterial wall hardening, skin changes, etc. Why such consistency if we're working from a random mechanism? It doesn't fit our other experiences with stochastic biological mechanisms.
Is there a good word for slowing aging? Even if none of the theories are complete, maybe making use of all of them buys an extra 50 years in decent health.
Deleterious mutations get selected out. This works because you are able to mate with somebody who doesn't have those mutations. Sometimes this selection pressure on a species weakens and you get mutational meltdown or an extinction vortex. I suspect this is the main reason why sexual reporduction exists.
I'm still unconvinced by this hypothesis. The idea is that all your cells are accumulating mutations all the time. Some more than others, okay, but then why does aging happen so consistently at the tissue level if it's so inconsistent at the cellular level? This does not match what we observe in other diseases.
And if we're accumulating mutations throughout our lives, but it manifests as 'aging' only after the first few decades, then we should STILL expect to see a gradual aging at the population level, regardless of the effects of the sexual selection mechanism. Accumulated mutations can't always and forever be happening somewhere else. Mutation isn't a directed process, so some cells are going to capture some of those age-related mutations (or epigenetic drift, or whatever) yet still be viable. It's just the next generation will need less to get the organism past the threshold, i.e. aging will be quicker with each successive generation.
Sexual selection has a major cost: 1/2 of all the organism's genetic material. Yet it persists, because it allows for genetic admixture within the population in a way that asexual reproduction cannot match (not even by passing plasmids around). It is beneficial to reproduce because you create more copies of your genes. It is beneficial to reproduce sexually because you get genetic change more quickly that way. Many nematodes can switch between asexual and sexual reproduction. In times of low stress, they preproduce asexually, keeping all their genes. In times of stress, they switch to sexual reproduction, which drives greater genetic diversity/change.
No matter how you splice it, an organism has to get its genetic material into the next generation, keeping the vital mechanisms of life as intact as possible in the process. I just don't buy the argument that these very mechanisms are in a state of constant decay because of accidental, stochastic processes that only ever manifest in the very old but are accumulating throughout our lives everywhere but in the gonads.
Here's an interview with Aubrey de Grey from 10 years ago about his own book on the same subject of human immortality, "Ending Aging":
https://hplusmagazine.com/2011/07/19/starting-to-make-sens/
I feel like a lot of the signaling pathways game misses the complexity of the system. We talk about "mTOR" as if it were a hormone like insulin that we can track, or that your body turns on and off. But mTOR is an intracellular signaling molecule. And intracellular signaling molecules don't work in PATHWAYS so much as they work as parts of NETWORKS. The complicated-looking diagram Scott showed is probably right for some cells, where other cells might have a different set of signaling molecules expressed. Thus activation (or suppression) of mTOR will have a different effect, depending on what else is being expressed in the cell at the time.
To say cell signaling is complex doesn't begin to describe the situation. I remember learning about promiscuous signaling molecules back in undergrad, and thinking, "Okay, now I know how NFkappaB works", or "so that's what ras is doing." Then I'd learn that NFkB wasn't just a single protein, it was made up of subunits, and each of those subunits had different splice variants which would do different things, and some scaffolding proteins changed which subunits came together in the protein complex, and post-translational modifications could also alter each protein subunit, and all the same were true of ras, and ... eventually I gave up.
I realized that the easiest thing in the world is to say that "signaling molecule X is the key to this whole operation". That's like telling a patient, "The reason you're having difficulty breathing is because of your lungs." Great. That's not really interesting or helpful.
It's the illusion of knowledge about the root cause of the situation without any actual understanding of time, place, and manner. Saying things like "we just need to turn off mTOR" is about as useful as saying, "you wouldn't have these breathing problems if we just shut off your lungs. No more breathing, no more problems." Or the seemingly more sophisticated, "we can solve your aging problems through better regulation of mTOR" which is functionally equivalent to, "we can solve your breathing problems through better regulation of your lungs."
What we should really be saying is, "It looks like mTOR is involved in this process, but we honestly don't know how or why. We're unclear how we might use the mTOR information to solve the problem. We're looking into it, but don't get too excited because until we understand the root cause of the issue we won't even begin to know how to solve it." Not as much hype that way, though.
> And the increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps.
Didn't most of the life expectancy increase between medieval and modern occur in the 20th century? And aren't most developed nations right now trying to cope with an abnormally large wave of increasingly long-lived people (e.g. boomers). And isn't the current zeitgeist that millennials have nothing while their parents/grandparents have everything? Saturday Night Live did a music video sketch about boomers not that long ago that contains this sentiment (paraphrasing) "they took all the money and they took all the jobs and they won't ever die!".
It's not a good reason to ban immortality, of course. And perhaps in the long-run steady-state, this would just work out OK, but people don't live in the long-run steady state - the first "old" generation to get the immortality pill is going to receive some truly vicious hate from the younger generations of the time.
I think a lot of the increase occurred earlier, but it mostly consisted of reducing child mortality, not increasing life expectancy for adults.
Here's a somewhat plausible modest goal. There are people who live into their 90s in good health and then die fairly quickly. It runs in families, so presumably hereditary. The best news I've heard is that these people don't lack deleterious genes, they have more (better?) protective genes, so there might be something which can be bottled.
The massive challenge for any sort of longevity is that we might not have the tools we need yet. More math! But which math? Better tools! But which tools?
Living into the 90s in good health and then dying quickly sounds ideal. Seems modern morals go against the dying quickly part, however. I mean, few people are against figuring out how to make us live longer, yet I suspect many would be against research into how we could die quicker after living longer.
"Finally, a friend wasn’t impressed with Sinclair’s clone argument. They point out: suppose aging is DNA damage, and it happens to every tenth cell. Having a tenth of your cells damaged is pretty bad, especially if they become senescent. “Senescent cells”, common in elderly people, have sustained so much damage that they can’t even die properly, and just sort of sit around being hopelessly confused and secreting random chemicals which freak out all the other cells around them. Everyone agrees these are an important part of aging, even if they’re not sure about the specifics. But if 1/10 of your cells are like this, then you have a 90% chance of grabbing a healthy cell for cloning. And even if you get a bad cell, no cloning process works every time, so you’ll just shrug and try again."
Couldn't you decipher an old person's original, undamaged genome by sequencing the genomes of ten of their cells, and the creating a composite genome that excluded any base pairs that were different in a minority of the ten?
For example, assume there's a gene made of six nucleotides. I extract ten cells from the same person, and the sequences for that particular gene are:
Cell A genome: AGGCTA
Cell B genome: AGGCTC
Cell C genome: AGGCTA
Cell D genome: AGGCTA
Cell E genome: AGGCTA
Cell F genome: AGGCTA
Cell G genome: AGGCTA
Cell H genome: AGGCTA
Cell I genome: AGGCTA
Cell J genome: AGGCTA
Cell B is the senescent cell, and so is the only one that is different. I throw out its results and conclude that the correct sequence for the gene is AGGCTA.
It's probably way more expensive and way more complicated. First of all, you need to sequence the entire genome in each cell. The costs for that have fallen spectacularly, from $300 million in 2000 to $20 million in 2006 to probably ~$1000 today. But it's not super cheap, and if you need a lot of them, which seems likely, the costs add up.
Don't forget you will also probably need many copies to correct the errors you make in sequencing. The human genome is ~3 billion letters long, and the chances that you get *all* of them right in each attempt at sequencing are miniscule. So you'll need to do more sequences, to try to fix the errors in your sequencing, and of course these will get mixed up with the natural mutations, too -- I'm not sure how you would easily distinguish between them, which you clearly must if you're going to try to identify natural mutations to correct.
Finally, the harmful mutations that are most likely to happen are probably not random point mutations, like those you describe, but cases where extra DNA has been inserted (perhaps only a nucleotide or two), or some DNA has been lost, or a section has been transposed from one place to another. In all of these cases you can get very long stretches of DNA that don't match from transcript to transcript, because the "reading frame" has shifted, which I think makes identifying the correct sequence in a brute-force way (i.e. without knowing the function of all the DNA sequences) much harder.
Correction for Scott: Rapamycin is made by a bacterium, not a fungus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561035/
One part of the definition of biological life, I think, is that it dies. Another implicit part of the definition, I think, is that it is unique, an individual entity. Are there cases where biological life as "an individual entity" are blurred?
Us fellow humans tend to view a bee hive as a composite entity, not life itself but composed of many individual biological entities. Part of the reason is the physical separation between one bee and another. Another part of the bigotry I mean bias I mean logical reasoning is that a particularly bee hive could last forever and not die like an individual primate is destined to in under 120 years.
Is it not a central reason that life can't become immortal because we define life as mortal?
A bacterium could in perfect circumstances live forever, yet I would call it "life".
Trees are immortal life forms. Unless you cut one down, but "immortal except in cases of violence or accident" is probably the closest you'll get without literal magic.
https://www.sciencedirect.com/science/article/abs/pii/S1360138520302028
Does anyone seriously think that any anti-aging intervention we are likely to make in the next 10 years will be remotely applicable to people who are 70+ right now? Seems to me like preservation is the only way to help these people.
I didn't know that cloning works well, I remember being said that clones have shorter lifespans. So cloning works ok? Why can't we have hundreds of clones of Neumann then?
Will we be able to grow human skin tissue in vitro indefinitely soon?
Sorry for stupid questions.
To my limited knowledge, the issues with cloning humans are ethical, not scientific. Experimenting with human cloning means you're creating a person every time you give it a try, and that's a fraught decision even before you introduce the risk that your new von Neumann dies tragically young because of technical problems.
(Also, von Neumann died 70 years ago and I don't think we have any of his cells lying around.)
Google tells me that cloned skin for burn patients is a real thing that's done rarely - the two articles I found say it was because the burns were so large there wasn't enough skin left for traditional grafts. So we can do it, it's just a practical problem now - there aren't that many applications for human skin outside medical emergencies, and simply taking skin from elsewhere on the patient's body is usually easier.
I suspect the ethical issue is driven by blank slatists who maintain that cloning Neumanns, even if succeeds, would be useless, and mount scientific defense to (nearly) blank slatism.
So... I guess in the end this supposed "cure for aging" would really only be a significant-but-not-orders-of-magnitude slowing of aging? If so, surely none of the usual arguments against preventing aging/death apply?
My first thought is that aging isn't just about DNA or generalized metabolism. There are all sorts of structural things going on. The body can repair itself, but the repairs rarely leave the body in the same shape as its original structure. There are all sorts of scarring, restructuring, and work arounds. You can reduce to damage by providing better medical care. You can induce repairs. You just can't eliminate the structural changes.
For example, there is work on inducing heart cells to reproduce to repair heart attack damage. It might even work, but how much growth can be induced and how much scarring endured without compromise.
Still, I'm optimistic. Every time scientists agree that we've reached some maximum age limit, new ideas and treatments come up and we move past it.
> The increase didn’t cause some kind of stagnation where older people prevented society from ever changing. It didn’t cause some sort of perma-dictatorship where old people refuse to let go of their resources and the young toil for scraps
Except it actually does -feel- that way. (Sorry I don't have any resources to back this up but my own experience). If you grow up in Italy you're definitely confronted with a political and economic system where older and powerful actors hoard resources and prevent younger dynamic forces to destabilise them. No wonder Italian researchers/workers/entrepreneurs do so well when they emigrate: the latent potential is there (they're educated in a modern, beautiful, powerful country) but they lack the opportunity to express their talents.
So yeah, maybe reversing again does have negative consequences to the economy.
Good enough for science fiction: energetic young people keep discovering new areas for their ambitions. I have no idea whether the older people eventually manage to lock all possibilities down, nor what structure of ageing and death would be best, in some sense, for the species.
Energetic young people in these countries will probably find out it's easier to emigrate somewhere else rather than trying to change things around them. So things don't actually change because there's an easy way out. Which is great for those that can escape but not so great for those who can't for a variety of reasons.
I finished this book 1 or 2 days ago. The end has a lot of discussion of political issues and I felt like it was a lot less enjoyable to read his analysis of the political issues related to aging and his progressive viewpoint on certain things.
his name appears to me to correspond to malkuth...
On the off chance that anyone will ever read this, I want to comment on Scott’s skepticism that sirtuins (or some other protein) can figure out the “correct” epigenetic state of a gene, esp because it differs for the same gene in different cell types.
One epigenetic modification is cytosine methylation when it is followed by a guanine, called CpG, to distinguish it from the CG base pair. One might notice that if one strand has 5’CpG3’ then the complementary strand also has CpG at that point (read the opposite direction - the strands are antiparallel. When CpG cytosines are methylated, they are methylated on both strands.
So, if somehow the methylation is lost in one strand, a hemimethylase could check the other strand. If it’s methylated, then methylate the first strand. Incidentally, methylation tells the cell which strand is old when DNA is replicated. If there is a mismatch, the unmethylated strand is wrong. It’s imaginable that breaking methylation ups the mutation rate, though probably only slightly.
There is also a possibility that the transcription factor(s) for being one cell type can suppress transcription from other sorts of promoters. Maybe that’s how a muscle cell knows to be muscular? Maybe that process breaks down when an animal is well-fed?
That said, I think epigenetic dysregulation is an interesting theory of aging. Probably wrong, but very interesting.
Bats would be super-interesting to study for aging research. There are lots of species, so cross-species comparisons are more reasonable than mouse <--> man. If two bats species have similar size, diet, and metabolic rate, but much different lifespans in captivity, then physiological differences might be causing slower aging. Some bats are roughly mouse-sized but live a lot longer.
On cancer and telomerase, the protein p53 checks for DNA damage and arrests the cell cycle/leads to apoptosis (cell death). It’s mutated or missing in half of cancers. Elephants have many more copies of the gene and much lower cancer rates. Upping p53 in all a person’s cells through germline or currently magical somatic cell genetic engineering would give them a lot more headroom for other changes that would increase cellular regeneration but increase cancer risk,
This would be a good point if aging were some kind of a random process. But what if it's biologically programmed as Harold Katcher rather convincingly argues here? https://www.amazon.com/Illusion-Knowledge-paradigm-research-rejuvenation-ebook/dp/B09C7JNB64
Then, it could well be possible to reverse this process quite easily by giving cells the signal(s) opposite to the pro-aging one(s). Katcher has essentially done it even more impressively than Sinclair in rats.
Also, are you aware that Sinclair's lab managed to make old mice regrow their optic nerves using Yamanaka factors? That's just one tissue but it's an amazing boost. And the cancer problem was solved because they removed one of the five factors which turned out to be cancerogenic.
The anti-cancer effects sounds fascinating (I dimly recall bumping into some article on the topic on reddit at some point) but it does raise the question why that biological programming evolved in the first place.
There have recently been controversies about Sinclair's work on resveratrol and sirtuins; video summary, from Lifespan News, here: https://www.youtube.com/watch?v=eBxw6_8PivA.
My favourite pop science book on aging is Andrew Steele's "Ageless" (2019); it's broader and less focused on one guy's theories. My goodreads review of it is here: https://www.goodreads.com/book/show/52954648-ageless