These were my same conclusions after spending 4 years doing a PhD that involved the basic study of aging at the genetic level. "It's all just random," a fairly prominent gerontologist on my committee told me about halfway through the project. This is still my main takeaway.
Further, a cure for aging would be one of the hardest things to actually test and get approved as a drug. Aging itself is not classified as a disease, so the FDA could not approve a drug for that unless this situation changed, which would get very political.
Even if you found a workaround for that issue, how would clinical trials ever work? They would take multiple generations to do safely. I will be dead before any such drug is approved, even if everything else goes right.
Ultimately, I realized that studying aging will almost certainly bring no personal reward to me or billions alive today. Even if it was a tractable problem even in theory, which I no longer believe it is. One of several reasons why I abandoned academia and now am just a boring old ER doc.
Presumably any good life extension drug would also reduce some of the symptoms of aging, so the most likely work-around is that as long as the safety profile is good enough (and wouldn't it need to be if you are giving it to the entire population of old people?) it will just get approved for treating some random secondary marker that it improves. "reducing the risk of heart disease" or even just "treating grey-hair". No political fight or multi-generation clinical trials needed there.
Some of these things aren't even needed as drugs per se, right now. Fisetin is thought to be a potent senolytic and widely available over-the-counter, for those who wish to take the risk. (Bioavailability is a major problem with the oral kind, though.)
I understand the strategy. It's been a strategy since at least 2000, around the time Aubrey de Grey and SENS became well-known.
Have there been any notable advances by SENS and allies since 2000?
The point of "it's all just random" is that things that treat secondary markers generally do just that... treat secondary markers. It's like repainting the one-hoss shay, when in reality the only thing that could "cure aging" would be to basically build a new shay.
Don't get me wrong, I'm not trying to discourage whoever wants to study this stuff. (Although in a sense I deprived myself of my 20s in order to do it just the way I wanted.) I want to return to studying this stuff whenever I can FIRE. It's fascinating and aging is the cause of so much human suffering. But, I suspect there is no solution to it. I'm just a guy who enjoys tilting at windmills.
I'm fairly ignorant of the details of FDA regulation so I have to ask: if ageing isn't a disease, then wouldn't there be no need for FDA regulation? Is it really a drug if it doesn't treat a disease? How does the FDA define a drug anyway?
I guess that word "FDA" was a distraction here. My main point was really about, like, actual personal safety for you.
Suppose some guy came up with a drug he says will make you not age. What conditions would have to be true to make you swallow this pill every day for the rest of your life?
If FDA does not regulate this, would you risk your personal safety by taking it? What if it's, like, the next DNP and there's a 1/10,000 chance it will make you spontaneously combust? What if it's so new that no one knows that?
If FDA does regulate this, well, then we need clinical trials eventually. What is the bar for a successful clinical trial in this case? Delayed death, really.
If "this" is just a cure for baldness and is approved by the FDA for that indication, sure, go ahead and take it off-label. It's probably safe and probably no combustion for you. But what makes you think it will delay your aging?
My main point is that my life is pretty good right now, I accept that I am mortal, and so the bar for me personally to take such a pill would be really, really high. It's OK if your bar is different though.
Aging isn't classified as a disease yet, but there's growing pressure to, and I think we're on the way. A couple years ago the WHO added a code in the International Classification of Diseases for "aging-related diseases".
I don't think it would get that political, due to the simple fact that everyone faces this. There would be political problems resulting, to be sure, but we always have them.
Clinical trials? People are actively working on that. It would get approved by using quicker metrics of aging with things like the various biological clocks, like Horvath's using DNA methylation. There are some aging clocks using blood markers, too, if I recall aright. In any case, the FDA's hand might be (probably would be) forced by medical tourism.
Oh, I'm 80% sure it would get political if there was a big move up-front to classify aging as a disease. Think of all the FUD that came out about GMOs 5--10 years ago. Now add in all kinds of narratives about class, the elites sucking young blood, etc.
In the popular imagination, with just a tiny bit of spin, immortalists are Voldemort. Many, many sides have many things to gain by attacking this straw-man.
(Full-disclosure: I'm anti-GMO because Precautionary Principle.)
I'm not sure most people would realize the implications if they classified aging as a disease. For many months now I've been telling friends, family and acquaintances the things I've been learning about this amazing science and the nearly weekly breakthroughs it seems to have, and they're invariably reacting with something like, "I had no idea!"
But as I pointed out earlier, everyone is facing this. Not only is the AARP a potent political force, but your average member of Congress is in the physical-decline part of current life- and healthspans, giving them a strong incentive aligned with that of the AARP and the most reliable voters, retirees. By contrast, I don't see a strong potential coalition to line up against them.
People were making the same arguments you just made 20 years ago when I got into gerontology. Indeed, that's part of the reason I got into it. I genuinely hope this time this will happen.
Fertility span is more relevant than lifespan. An asocial geezer who no longer reproduces is irrelevant to evolution, except as a competitor for resources to those who are still reproducing. A social geezer however might contribute to the chances of offspring reproducing, and this is I think a typical proposed explanation for longevity (though would seem to be only necessary as an explanation in those species for which longevity/fertility is unusually large).
I think this is thinking about evolution as acting on a species level. Evolution can't design creatures to die off so that they stop competing for resources with the rest of the species, it doesn't act on that level. The closest you could get to an evolutionary advantage of dying off would be leaving more resources for your children, but your children are only half you, and you are all you, so it would be better, from a relative gene expression point of view, to stick around and continue breeding, even if it means competing with your children (every child you have is another 50% you, every child your children have is only 25% you).
Evolution doesn't care about how many rolls on the mutation table it gets, because it doesn't work on that level. It's just the understanding that an entity that replicates more will be more prevalent than one that replicates less. This *ends up* as a search for good replicators, but it is not a goal. And a replicator that dies off is going to replicate less than one that sticks around and continues to replicate.
It seems unlikely for evolution to select for eventual death (it also seems unlikely for evolution to select for eventual infertility), simply because things that stop replicating... stop replicating. Therefore, it's more likely that death and infertility are just problems that evolution failed to solve yet. Which does still end up suggesting that these things are difficult to solve, but for different reasons.
It gets subsumed in replication. A thing that can't escape predators dies and fails to continue replicating. A thing that can't manage to feed itself dies and fails to continue replicating. Successful replication requires those additionals.
I wish I could claim to mastery on this, but one thing I do understand is that evolution is not a force. It doesn't actually push in any direction. Evolution is something that falls out of the math that if you have two things growing exponentially, one growing at x^t and one growing at (x+1)^t, at some future point the second population will vastly outnumber the first. Draw in complications like portions of the population dying off, and it won't affect the core conceit.
From a empirical standpoint, evolution actually selects against mutation. Polymerase has an exceptionally low error rate, and this doesn't seem to be an accident. It makes sense: In evolution, the "populations" aren't of organisms, they're of genes. The organisms are just housings for those genes. Mutations just mean that some of your replications aren't actually replications, so in terms of increasing your population number, you can get better results by decreasing mutations, and thereby increasing replications.
If organism A doesn't create more organism A, but instead creates copies of organism B, in the future you should expect to see a population that contains mostly B, and very few A. A has been selected against.
No reason for false modesty, you can claim mastery on this. You avoided the classic traps of goal and group selection, and got kin selection right.
Death or aging will not increase the genes copy you can output, so it is not evolutionary selected for. It's a byproduct of other things selected for, the result of a trade-off. But such trade off are super common, because short term benefit is so much more important than long term ones (earlier gene copies are amplified because they coupound faster) , and accidental death ensure there is a quick diminishing return for late copies.
Not necessarily; there are serious arguments that longevity is selected for in part because there are natural selection pressures on society, too. That is, societies with older individuals helping take care of the kids can work sufficiently better that longevity gets selected for.
One thing worth noting is that older men are much more likely to be fertile than older women, which may be because of the high rate of mortality from childbirth.
>I think aging might be one of the hardest conditions to reverse or cure. Death is a significant driver of evolution.
But we're talking about AGING, not death. These are two different subjects: it's possible to grow old without dying, and possible to die without growing old.
I don't understand your logic. How does dying faster help a species evolve? How is having 2 offspring and then dying at 40 better than having 2 offspring and dying at 80?
In most premodern societies, older people serve a function. They provide childcare, and act as carriers of tribal knowledge (which is important when you can't read or write). You don't want them to die off as fast as possible.
My own theory of aging:
Mankind evolved in an environment where there was a high chance you could suddenly die from disease, starvation, predator attack, and so on. For this reason, evolution never had a reason to "crack the code" of aging, because it wouldn't have benefitted anyone. By age 70 something probably would have killed you.
Greg Cochran had a cool metaphor: it's like inventing a type of car paint that never rusts or fades...and putting it on a car that's about to enter a demolition derby. It's just a waste of money. The car will be scrap metal long before the eternal paint can pay for itself.
I've heard pop-culture anecdotes that some ethnic groups age slower/better than others ("black don't crack", and so on), but no strong evidence. It doesn't seem to be something evolution strongly pushes towards.
Not having researched this at all / just off the top of my head, the "black don't crack" phenomenon may be due to high levels of melanin giving protection against skin damage from sun exposure, which is known to contribute to skin's appearance of age (wrinkles etc.) If so, this probably wouldn't have much effect on actual lifespan, just on how young one looks.
> Mankind evolved in an environment where there was a high chance you could suddenly die from disease, starvation, predator attack, and so on. For this reason, evolution never had a reason to "crack the code" of aging, because it wouldn't have benefitted anyone. By age 70 something probably would have killed you.
By age 3 something probably would have killed you. But if you made it past that, you'd most likely live into what we call middle age, which is old enough for aging to be a problem and probably a contributing factor to your death. Aging is a clear negative; one that only sticks around because evolution can't fix it without breaking something else.
That seems a lot like group selection, and it seems unlikely to me that something as long term as evolving more slowly would have a huge effect.
My impression is that lifespan has a lot to do with not being easy prey. Longevity correlates with size, group living, flight, poison, and armor. You can't maximize all of these at the same time.
This doesn't mean that speed of evolution is irrelevant, but is older members of the species still being around (and still fertile, presumably) a major factor?
I'd thought that progeria could be a big clue because it suggests that aging is a well defined syndrome which can possibly be blocked. I'm not sure whether a drug for one type of progeria argues against the premise.
Your logic assumes that conditions are continuing to change relatively rapidly that must be adapted to or the organism will die. That doesn't seem to be the case. In any case, there are a fair number of organisms that are effectively immortal-- certain hydra and jellyfish are the most famous-- which by your logic should not occur.
They're much less complex than primates, that's true, though I'm not sure more evolution inherently means more complexity.
It's early days yet with our knowledge of the kinds of evolution, so I'm not sure anyone knows why immortal species exist. My point is only that they can. In particular I'd like to know where they fit in with the theory that longevity goes along with a lack of external causes of death, like predators, such that species with many predators, like mice, select for fast and fecund breeding rather than for long lives the way even closely related but safer species, like bats, do. I wouldn't think hydras were particularly safe from predators or disease, after all.
Well, it's not pairings for most predators or prey. Mice can get eaten by a lot of different things, for example, so how are you going to evolve to defend against one without potentially opening yourself up to vulnerability to another? Against flying creatures versus ground creatures, say. Evolutionarily they're being attacked on several fronts at once. And, too, there's probably only a certain range of potential traits for evolution to create, limited by things like the nature of chemical bonds.
I don't think, furthermore, that cancer is thought of as a circuit-breaker to enforce anything. Cancer seems to be an accident-- the result of a certain kind and number of mutations-- which we have evolved to deal with, like our two-classes-of-cells arrangements by which somatic cells "intentionally" die off after hitting the Hayflick limit, to be replaced by new somatic cells produced by stem cells that live a lot longer using telomerase. In any case, again with the examples from nature, there are animals that appear to be effectively immune to most cancer, like the naked mole rat, and if your theory were correct that shouldn't happen.
I'm still not sure why you think species that have evolved less could be immune to these things where more-evolved ones are not. Less complex species, sure, that's possible, but as I mentioned I don't see a necessary link between complexity and more evolution. But if cancer were a way of limiting lifespans to the optimal level for evolution it would kind of assume the species that don't get cancer need to evolve so rarely that there is no optimal period of lifespan for evolution. I don't see how that could happen over millennia.
The most obvious counterargument to this logic - I'm surprised nobody seems to have mentioned it - is that there is in fact quite a few species which do not age, i.e. for which the chance of dying per year doesn't increase over time: https://en.wikipedia.org/wiki/Negligible_senescence#cite_ref-FinchLSG_1-1 Obviously those all are products of evolution. So whatever the mechanics are, it's just a matter of fact that aging does not follow from evolution inevitably.
Also, there's no such thing as "evolutionary left behind". Many of organisms living today are not meaningfully different from what they were hundreds of millions years ago. It's a common misconception that evolution is a steady progress from more primitive to more advanced, but it's not exactly true, there's plenty of room for sticking to "tried and true" and even going backwards (in some sense).
More centrally, the natural selection does not work "for the good of the species". The only factor determining which genes are going to propagate more is - which are more likely to replicate? If some organism could live forever while flooding the world with its offspring, that would create a ton of copies of their genes, each making new copies. The problem is in the "live forever" part, for most organisms the mutations allowing for extremely long lifespans are not particularly useful because they're likely to die from disease or predation too early to make use of them, so most don't evolve negligible senescence.
Well, greenland shark is the apex predator in its ecosystem and is reasonably complex. But it lives in extremely cold waters and has very slow metabolism so I guess you can make an argument it doesn't count. Bowhead whale is basically as complex as an organism can be and is extremely long lived, although it does age eventually.
But it doesn't really matter, because even if true I don't fully understand how it supports your point that that primates have "many different and de-correlated defense mechanisms against longevity". In the model you describe below, longevity is connected with the evolution rate solely through the reproduction rate. And that is something we can observe directly, and see that primates and other apex species (btw the only primate to be the apex predator is human) generally have slower reproduction rates and longer generations for their size. Which apparently doesn't stop them from being very evolutionary advanced, and there's in fact quite a few known and proposed mechanisms for how that might work.
I think the best critique of this logic is to look at the natural world, where species lifespans and rates of aging vary incredibly widely, and there doesn’t seem to be any kind of limit associated with a need to adapt.
I think the most useful definition of aging for this discussion is the statistical one: how long it takes your risk of death to double with age. For humans, this mortality rate doubling time is about eight years. For mice, it’s a few months. For animals with what’s called negligible senescence it’s infinite: their risk of death is constant with time. We know of quite a few species with this property—some tortoises, salamanders and fish, naked mole-rats, hydra, and I guess quite a lot more that we’ve not found yet. They also don’t seem to degenerate appreciably in terms of physical frailty, reproductive capacity etc with time, so in that sense they seem quite literally not to age, which your logic would suggest is impossible. In fact, there are even some creatures with _negative_ senescence, whose risk of death _decreases_ with time.
The distinction between aging, the diseases it causes, other diseases (most of which become more likely to kill you with age) and other causes of death from an evolutionary perspective also isn’t that clear-cut. The spectrum of diseases different animals die from varies widely too—for example, naked mole-rats were thought until recently to be entirely immune to cancer, though the discovery of a few tumours in them now shows that they’re in fact merely highly resistant. Cancer therefore isn’t a circuit-breaker for them, or many other species.
Basically, evolution will do whatever it needs to do to lifespan and ageing rate to maximise the chance of genes being propagated to the next generation. Ageing evolves in certain scenarios due to evolution only caring about you up to reproductive age and, after that, allowing deleterious mutations to kill you (aka https://en.wikipedia.org/wiki/Mutation_accumulation_theory) or, worse, optimising your body to reproduce more effectively in ways that kill you in the long run (https://en.wikipedia.org/wiki/Antagonistic_pleiotropy_hypothesis).
Those Wikipedia pages are a good start, but another good place to read about how aging evolved—and more on what we can do to treat it—is my book! https://andrewsteele.co.uk/ageless/
Incidentally, I agree with Scott’s assessment of progeria and its lack of significance to normal aging—it only gets one mention in the book, and that’s to ask the ethical question of why we consider these premature forms of ‘aging’ a disease, but are sanguine about ignoring these symptoms when they occur at what’s currently the ‘normal’ time…
I agree, there could be some complex, high-level meta-selection going on from the species up to the ecosystem or even Gaia level (!) but I think the consensus in evolutionary biology is that it’s far weaker than individual-level selection. Immortality actually confers a disadvantage at the individual level too—the protective mechanisms necessary come at significant energetic cost, and that energy could be more profitably invested in eg bigger muscles to outrun predators, or simply having more babies more quickly for many organisms. That’s the essence of antagonistic pleiotropy theory, and its descendant disposable soma theory.
So yes, there probably are second-order effects, but I think they’re probably much, much smaller than the effects on the individual organisms, which are sufficient alone to explain (most of) what we observe. :)
Some of the hydras, jellyfish etc. actually revert their cells to juvenile status to undo aging, if I recall correctly. Which is something we can now do with the Yamanaka Factors.
We’ve certainly got a foothold! We can’t go full jellyfish and revert to a stem-like state to refresh our tissues, but the good news is that the ‘reset biological age’ and ‘reset cell identity’ levers appear to be somewhat distinct, and the Yamanaka factors activate them in a favourable order. It’s definitely one of the areas which I’m most excited about!
If this was the case, evolution would select very strongly for short-lived species with extremely high rates of reproduction.
In real life, we see numerous species - humans included - which actually live for a very long time and reproduce relatively slowly. In fact, humans age abnormally slowly - humans live an extremely long time for animals of any size, let alone the size they are. Lifespan generally increases with size, but humans outlive every mammal except maybe baleen whales.
But the logic is more obviously flawed, as it relies on incorrect notions about group selection.
Evolution will happily select for longer lifespan, because more babies = more genes passed on = more offspring with those genes. Being able to produce offspring forever is great.
The reason why animals are limited in life expectancy is likely simply that most animals *don't* live very long. There's no reason to select for a mouse that lives to ten years of age when most mice die inside a year due to predation. Longevity thus gets selected for in species that are really good at avoiding predation and living a long time - which is why you see very large animals that live for a long time, because they're not terribly vulnerable to it as adults. Humans, by being able to avoid predation, likely underwent the same process. It's likely that humans have gradually been selected for longer life expectancy and longer reproductive years.
Indeed, the fact that men can reproduce to a greater age than women can is likely due to exactly this - women used to die a lot more frequently in childbirth, whereas men did not. As such, there was stronger selective pressure for older men to still be able to reproduce than older women.
Lorfarinib is a farnesyltransferase inhibitor, and those have some pretty bad side effects, since many important proteins are farnesylated. I wouldn't want to take it unless I had no other choice.
Gene editing for progeria is coming along quite well, there was a mouse paper recently published and the scientists involved are already working on moving into clinical trials. https://www.nature.com/articles/s41586-020-03086-7
"astrointestinal toxicities (diarrhoea, nausea and anorexia) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection, and the treatment was stopped in one other who developed atrial fibrillation. Doses were reduced in all but one patient treated with more than one course of farnesyl transferase inhibitor. Responses were assessable in 12 patients. A partial response in one sAML patient and a very transient decrease of blast cell count with normalisation of karyotype in one MDS patient were observed. No relation between improvement of marrow parameters and detected Ras mutations was observed. Lonafarnib alone, administered following our schedule, has shown limited activity in patients with MDS or secondary AML. Gastrointestinal and haematological toxicities appear the limiting toxicity in this population of patients."
I have virtually zero expertise in this area, but my understanding is that a common problem with lifetime extension research in mice is that it turns out that humans are already doing most of these tricks (and that's part of why we live so much longer than mice). Is this an exception?
Can you give examples of tricks known to the human body but not to mice? My understanding was that lifespan is fairly predictable based just on size (1/4 power rule). There are also some theories trying to explain the 1/4 exponent. See “allometric scaling of lifespan”.
It's actually not just size. Compare for example bats and mice, which have comparable sizes - bats live about an order of magnitude longer than mice. One theory about why is that bats are generally better at escaping from predators, meaning it's made evolutionary sense not to have them die after two years, on the premise that the longer they live, the more they can make more of themselves. Mice meanwhile, in the wild, are fairly unlikely to survive longer than that anyway, so evolution hasn't "bothered" to remove cruft that makes them short-lived -- all of their evolutionary fitness is optimised for getting as much out of their lives before they get eaten. Very simplified: The fewer things eat you, the longer you (eventually, if evolution is given the time to improve your lifespan) live.
For anyone else interest in this thread: I've read that they might be an immunological response of the body's and Alzheimer's is "just" your brain's immunological response going into overdrive and starting to do damage. Struggling to find a good and succinct paper to link to right now, but this was an early find in my searching process - https://www.intechopen.com/books/exploring-new-findings-on-amyloidosis/is-alzheimer-s-associated-amyloid-beta-an-innate-immune-protein - In any case, I've heard the hypothesis that it may be outright counter-productive to try and reduce the beta amyloid levels directly, because the body'll just produce more to compensate, although I don't at all know if that's true. I don't think it necessarily follows, anyway. (Though I do think it follows that one should try figuring out what's causing the immune response in the first place. The book "The End of Alzheimer's" argues one should try drastically reducing carbohydrate intake, amongst other things, to reduce inflammation levels. See also https://memory.ucsf.edu/sites/memory.ucsf.edu/files/CanWeTrustTheEnd2020%280420%29.pdf for miscellaneous book criticism.)
Would make most sense for there to be a reason for immune system attacking there. Usually immune system overdrives mostly hurt young people with effective immune systems, underdrives old people with non-effective immune systems.
Carbohydrate connection would make most sense if it was a bacteria or mushroom, getting food from them.
Remember someone writing they found some species of small bacteria in brains of some dead patients (though of course they could get there after death aswell).
You might be interested in looking at the other progeroid syndromes, Bloom Syndrome and Werner syndrome. Both are caused by mutations in helicases, responsible for unwinding DNA during replication. Their absence leads to DNA damage due to stalled replication forks.
Excited to see a post related to longevity here (and would be even more excited to see more in the future)!
It's worth noting that many substances that help to remove senescent cells do appear to sometimes be able to extend the lifespan of several organisms, although the only higher-quality data we have for this is generally in mice (as one expects). See https://pubmed.ncbi.nlm.nih.gov/33555034/ for a recent example, although there's tons of other interesting substances and papers out there by now, just search pubmed or google scholar.
I personally believe that some of this mechanism of action applies to humans as well as most of what is involved appears to be pretty evolutionarily conserved (although even if correct, this doesn't implicate that the drug this post is about would be beneficial at all!). I am lately finding longevity to be a pretty exciting area and now consider it one of the most important fields of the next decade and beyond (along with machine learning and biotech). The unfortunate side to this is that, in general, we have little idea what we're doing, and doing proper longevity RCTs on humans is very difficult and slow, so we are lacking the data we'd want in almost every area).
I'd guess that the most one could hope to gain from the above would be around 1-15 years in lifespan. The good news there is that this is an absolutely amazing prospect, even if it ends up being on the lower end (which is perhaps likely, or perhaps it is even negligent), especially when contrasted with the fact that curing cancer would only extend the average human lifespan by around 3-4 years (see https://news.usc.edu/55969/delayed-aging-is-better-investment-than-cancer-heart-disease-research/, the short answer being that if cancer doesn't get you, something else will only shortly afterwards on average, as you are still fundamentally aging). For a great introductory paper that tries to give a rough outline of what some root causes of aging may look like, also check out the hallmarks of aging: https://pubmed.ncbi.nlm.nih.gov/23746838/)
I'll probably manage to resist posting all of the other weird things that I think might notably extend human life span, but I'll read about progeria now for a bit which I haven't learned much about, so appreciated this post.
One thing I'm not sure people fully appreciate is that if you slash mortality in half, you only end up increasing mean life expectancy by about 8 years. Aging is an exponential process, and it's often hard to get a grasp on just how strong that is.
According to the SSA's period life tables, you have around a 1/1000 chance of dying during your entire elementary school years (around ages 5-12).
At age 25, you have the same chance of dying just that year alone (not preconditioned on your sex... at this age in particular it's much worse for males than females).
When you're 50, it's around 3 months.
At 65, one month.
80, a week.
And lastly, when you're 100, you have a 1/1000 chance of dying every single day -- the same as your entire time in elementary school.
When you're dealing with an exponential like this, quite large changes in chance of death end up having relatively little effect on life expectancy, because the rise catches up quite fast. I'm hopeful that more work can be done in the future on therapies that can actually slow down the process (and "flatten the curve", if you will), which would have a much larger downstream impact in the end.
That assumes, I think, that mortality is the same clear through. But I think different forms of aging probably compound at different rates. Slash the correct half of mortality, such as senescent cells whose emissions not only spread disfunction but encourage other cells to become senescent, which is the single most obvious form of compounding in aging, and it's likely to be a different story. And senolytics are one of the geroscience therapies that we're most advanced at, so we may see what the numbers actually are pretty soon.
>"except that in doing this research I kept finding people saying that maybe some of aging is caused by this one weird mutant protein..."
I suspect this might be a general phenomenon; anybody who studies an aging-adjacent disease or molecular process will say that it might also be implicated in normal aging, whether the case is strong or weak; otherwise, why should anybody else pay attention / for that matter, why are they themselves studying it? It also helps (or hurts) that despite the progress that's been made, aging is still mysterious enough that anyone can say anything *might* be involved, and it's hard to say they're wrong.
When gerontologists who don't specialize in that specific disease also start saying they think it's implicated in normal aging, that's when I'd give it extra weight.
Here's an exchange between some biogerontologists on whether accelerated-aging models like progeria are or aren't useful for understanding normal aging (Miller's a skeptic):
Ah: I'm looking now at the papers Scott quoted, and they do seem to have a specific link in mind, not just general handwave-y speculation. Looking more closely now
>"All of this suggests lornafarnib shouldn't help prevent normal aging. After all, normal aging is caused by lots of processes including gradual expected accumulation of DNA damage - not just the downstream effects of one weird mutant protein.
...except that in doing this research I kept finding people saying that maybe some of aging is caused by this one weird mutant protein..."
Ok so from looking at stuff, it looks like: they're not claiming that normal aging is caused *just* by this one weird mutant protein, they're just claiming that of those lots of processes, lamin A is involved in one or some of them (as opposed to none, with progeria just bearing a superficial resemblance to aging).
You're pretty much designed to get old and die- we wouldn't be here if that wasn't our inherent actual purpose. You can make random interventions which usually are a winning tickets for cancer, but your CNS is going to reach thermal equilibrium sooner or later.
We're not /designed/ to get old and die; that's just a tradeoff evolution has decided for us. We may have lots of genes that have a short-term advantage (e.g. better fitness in our teens and twenties) but end up killing us in our 80s. Staying alive long enough to nurture your grandchildren and great-grandchildren has /some/ genetic advantage, but one generation more and the effects are too dilute, and evolution stops having any reason to keep us alive. So, all the tradeoffs where we get an early benefit but pay the price in old age are greedily selected for, and everyone who could easily live to 100 but can't pop out more babies in their 20s gets kicked out of the gene pool.
Absolutely. There's no advantage to my body slowly becoming weaker. Evolution would not preserve that trait unless it were accompanied by some greater benefit.
I've seen this argument before and I still don't completely understand the reasoning. If non-aging organisms of both sexes remained fertile indefinitely and kept producing new offspring, how could that *not* be a selective advantage?
Think of evolution as an editor that can only correct some errors. An error that kills you at 80 will be far less important to correct than one that kills you at 20. Because of DNA copy errors that happen in reproduction, there will always be significant errors. If all errors could be corrected, evolution would work to increase the complexity of the creature creating more opportunity for errors. The error correction mechanism is creatures with fewer errors having more kids.
To expand on this (in case the framing I'm about to give is a better framing for someone else reading this thread) - It's really worth noting that evolution doesn't care very much if individual animals die, as long as they die *after spreading their genes* - so genetic cruft that kills you very slowly can accumulate over time.
This is especially true if there are predators that would put an "unnatural" (extrinsic, really) end to your lifespan, where it's unlikely you're even going to live to your then-"natural" (intrinsic) lifespan.
I assume you're talking about menopause, which is not what I meant exactly, so I'm not sure the same argument holds. Rather, assuming equal lifetime fertility, the offspring who grow up to be stronger, more resistant to disease or starvation, etc. in their 20s will outcompete the others. If evolution can find genes that improve those traits, those genes will propagate, even if they also make you decrepit by the time you're 80. This matters a lot more to humans, who reproduce slowly. A young mother who can devote all her resources and attention to her first child is going to outcompete an old mother who has 10 children vying for her attention. The earlier you can gain an advantage, the better.
I'm imagining that a healthy woman who can have ten children (not all at once) is founding a clan. If the work is done competently, there will be a lot of mutual aid. In the real world, older children (possibly mostly daughters) help take care of younger children.
True, but all of that is (somewhat) secondary to how their genes propagate. A woman with 10 children is very successful, but even so her genes can get outcompeted. It's been a while since I read up on this theory but I remember early life fitness being considered the decisive factor.
Direct offspring is not the only way to help your genes propagate. A woman with 10 children will gain some extra gene propagation by birthing an 11th kid, but perhaps she can also get much more gene propagation by facilitating a good life for their 10 children so that they each get one more healthy kid; and for social animals like humans, someone who's "non-reproductive" (for whatever reason) can definitely help their genes propagate by helping their siblings, nieces and nephews who, especially in a close-knit clan, are pretty much the same genes anyway.
That brings up an interesting thought related to the earlier comment you replied to (about organisms that just live a long time with reproductive ability, like tortoises or something). Human reproduction is an inherently risky endeavor. Even _if_ we had genes that would let us be reproductively capable for 100 years, for women at least, the odds of continuing to have children without _ever_ dying from complications (in the pre-historical, evolutionary context) is practically zero. So genes that give you an early advantage and make the odds of your first few children being successful, are _even more_ advantageous because anything that gives you a chance to have more children on the downstream end are less likely to ever come into play at all.
> If non-aging organisms of both sexes remained fertile indefinitely and kept producing new offspring, how could that *not* be a selective advantage?
Immortal parents would end up competing with their children for resources, so this selective pressure would drive low fertility. Low fertility means low mutation rate, and if the enviroment changes, old cells may not be well suited to the new environment and your whole species might suddenly go extinct.
Not to mention that immortal multicellular organisms are resource hungry on their own. For instance, a lot of energy in computers is spent on signal fidelity and keeping the voltages within tight tolerances. If computations were robust against a certain error rate so these tolerances could be relaxed, computers could be considerably more energy efficient.
That's more like what organisms with sexual reproduction are like: computations that can tolerate some error rate but that will eventually crash due to accumulated errors, but that can spawn a new set of computations using considerably less information, ad infinitum.
Parents aren't competing with their children any more than they're competing with everyone else. It's still worth it to have children because that's the definition of inclusive genetic fitness. So selective pressure wouldn't "drive low fertility".
Think of an animal whose fertile period is 2x normal, then 3x normal, and so on. In each case the optimal thing is to have as many kids as possible during the fertile period (or at least as many as you have the resources for), while surviving yourself as long as you can. An immortal animal is just the limit of this.
> Parents aren't competing with their children any more than they're competing with everyone else.
Parents and offspring are necessarily in the same geographical area and thus are necessarily competing for the same finite resources. "Everyone else" are not necessarily in the same area, and thus, not necessarily competing for the same resources.
> It's still worth it to have children because that's the definition of inclusive genetic fitness. So selective pressure wouldn't "drive low fertility".
Parents that live alongside descendents are competing for finite resources, ie. food, water, etc. That's just a fact.
Organisms with no check on their populations inevitably destroy their habitat; we have ample evidence of this, and humans are doing this right now with climate change.
If you extend lifespan to "immortal" and fertility does not go down, they will destroy their habitat and go extinct. Only those populations that don't destroy their habitats with out of control reproduction will survive. Therefore, in surviving *immortal* species, fertility will necessarily be lower than non-immortal species.
Fertility will not be zero of course, because even immortal organisms will have accidents or natural predators, but it will definitely be lower than the fertility rate of species with a shorter lifespan.
It can be a *negligibly small* selective advantage, because by the time you reach 80 you've most likely been eaten by the lions or cholera or something. And for this mutation to fixate, at least some of your children must reach 20, and some of their children and so on for quite a long while.
In the natural world, there are many things that can kill you, not just aging. For example, mice typically only live for a few years before being eaten by predators. Consequently, there is no selective pressure for long-lived mice. Even if a mutation appeared that might have caused a mouse to be healthy and fertile for decades, it wouldn't be more likely to be passed on, because the mouse would be eaten by a hawk long before then.
In the absence of selective pressure, there is no reason for DNA/senescence/cell repair mechanisms to evolve past the bare necessity. Without repair mechanisms, damage accumulates over time. So every species on the planet tends to die of old age shortly past the time at which it would ordinarily die of other non-age related causes.
Species which don't have predators (e.g. Sequoia trees) can and do live and reproduce almost indefinitely.
After mating and brooding, their optic gland triggers endocrinological changes and they quickly stop eating and start to deteriorate. Remove the gland and they live significantly longer.
I'd like to know how progeria is explained by the Information Theory of Aging. By that theory, actual aging occurs when your cells progressively "forget" what sort of cell they're supposed to be as a result of damage to your epigenome, the "analogue" information that controls which parts of your "digital" DNA get expressed and how much. Progeria is cellular damage, but from the sound of it, not the same mix of cellular damage as aging.
Sure, but it is a ridiculous subject on which to focus our resources. Let's make the next generation better off and stop worrying about ourselves. There's one big soul not a bunch of small ones. Almost everyone is behaving like solipsists even though most reject that label.
I don't fear my death (maybe because It's probably still a decent ways off, but I don't think so). But I enjoy being alive and would rather not have death thrust up on me. Maybe I would eventually get to a point where I didn't enjoy being alive, in which case I would like to be able to choose death. But I would much prefer that choice to be in my own hands than in the hands of some stochastic process. I find it unlikely that, presuming a decent level of health, that I will have wrung all the enjoyment and happiness that is possible out of life by the time I'm 80ish.
No one person is ever going to wring all the enjoyment and happiness that is possible out of life. The good news is that there are billions of people on the planet, billions and billions more to come, and trillions and trillions of other creatures. Let's wring all the enjoyment and happiness (and pain and sorrow) out of existence together. The best anti-aging technology is sexual reproduction.
Ever read The Magic Mountain by Thomas Mann? Written just after WWI. There is a great scene where the protagonist has a brush with death and has an experience of his small soul joining the great soul. There were an awful lot of German writers of that period putting forth ideas cribbed from Vedic Cosmology. Even Erwin Schroedinger talks about how each of us is “God Almighty” in the Hindu sense. That is in the afterword of his What Is Life lectures.
Okay, that's a nice pretty sentiment and all, but *what if you're wrong*?? What if there's no "one big soul," and there really are just trillions of tiny isolated souls, and every time any one of us dies, something precious and irreplaceable actually is gone forever? On that premise, surely the existence of death is doing an incalculable amount of harm.
So, how sure are you about your "one big soul" assumption? 50%? 90%? Even if you're 99.9999999% sure that you're right, isn't even the 0.0000001% chance that you're wrong worth taking into account, considering the staggering moral implications of that possibility?
Bear in mind as well that assuming on the basis of religious convictions that the suffering of large numbers of beings doesn't really matter is not an attitude that's led to terribly positive results, historically speaking.
And, by the way, the belief that trillions of unique and irreplaceable beings and/or souls exist and are worth preserving is literally the exact opposite of solipsism.
Not at all likely IMO. It’s part of the South Asian take on the unknowable. To me it’s much more appealing - as metaphor - than the angry bearded guy that Bronze Age pastorals came up. It’s poetry and a philosophical way to get by in a cruel world.
A lot of this is probably because of the aging process. If you were just as healthy as you were when you were 20, you'd probably be less into the whole dying thing.
And if you even then would still have qualms against living forever... well, that's fine, it should be optional. Doesn't change the fact that aging is by far the biggest public health crisis facing humanity.
I’m just 2 years shy of my allotted 3 score plus 10. Maybe I shouldn’t even mention this but I’ve never been happier. My wife is a year younger and her daily level of joy is up there with. It’s the old happiness is a choice thing I guess.
Because it's a problem to solve, and humans are natural problem solvers? What is unnatural about humans, a species that evolved on this planet, using the natural resources of this planet to challenge aging anyway? We're not an alien species, and we're not bringing in materials from outer space/another dimension or using magic here. It seems to be natural for the primate species homo sapiens to seek to manipulate and change itself and its environment, and this is just another example of this. Like it or not, humanity and our environmental manipulation is a major part of the nature of this planet, and seeking to challenge the progress of aging is just a normal human behaviour, like eliminating Smallpox or treating wounds.
If you found out that you have some deadly disease, but fortunately there's a cure available, would you take the cure or let nature take its course? If your hip went bad and you needed a hip replacement, would you take the surgery or crawl around like nature intended for you? Do you use fluoride toothpaste or let your teeth rot and fall out at nature's preferred schedule? If you happen to have bad eyesight, do you grope around with the half-blind eyes nature decided to give you, or do you uses glasses or contacts or even laser surgery to correct them? If, as you get older, your doctor advises you to take certain vitamin supplements, does that count as not trusting nature?
Where is the boundary between using technology to fix a problem with your body, and "distrusting nature" in the way which you apparently consider bad?
I'm all for improving the quality of individual lives just not the length of them. One should outlive their parents. Beyond that the length of life should not be a priority.
I don't mind dying, but ageing is pretty horrible. >50% of your life is spent getting weaker, enduring more pain, sleeping less and less well, and being more prone to various illnesses.
The definition of "nature" is unclear here. After all, modern lifespan is considerably greater than it was in 20,000 BC. Should we eschew antibiotics, clean water, wheelchairs, indoor living, because these things extend lifespan beyond what was "natural" for Mitochondrial Eve?
What some people hope is that similar technological tweaking will establish that if humans not only live indoors, have clean water, have antibiotics for disease, avoid breathing radon and plant smoke, and....use some as yet unknown therapy for some as yet unknown problem -- then we will find that the "natural" lifespan of human beings is, say, 250 years instead of what we currently view as "natural" (80 years).
Then our great-great-great-grandchildren, once they have become habituated to lifespans of 250 years and write anguished odes to the finiteness of life, will get to have the argument all over again.
I don't think this cycle would continue forever, though. If people were somehow able to live for Graham's number years, I don't think that they would write paeans at the end about life is far too short for them; on the contrary, if I lived for that many years, I would probably be scared and lonely and bored for all but the first ~million. (C.f. https://waitbutwhy.com/table/how-long-would-you-live-if-you-could-choose-any-number-of-years)
It seems unlikely to me that augmentation could supply endless new experiences at the scale of my earlier comment though. Purely based on a rough estimate of the number of ways that quantum particles could possibly be arranged to form this universe and taking this as a rough upper bound on the number of possible experiences therein gives a rough upper bound of 10^10^10000 different experiences, which, though very large, is *much* smaller than Graham's number.
Maybe. Human beings are notoriously adaptable, and seem to reach the same set point regardless of their situation. It's often assumed that people with severe handicaps would be generally much less happy than those who don't, but they aren't. The rich aren't, in fact, significantly happier than the poor. Those who live in countries with high life expectancies aren't way happier than those who live in low. (Way more people in Japan kill themselves than do in Nigeria, just for example, and Japanese on average live almost 30 years longer.)
So a priori I think it very likely human beings would psychologically adapt to whatever new lifespan they got. The first generation or so that got to live an extra 100 years would be ecstatic, but by the 5th generation it would be taken for granted, and people whose lives were "cut short" by being allergic to boosterspice would feel as tragically wounded as someone today who is diagnosed with fatal cancer at age 25.
What would happen if lifetimes were really long, like a million years? The only noticeable change I can imagine is that we would become very, very careful about accidents, because over that lifespan accidents are the major determinant of lifespan. (IIRC average lifespan for Americans if accidens were the *only* way to die would only be of order 1000 years, I believe definitely less than 10,000.) So that would be a little weird. But a million years is actually not that long by cosmic standards. If you were born a million years ago, the Earth wouldn't be all that much different than it is now. Most of the same species would be here, although many would have changed a bit. You'd have experienced Great Winters (Ice Ages).
But the universe doesn't become more boring when you experience it on a much longer timescale. It's just that we're *unaware* of events that happen on much longer timescales, because thinking about them is existentially uncomfortable (or pointless), so we are unaware of the ebb and flow of events on multi-thousand and million year timescales that would be interesting, if you could live long enough to see it.
Not sure about not aging meaning you get extra careful about accidental death. It's a common sf theme, immortals turning into paranoiac cowards so obsessed about accidents that they do not really live anymore, and it's logical... Except it does not works like that in real life, it seems fear of accidental death and illness is only slightly affected by a rational risk benefit analysis and more under instictive control, probably largely hormonal: when you get old, you get more and more afraid physical risk, more concerned about health issues,while you obviously have less and less to lose. You can say it's experience, but why are women much more careful on average than men at the same age? I guess it's largely testosterone and adrenaline-controlled. I am much more physically cautious than when young, and it's not experience (my assessment of risks is more or less the same) not confidence in my physical abilities (although it play a role). It's just a less adventurous mood, i evaluate risk the same but i am morr averse to it (physical ones for sure, but i think it's general). So my guess is that immortals that stay physically fully young will maybe get a little bit more cautious than teenagers or young adults... But far less than middle aged or old people.. .
Let me suggest that instinctive control is merely a rational risk/benefit analysis that your DNA (assisted by 40,000 years of natural selection) have already done for you.
I almost fully agree : my dna didn't do it for me, it did it for him (it?). It's obviously adaptive to engage in high risk activities to gain early advantages, social status and impress mates, because it maximize amount of offspring. The risk/benefit is not in term of lifespan, it's in term of fitness...
This still say something about possible immortals: their risk aversion will not be affected by their extended life expectancy much, but by their (likely edited, because that's will be needed for immorality anyway) genome. You can get careless violent immortals that do not die later than nowadays, although society will certainly opt for the opposite (select tameness)
Thanks for the reply; I think that I feel better about the Graham's number longevity hypothetical.
(Also, your comment seems cut off, merely ending with "So". Is it a length limit thing? If you were going to write more about it you could finish your thing below.)
Are you sure the modern lifespan is considerably greater than it was in 20,000 BC? Life expectancy is surely shorter, but couldn't pre-historic man also live into their 80s or 90s? Do we know?
Not sure what you're asking. Are you asking: is it possible for *somebody* to have lived to age 80 in 20,000 BC? The answer to that is obviously yes, but it was almost nobody. And the average matters, it's why we compute it. In 20,000 BC most bad bone fractures meant prompt death. Now it doesn't, because we have splints, casts, surgery, wheelchairs, and a civilization that let's you hang out in a safe place, completely immobile, for 8 weeks while you heal. Even in historical times death during childbirth was a major risk factor for women -- old graveyards are full of twentysomething women buried next to their newborns. That is no longer true, because we have ultrasound to diagnose problems, and can intervene surgically. There are many people who died in their 50s from heart disease circa 1900 who would live into their 70s or 80s if their physician had been able to prescribe statins for them, or they had been able to get an implantable cardioverter.
In principle any technology life-extension method or drug falls into the same philosophical category. Someone from the perspective of 2200 AD could look back and say, gee, almost nobody in the 2020s lived to the "natural" lifespan of 150 that you get if you go on foobarbazib 5mg once daily at age 50, what a primitive period that was.
When we *get* to the point where Method X promises to extend lifespan *indefinitely* then we can have the genuine philosophical discussion of whether immortality is a good idea. But at present, at best we're talking about quite modest extensions, at best letting us live as long as Galapagos tortoises, nowhere near bristlecone pines.
"a civilization that let's you hang out in a safe place, completely immobile, for 8 weeks while you heal"
You don't need a civilization for that? Where hunter-gatherers unable to provide for their sick and injured? Isn't your tribe's camp a pretty safe place? I was under the impression there was even evidence of neanderthals taking care a permanently disabled member of their tribe.
Few things terrify me more than the thought we will one day prevent aging.
There are already more people living on this planet than it can reasonably support. If new births are no longer balanced by deaths from old age we will arrive in a dystopian nightmare scenario very rapidly.
Any effective anti senescence technology will reveal that we have a moral obligation to die anyway.
I sort of agree with you, but I don't think it's quite as bad as you think. Certainly if you snapped your fingers today and completely cured ageing, that would be terrifying, but if we gradually slow it over the next few decades, other technological changes are going to be relevant as well. The world could support more of us if we all lived sustainably, and I hope that will become easier with better technology.
Also, I think if people have longer to live (and no menopause to think about... I guess I'll hand-wave that away as part of ageing for now) they'll have children later, so the birth rate will fall. Even if they don't, states could enforce lower birth rates, and they wouldn't have population pyramid problems down the line because old people are still working.
The saddest thing about all this in my opinion is that the older we live, the fewer children there are in the world. There was an almost throwaway comment about this in a Banks book (possibly State of the Art) and it hit me quite hard.
Unless people scale up their child-bearing in proportion to their lifespan, this will not happen. The rate of child-bearing will slow to match the lengthened lifespan.
The evidence already suggests that people do *not* scale their child-bearing in proportion to their lifespan. In fact, if anything, the correlation goes the other way rather: the average lifespan in the Nigeria and the US is 53 and 79 years, respectively, and their total fertility rates are 5.4 and 1.7 children/woman/lifespan. That is, longer lives lead to *fewer* children per lifetime, not more.
I can imagine that most people don't want to have many children, but a small proportion really *like* producing large families. That would be an interesting future, and it's certainly a good enough premise for science fiction.
I hope you're right, but I'm doubtful. I suspect the different lifespans and birth rates in the US and Nigeria reflect differences in economic development. There's no reason to think directly extending lifespan will have the same effect on birth rate.
Besides, if it is possible to extend life indefinitely, no amount of reduction in the birth rate will prevent a population explosion.
That is basically the point I am making. Carl Pham claims that longer life leads to fewer children. I disagree; I think the economic factors driving increased life expectancy also happen to reduce birth rates.
There is no reason birth rates should fall when life expectancy is altered by a different mechanism, like life extension technology.
You're assuming that fertility will extend along with longer life. I'm not at all sure that's the case-- 80 being the new 50 is still going to have the fertility of 50, for women-- but in any case I think the extra years are going to be under the control of science, which is not the case at present, so I think the question of extra fertility is going to be more within our grasp than the standard period of fertility is.
Yes there is. There are people in Nigeria who are rich (at least by Nigerian standards) and they *still* have lots of babies. Furthermore, you have only to look at the advancing age of first birth that you see in developed countries. Why do so many women put off childbearing until their 30s? Because they can. Because they can count on living to age 75. If their realistic horizons were more like 50-60, as they once were, they would not.
> There are already more people living on this planet than it can reasonably support.
I read somewhere that the world produces more than enough food calories to feed everyone on earth (https://www.huffpost.com/entry/world-hunger_b_1463429 ?), so to me world hunger/etc seems a lot more like a logistical/political issue than an issue of supply. Even if there are way too many people, we might have interplanetary populations and food supply systems, so it might not be that bad. Also, in the premise of the serialized web fiction 17776, the death rate drops to zero, but the birth rate also drops to zero, making for a stable population.
Well, perhaps we could support a population of 100 billion if everyone ate processed insects and lived in ten-foot-square boxes... but would we want to?
I'm being flippant obviously, but the absolute maximum number of human beings isn't what I had in mind. A better target would something like the optimal population for human flourishing, which I suspect we have exceeded already.
In any case, we have yet to solve the political and logistical problems you mention.
There may be technical solutions but there are too many "ifs" for me to be reassured at this point.
What about the incredible burden that an aging population has on our economy, in the form of costs of medical treatment, long-term care for people who can no longer care for themselves, and palliative care? How many deadly car accidents do geriatrics get into per day? How many sharp, inventive minds are dulled by dementia at a point when they have so much more to give us? If we didn't have these problems, what strides do you think we could make towards a better world?
The status quo is often more terrifying than your imagined future dystopia, if you stop to consider it.
I agree that there is a very large burden of aging and related diseases. I would be very glad if this burden could be reduced. But we'd need to do it without eliminating death, which is challenging.
If they cannot work, care for themselves, drive a car safely, etc, then they're going to die soon enough and you won't have to worry about it. You can't plausibly hope to "treat" aging by patching together geriatric bodies every time they stroke out or whatever; that problem increases literally exponentially on a roughly eight-year timescale. If there's a treatment (really, set of treatments) for aging, it can only plausibly work by preventing 40-year-old bodies from turning into 80-year-old bodies.
Which incidentally means being as capable of working, driving a car, and generally taking care of yourself as any other forty-year-old, even though you happen to be eight. Or eight hundred. This happening any time soon is a medical long shot, but it's at least theoretically plausible. The struldbruggian horror of being trapped forever in an increasingly decrepit body makes for nifty drama in fiction, but it doesn't work in reality because increasingly decrepit bodies increasingly die no matter how cleverly you try to save them.
Might as well try to run your car forever by letting it rust and the superglueing the rust flakes back into place as they fall off.
A continually increasing population on a finite planet doesn't sound to me like a problem we can deal with. I'd be interested to hear your suggestions.
It wouldn't be a dystopian nightmare any more than today's world is, just a different one to get used to. We've had clashes of human beings about everything. Why should this one be avoided particularly? Eventually a new equilibrium would be reached. Certainly I think that it can't be avoided any more than the people railing against the A-bomb succeeded in getting it uninvented.
You go ahead and die if you wish. I don't think much of your "moral obligation" talk.
If nobody dies, the "equilibrium" we arrive at will be one where finite resources are shared between an extremely high number of people. This will not be a pleasant world to live in.
You sound like Thomas Malthus. It's not as though people won't still die; they destroy themselves in all manner of ways. But your objection boils down to a matter of timing and nothing else. Population is growing as it is, we are going to have to find ways to deal with more people, no matter what, and we might as well find it out sooner as later. But Norman Borlaug came along and genetically manipulated crops came along. I don't think there's going to be any way to rationalize not saving people, most especially in a democracy where some will call you a murderer for that, on the assumption that nothing else will come along.
Would you support a policy of killing everyone at the age of 50 in order to free up the planet? If no, how's killing everyone somewhere around 70-90-ish morally different?
I think that the real danger is developing anti-aging technology before we engage in mass genetic engineering of humans to greatly increase IQ, health, and similar things.
It'd be a bad idea to make probably close to 98% of the population today immortal, simply because they would continue to create problems indefinitely.
Once you have increased those traits to high levels, there's no particular reason to worry about it; there's no reason to replace old people with new ones at that point.
It looks like you actually can, and people are wanting you to, try something very much like this drug! I first went to learn about lornafarnib, which is a farnesyltransferase inhibitor, actually spelled Lonafarnib? which got me to read about Progerin, which lead to Progerinin, which pointed the way to [0].
Quoting from the study:
In the LmnaG609G/+ mouse model, improved morphology such as status of coat hair and body size, increased body weight and extended life span for about 16 weeks was noted following Progerinin treatment. In addition, Progerinin can suppress muscle weakness including the heart muscle. Safety pharmacology studies did not indicate any Progerinin-related effects on vital organs and systems including respiratory, cardiovascular and central nervous system.
Prior to studies in the disease states, this study PRG-PRO-001, an initial first-in-human study, will be conducted in healthy volunteers to assess the safety, tolerability and pharmacokinetics of Progerinin.
Would lamina treatments help with "normal" aging? To the extent lamins are defective in regular old people, maybe they can slow it little. But aging has many causes, and in some sense it's a self-causing problem with many feedback loops. So what I would like to see are complex treatments that address multiple causes at once.
John Wentsworth makes a point on LW about how while DNA damage certainly seems to be part of the mechanism of aging, pure accumulation of DNA damage over time (as opposed to an increase in the rate of such leading to such accumulation) doesn't make sense as a reason for aging: https://www.lesswrong.com/s/3hfjaztptwEt2cCve/p/d4DvqS88Q29ZaJAj3
He's got a whole series on aging-related stuff and the question of what the root causes are (https://www.lesswrong.com/s/3hfjaztptwEt2cCve), which I'll admit I don't really know enough to evaluate, but it's pretty interesting at least.
I find the essay to be a good demonstration of the fact that pure reasoning is not an effective way to produce knowledge in biology. Frankly the central argument, that ageing has a root cause, is simplistic (it assumes that dna repair is perfect) and the proposed mechanism for this root cause (transposon) is highly improbable.
Ah, and the arguments at the beginning of the essay to explain why he has an interesting theory of the origin of ageing whereas academics are wrong, are quite comical: "Most overviews of aging suffer from multiple problems: [...] They are usually written by working academics, who are shy about telling us when their peers’ work is completely wrong." Hum, no, quite the opposite in fact.
The entire reason empirical science exists is because we discovered in the 1600s that pure reasoning is not an effective way to produce knowledge in *any* field of natural philosophy. It is, nevertheless, fascinating how the errors of Scholasticism are rediscovered, over and over again, as the centuries roll by, no matter how often they are shown to be errors. Feynman argued that it was just inherent in human nature.
That is inherent in human nature seems plausible to me, we love to make sense of stuff, even if the story we tell is wrong!
I would expect that reasonig is less efficient in biology than for example physics, because biological process are frequently very "messy" due to their gradual origin by evolution, but this may be just because I know almos nothing about physics.
Ha ha no, physics also has alas a long history of beautifully argued theories that were, empirically, just wrong, starting with geocentrism and Ptolemaic epicycles and moving right up into the luminiferous aether.
I grant you that biology may be a special realm, or at least has been, because we all *experience* biology just living.[1] That is, because everyone inhabits a "biological system" (his body) he kind of assumes he has some kind of built-in natural expertise, because he can query his own experience to derive wisdom. That was no doubt true in physics in the 1600s, which is why people could have fierce arguments about whether inertia existed or not, on the basis of how "obvious" it was to them from their experience with forces and motion.[2]
But once physics moved into realms far beyond daily experience -- quantum mechanics and relativity -- people stopped thinking their daily lived experience was a source of wisdom. *Maybe* that is starting to happen with biology, as it has become increasingly complex and removed from daily experience. How do you mine your daily lived experience for insight into the function of retrotransposons? Difficult.
I'm not a biologist by training, but I have had increasing occasion to learn it over the past 10 years or so, and the one constant is that the more I learn about it, the less I trust my native instinct and/or sense of how it "ought" to be. It's....weird. A system designed by Hieronymus Bosch and Rube Goldberg in collaboration. Elegant, but...weird.
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[1] My experience is that the same is true of economics. Because everyone lives a live as an "economic unit" they will argue freely with their economics professor in a way they won't with their physics professor.
[2] There's a fascinating historical tale one can ponder of how people labored long to dismiss the evidence of inertia that came from observing heavy ships in water. Yet another example of how man is more the rationalizing animal than the rational animal.
"I'm not a biologist by training, but I have had increasing occasion to learn it over the past 10 years or so, and the one constant is that the more I learn about it, the less I trust my native instinct and/or sense of how it "ought" to be. It's....weird. A system designed by Hieronymus Bosch and Rube Goldberg in collaboration. Elegant, but...weird."
Il love it! A common metaphore is that evolution is a tinkerer not an engineer, but this description is so much better!
"But once physics moved into realms far beyond daily experience -- quantum mechanics and relativity -- people stopped thinking their daily lived experience was a source of wisdom. *Maybe* that is starting to happen with biology, as it has become increasingly complex and removed from daily experience. How do you mine your daily lived experience for insight into the function of retrotransposons? Difficult"
Indeed, some domains of biology, molecular biology for example, are not connected at all to our daily experience, but but other fields of biology like evolution seem (wrongly!) to be possible to intuit from our daily experiences. There is a rich tradition of "Darwin was so wrong" essays from both laymen and scientists from fields other than biology, math in particular I think.
Inspired guesswork, largely. Hypotheses by definition cannot come from deductive logic, they are efforts at induction -- attempts to create brand new axioms from which future implications can be deduced. So people just guess. It's a weird process of blue-sky imagination, and some people are much better at it than others, and it has nothing at all to do with intelligence. Very smart people can rarely come up with interesting and useful hypotheses, and by contrast people who aren't very smart can sometimes be founts of creativity.
It's certainly true we use deductive logic to prune dumbass hypotheses from consideration early on. Few people will take seriously a hypothesis that violates Conservation of Momentum, unless they need to. But this is not part of the origination -- it's already part of the vast machinery of pruning and winnowing that constitutes the bulk of empirical science.
Perhaps this criticism applies to the short version. But after reading the much more elaborate variant of the same argument here, I disagree with the criticism:
I don't see how this is based on "pure reasoning". It doesn't make up anything, it gives a summary of what Wentsworth has extracted from the existing literature. I don't even think he claims that it is "his" theory.
On:
"They are usually written by working academics, who are shy about telling us when their peers’ work is completely wrong."
I can absolutely confirm this point for neuroscience. I have come to this field as an outsider. A problematic issues is that a lot of papers are wrong, and a lot of labs are not reliable. The way I have found to deal with this issue is to directly ask my colleagues who do experiments themselves. They can tell me which lab to trust, and which papers just to discard. But they would never write this knowledge in a research article, it's more like gossip. If I am very lucky, I find hints in reviews, but most of the time not. I think it is really hard to get this knowledge without talking to experts in private.
Also, it seems you misread the main point: The short article says that imperfect DNA repair does happen and *is* a possible candidate for a root cause.
" It doesn't make up anything, it gives a summary of what Wentsworth has extracted from the existing literature. I don't even think he claims that it is "his" theory."
I disagree. The essay contain short syntheses on various points that are indeed based on the existing literature. But the main idea, the big idea, is that the field lacks "high-level picture" , and the author has one, namely that ageing has “root causes”, and he has identified this root cause (transposons). Both points, the existence of a root cause, and that transposons are important in the ageing process are based on reasoning and not experimental data (and I am pretty sure the are incorrect).
"they can tell me which lab to trust, and which papers just to discard. But they would never write this knowledge in a research article, it's more like gossip. "
Indeed, this kind of gossiping ('I think this lab is crap') has no place within a research article. But if someone can disprove an established theory, it is usually highly publishable. Not so much if it is just a non replication, though.
I don't understand what you mean that there might be no root causes.
I could understand if Wentsworth and you disagree about *which* root causes are more or less likely. You seem to prefer accumulating DNA damage as explanation(?), while he prefers transposons and/or mitochondrial mutations.
But you explicitly say that you do not believe in root causes at all. What do you mean by that? It won't be that there is no reason at all for aging? That there is a very long cycle causal pathway so that it doesn't make sense to talk about "upstream causes" and "downstream causes"?
The current scientific model (the one of these shy academics!) is that ageing is a multifactorial accumulation of damage at multiple levels (DNA, proteins, cells, etc.) whose rate was modulated by natural selection during the evolutionary history of a species and is strongly related to the ecology of the species.
The idea that there is a "root cause" of ageing, ie a unique cause of ageing that, if fixed, would suppress ageing entirely, is an old idea that is not well supported by data in my opinion.
The article defines "root causes" as "causally upstream". Not as "unique cause". The article explicitly says that there might be several ones. There is even a section which discusses whether it's more likely to have a single or several ones.
With respect, but are you sure that you understood correctly what the article said? If you have conflicting terminology about the core concept of the article, then you may have got a lot of the arguments wrong as well.
Re root causes: what do you think of Sinclair's information theory of aging, if you're familiar with it? The theory does propose a single root cause, but it's more along the lines of "this whole complex mechanism breaks down" than "this one protein/gene is the problem".
My impression was that this theory was quite focused on epigenetic changes, which I do not think is a probable main factor of ageing.
But "this whole complex mechanism breaks down" does seem very correct to me. I'd just add the caveat that organisms could avoid the breakdown, several species show negligible ageing, but humans and mammals in general do not, very probably due to our life history.
It breaks down the aging process into hallmarks based on the 2013 ‘Hallmarks of Aging’ paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ (but I have added and combined some, ending up with ten hallmarks overall), and examines how they impact the aging process and what we can do about it.
I think DNA damage and mutations are a really interesting case where new evidence is making us reevaluate their contributions—there’s accumulating evidence that mutations leading to cells that expand when they shouldn’t (though don’t necessarily go on to become cancers) may be the primary mechanism by which mutations contribute to aging.
I think it’s probably at least partly true—the fact we can reprogram the epigenetic clock and seemingly reverse aging, and that clones are born young are both good evidence that there’s lots going on in our epigenome! But I don’t think it can explain everything, eg I don’t think there’s much resetting the epigenome would do about mutations in the ‘digital’ copy of the code as he puts it, ie the DNA itself, and the idea of non-cancer clonal expansions makes me worry that this is a relevant potential cause of aging too.
Like everyone with a nice narrow theory of aging, I hope he’s right—but I think we should be going after every plausible cause of aging, and trying to build models to understand how they all link together, just to be on the safe side!
I quite agree! Speaking of the "digital" DNA, I have noticed in my reading a fair amount of evidence that having duplicate copies of the coding for certain proteins is often correlated with longer lifespan, which, IIRC, is speculated to be because DNA damage to one copy doesn't keep your cells from producing the protein using the others. I think women living longer is said to be related to this-- the extra X chromosome. Have there been to your knowledge any papers or serious talk about changing DNA "on the fly"-- that is, in already-living beings? I know there are tens of trillions of cells, but I would think that if they could just target DNA alterations to stem cells alone, it would be a smaller task, and we could then steer somatic mosaicism the way we want, with more and more somatic cells over time being daughter cells of the altered stem cells.
(Thanks, by the way, for the opportunity to geek out about this and ask questions. It's a privilege.)
That’s certainly one theory why women might live longer—in birds, where it’s the females who get the smaller, mismatched sex chromosome, the trend is reversed, and evidence from clonal expansions seems to show you need both copies of a gene to be disabled before there’s a problem.
The good news is that there’s a lot of work into somatic DNA editing, though actually I don’t think this is how we’ll solve this problem (of course I could be wrong!). I think the clearer path to success is finding a way to kill the mutant cells rather than editing their DNA, and letting daughters of non-mutant stem cells take their place. The more futuristic approach could be to extract some cells, create stem cells from those with intact DNA, and use those to aid repopulation. Possibly directly editing DNA will be useful for particularly common mutations in certain cell types though—I guess we’ll have to see!
And you’re very welcome, always happy to geek out. :)
Symbolism pedantry: the cover picture shows the personification of Death being pushed away by a figure holding a caduceus (wings and two snakes) rather than a rod of Asclepius. So the latter figure is a personification of Commerce rather than of Medicine? That would fit just as well.
Even though the specifics may not be entirely accurate, I felt significantly less confused about aging than before I read the essay.
Key quote from the Homeostasis post:
> "a root cause of aging cannot be a higher or lower value of any parameter subject to homeostasis on a faster timescale than aging itself...
> DNA damage (as opposed to mutation) is normally repaired on a timescale of hours - sometimes much faster, depending on type. “Accumulation” of DNA damage cannot be a root cause of aging; either the rate of new damage has increased or the repair rate has decreased...
> Note that the homeostasis argument does not mean the factors ruled out above are not links in the causal chain. For instance, there’s quite a bit of evidence that DNA damage does increase with age, and that this has important physiological effects. However, there must be changes further up the causal chain"
I did not find the essay good. For me the author mixes well-established knowledge with wild speculation, without seeming to differentiate well between the two. And I think that the substance of his argument, the existence of a root cause for aging, is incorrect, as is his hypothesis that transposons cause aging.
What do you think of the specific claim that DNA damage is normally repaired on a timescale of hours, so an increase in DNA damage over time must be caused by some other slower change(s)?
I think this is true, DNA damage is normally repaired quickly. This does mean that in a small percentage of case, it is not repaired quickly, or repaired but with a mistake.
I googled but couldn't find any reference to experiments treating normal mice with lornafarnib (mice with 'a mouse model of progeria' have been treated, and seemingly it works.) But the drug is new, and I assume somebody will do the experiment before long.
The Scaffidi and Misteli paper is a less conclusive than it might at first seem. If you dig into it, one thing that is very strange is that they find that the amount of abberrant lamin A does *not* increase with aging. So it can't be as simple as that the abnormal splicing *itself* is causing aging, because the rate of those mistakes does not increase with age. Rather, what they observe is that in younger cells the abnormal protein doesn't get localized to the nuclear envelope -- it has a much wider distribution. So there has to be some (as yet unknown) mechanism that localizes the abberant protein to the nucleus where it can interfere with DNA repair. Arguably it's *that* mechanism more than the abnormal splicing itself which is more central to the problem. They did show that preventing the splice reverses signs of aging, which is pretty cool (and probably why the paper was worth writing), but this only says the bad splice is *part* of the problem. The unknown localization mechanism is also key.
This seems like as good a place as any to bring up a thought I've been having on aging research: why does the focus seem to be so confined to humans? Obviously the end goal is extending human life and health span, no argument there, but in the short term it feels like there are easier options. It is often stated that extending life in mice, rats, and other small mammals is much easier than doing so in humans, so what about pets? I know I would pay hundreds of dollars a year for a treatment that would let my cat stay young and healthy for an extra ~5 years on average, lots of other people would too and it would get way less push-back from the "you're playing god!" types than work directly on humans. If a cheap enough treatment were found it might even be economical to use it on farm animals that are not intended for meat (Dairy-cows, egg laying chickens, wool sheep etc) to allow them to remain at peak productivity for longer and not have to go to the expense of raising new ones as often.
I'm don't remember hearing of any others (besides loyalfordogs), but the overall idea is out there. And if you're serious about the cat, the "good" news is that most of the research is done in mice anyway, and it presumably should generalize to nearly all placental mammals (or even all eukaryotes in some cases). So you can take the numbers for the mice and scale up or for humans and scale down, with the help from some openly-minded veterinarian.
Using it for farm animals is an... unorthodox proposition for sure. I've never heard of anyone even thinking of it. But it might be trickier and potentially impractical, because at the end of the day the metric a farm is trying to maximize there is produce per life, not lifespan, and those might be at odds. E.g. the best proven longevity intervention is caloric restriction, but I'm sure applying it to farm animals will cause them to produce less or none at all of whatever they were supposed to be producing.
Others have thought of this too. There's the Dog Aging Project. They've been approaching it from a scientific standpoint rather than a commercial or emotional one-- the argument being that dogs are closer in size and so on to humans than mice or yeast are-- but it's still the same sort of thing.
I think human aging comes from loss of degeneracy in the complex systems of an individual’s biology. The examination of edge cases, such as progeria or cystic fibrosis, provides changes in the surfaces of the examined parameters that are within the resolution of the tools we currently have available to examine them. As the complex system gets closer to the failure cascade— moves from the “flat part” or “healthily living” part of the response surface to the curved surface— our existing tools can start to measure parameters that tell us something new about the many possible control mechanisms involved in healthy aging. I don’t think the tools and methods currently available have the resolution or detection capabilities sufficient to see a way to extended lifespan-- yet. They can give us some insight to extending health span but I think it’s safe to say learning how to extend life span (healthy life span because otherwise why?) is beyond our current tool capability. Good to know people continue to work on more capable tools.
starts a list of ways degeneracy plays into biology from genetics to social structures.
A paper with definitions of degeneracy, redundancy and robustness as considered in biology along with an explanation of different hypotheses for why doi:10.1186/1742-4682-7-6
I also seriously doubt there is a single mechanism (excluding things such as a catastrophic accident or obviously unhealthy habits like smoking tobacco) that lead to the failure cascade toward death. This means there isn’t a single chemical/pharmaceutical that extends healthy lifespan.
The idea of different pathways to aging, “ageotypes”, is gaining some visibility and quantification. See, for example, https://www.livescience.com/four-types-of-aging-revealed.html. Knowing my ageotype gives clues to things I can do to aim for healthy aging. All I can do is try and wait for better tools to change my hypothesis.
Thanks for pointing out a potentially more easily read book on the topic. I'm not surprised it exists. From the review in the hplus link, the list of mechanisms is part of the list shown in Table 1 "Degeneracy at different levels of biological organization".
IMO, it is valuable to furthering what is known and actionable to combine different knowledge domains with similar mathematical underpinnings. Complex systems have a math mechanism with applicability in biology, information theory and linguistics (at least-- see, for instance, doi: 10.1073/pnas.96.6.3257) More recently, I've been actively seeking simplifications in information theory math that might have actionable application in biology. It really hits the "need for cognition" itch.
You're welcome. I think Dr. Sinclair's work is one of the best out there, and I've read quite a few by now. (Andrew Steele's book, that he linked to elsewhere here, is up there in the top few, too.) Sinclair, as I recall, specifically cited Claude Shannon's work on information theory as a strong influence on this line of thought.
"After looking into this more, I find some evidence *the* the answer is no, but also some reasons why maybe it's less clear cut than that?" Should be 'that'
Incidentally, "Reason", who writes the FightAging blog that covers this topic well (I rely on his newsletter to keep up on the latest), has noticed this discussion and weighed in.
The recent observations in mice are fascinating, as is the discussion about derivative anti-aging indications for Lorfarinib, but... I'm still intensely skeptical about the societal and political implications of life extension. With all due respect to Aubrey de Grey and a host of VC's that get lathered about the possibilities, it seems quite probable that the emergence of a legitimate life extension protocol would be intensely toxic for human societies.
My conclusion is based on a few simple assumptions. A practical life extension technology:
A) will be very expensive. (Even if the pharma production and therapeutic costs are modest, the pricing power would be so asymmetric that enormous price gouging is certain).
B) will be very limited in availability (because it is expensive).
C) will, therefore, accelerate economic and social inequality at unprecedented rates.
Difficult to see how such a technology could be deployed without fracturing every industrialized society, whether democratic or authoritarian. The perception that elite privilege suddenly includes the addition of an extra 20-30-50 years of active life would be so politically toxic it isn't hard to imagine revolutions sweeping the globe.
The part where "potential for tremendous social and political fractures" is not a good reason for condemning literally everyone to literally certain death. And the part where human societies got through equally drastic changes (see: neolithic revolution, industrial revolution) and eventually came out of them better off on the net.
I think that argument is actually the most interesting topic in re life extension. Utilitarianism a la Mills would suggest that the greater good (societal stability and reduction of wealth asymmetry) should prevail over benefits granted to a few elites (i.e. 10% of humanity living an additional 20 years).
Are you actually suggesting that there wouldn't be friction when a minority of the wealthy suddenly has access to life extension, or simply that it is worth the risk of social upheaval for some folks to have access to a longer life?
First of all, where do those numbers come from? If we do start to prolong human lifespan, nobody knows where's the limit and if there's one. And whatever technologies we discover along the way, they'll be gradually spreading until they're available to almost all of humanity. If we don't work on longevity, literally everybody literally dies, which is not considered a good outcome in most non-religious moral frameworks I'm familiar with.
Secondly, longevity and access to medical technologies is already correlated with income. And top 10% includes most people on this forum, and most likely yourself if you live in the US, Commonwealth, or Western Europe. "the elites getting to live extra 20 years" sounds all so evil and sinister, but "my grandma gets better medical care than some poor schmuck from Uzbekistan" not so much.
To your question, of course there will be a friction. As there is and there always has been and it always increased during great societal changes. But a *temporary* increase in this friction is a worthy trade off for a *permanent* increase to (eventually) everyone's life expectancy, and for the first step to even further increases.
And if you want to argue that it won't eventually spread to be available to everyone, could you please give an example of one major technology that stayed restricted to the same % of society for e.g. last 100 years?
Unfortunately, there is no rational way to analyze the probability of ubiquitous distribution of life extension technology without further insight into the nature of the drug / treatment protocol. Those factors will have an outsized influence on the degree to which mfg. at scale can reduce costs, or not.
I don't have a perfect counter example for the ubiquity of distribution question, but lets use neonatal incubators. Introduced to market roughly a century ago. Relatively inexpensive. Enormous impact on infant mortality. And yet, still a meaningful skew in access based upon individual and societal wealth. Multiple reasons why, including design lock and bundling practices of the medtech companies that mfg. them. Design lock refers to difficulty in repair. Studies show that many incubators - often donated via Western Aid programs - in African / Middle East hospitals sit unused because when they break the facilities do not have sufficient funds to contract the mfg. for repair, and they are often engineered to hinder third party repairs. Differential access also occurs within relatively wealthy countries based on variations in insurance coverage schemes, geographic isolation, and other factors.
Surely, a technology that saves the life of an infant is even more beneficial, morally defensible and economically justifiable than a technology that helps adults extend life? And yet, access to incubators is not universal, even after a century of deployment.
To paraphrase William Gibson, "the future is already here, it's just unequally distributed."
FWIW My numerical examples were simply for illustrative purposes.
As a general thing (and probably worth bringing up in an open thread), is there any way to make maintaining a thing as prestigious as starting that thing? Or at least more prestigious than it is now?
>Unfortunately, there is no rational way to analyze the probability of ubiquitous distribution
For the record, I disagree with this statement - there's a rational way of analyzing it, there are entire fields of study devoted to judgement under uncertainty. But if you believe it is true, how exactly do you go from saying "we have no way of knowing what the probability is" to saying "the probability is precisely 0%"?
>neonatal incubators
So they were spreading over the last 100 years from being available to the very reach to being available to most people in the developed countries and many people in the undeveloped world. How exactly does it prove that technologies do not spread? Are you claiming that there's some evidence that spread of this particular technology has just stopped and is not going to continue long term? Otherwise, my point never was that any technology is guaranteed to spread to 100% population in 100 years, just that it will spread to the most of the world *eventually*.
>Surely, a technology that saves the life of an infant is even more beneficial, morally defensible and economically justifiable than a technology that helps adults extend life?
Not terribly important for the argument but I very much disagree with that. Saving a life of a premature born infant adds around 70 years of life per person and affects only a fraction of the population (most people are born on schedule). Completely solving aging adds hundreds if not thousands of years per person and affects 90% of the population (most people die of age-related diseases).
Your argument ignores the recent examples of PharmaBro Martin Skreli and other documented examples of 'repricing plays' by PE firms and generic drug portfolio owners. Repricing of commonly used drugs with relatively low manufacturing costs is a documented pattern of behavior. It appears to be a way for patent holders and orphan drug producers to beat the algorithms used by PBM's and insurance companies. If there is a compelling example of, or case to be made for, industry pricing restraint I am not aware of it.
Those drugs are not widely used because the market is limited. There is no way they could pull that off with something as widely used as say a statin. Apart from the political and public backlash, it would be a bad business move. The loss in number of sales would overwhelm the increased profit per sale.
Well, for one thing, you're missing the fact that our current systems against the accumulation of wealth are predicated on current average lifespans. Politics would simply adjust.
Not true is if access to life extension is asymmetric. Longer life would certainly imply more wealth accretion for those with access to the protocol. But if limited access mirrors existing disparities in wealth, healthcare, political clout, etc., it would seem logical to assume that introducing life extension technologies would simply increase social friction and generate new vectors of instability.
Lifespan is already asymmetric, not only from some being able to afford better health care, but from some people being smarter and more able to think abstractly. They're more likely not only to accumulate wealth more but to take better care of themselves with personal habits. And they're more likely to believe in science, with the current asymmetric situation with regard to vaccines a contemporary example. We wouldn't have refrained from the development of the COVID vaccine if we knew in advance that richer people were more likely to take it than poorer ones. My point is, we already have political and economic responses to differences like that, and I don't know why they wouldn't operate similarly to encompass life extension too.
At least in developed countries, even poor people have access to expensive cancer treatments that were created through multimillion dollar trials. There would a massive public push to make effective anti aging treatments similarly available to everyone.
And from a purely cynical standpoint, it is in the best interests of the wealthy to allow for widespread access. That will allow for faster and more thorough testing of the technology. And insurance companies will certainly pay for any treatment that reduces all of the other costs of aging to zero.
I don't think preventing normal aging would be a sustainable thing to do, given the current overpopulation problem. Besides, it won't give you immortality, as from the statistical point of view some accident would inevitably happen sooner or later that will give you a very painful and violent death, as opposed to peacefully dying in your sleep at 90+ years of age. I personally would never want that.
What makes you think dying peacefully in your sleep is the expected outcome? What about your body slowly being ravaged by cancer, or your mind by dementia, or pneumonia choking you to death?
I think instead of preventing normal aging, medicine should concentrate on treating age-related diseases, so that dying peacefully in my sleep would in fact become an expected outcome. It certainly is a possible outcome, and we should work on making it the default one.
Maybe. But I still prefer that way of dying to, say, burning alive in a fire. You may have different preferences, but I just wanted to remind about the downsides. Besides, you haven't addressed my point about overpopulation.
I'm not disagreeing on your preference to die sleeping. I'm just saying that, out of all the age-related causes of death, the ones that are quiet and painless are a tiny minority, and no matter which one kills you, it's probably going to cause you immense suffering in the lead-up. You're assuming that preventing aging makes you /more/ likely to suffer, which is obviously false.
And if I had to address every overpopulation argument here I'd be here all day. Suffice it to say, every prediction that we'd suffer catastrophic worldwide famine as a result of overpopulation by this point has been proven false, so I'm not convinced by the ones that predict it now.
It's interesting to me how the second part of your statement kind of argues against the first. The first assumes that everyone will prevent normal aging, but since right now a lot of people accelerate their own aging with fat, too much sunlight, smoking, drugs, et cetera, or wind up killing themselves either deliberately or negligently in accidents, that's not likely to be the case, even aside from the question of whether they can afford anti-aging processes.
So, to be clear. Imagine your natural lifespan is 200 years, accident statistics are exactly the same. Would you take a pill to die peacefully once you're 90, just to avoid dying of accident?
(Of course "dying of age peacefully" is mostly a comforting lie, but lets assume it for the sake of the argument.)
I probably wouldn't want to commit suicide, even through peaceful means, because my instinct of self-preservation would prevent me from doing that. But it won't prevent me from not trying to prolong my lifespan artificially.
So if you're sick you're not going to a doctor? And what about the lives of your older relatives, when they die of age do you genuinely feel happy for them that they didn't live longer to eventually be hit by a car or something?
Of course I will go to the doctor. It's just that with biological immortality, I imagine I will live in constant dread, constantly awaiting violent death to suddenly come after me.
So your logic is that you need to die in order to escape the fear of death? Hmmm I feel like there might be some miscalculation involved here. Also, do you live in constant dread now? If no, why *lowering* your chance of dying at any given moment should create the dread?
Because despite everything I still may hope for at least a small chance of painless natural death. Whereas if I didn't age, I would be not only 100% sure I'll die someday (statistically speaking), but I also would be 100% sure it will be an unnatural, violent death. OK, I admit, violent death can also be painless, if I'll die instantly. So for better calculation I need to know what are the chances of dying instantly in an accident vs. dying painlessly of old age.
Did you just recommend NOT looking at a person because they have a genetic condition? For what reason, the privacy of the child or the perceived disgust of the viewer? If the second, that strikes me as a very odd and judgmental comment from someone who works in healthcare.
I'd suggest the work of Dr. Loren Fong and Dr. Stephen Young at UCLA. They're building a compelling case that a defective nuclear lamina leads to literal nuclear membrane ruptures which in turn causes DNA damage which leads to cellular death. Some have already been published and expect more in coming months.
In the context of progeria, this occurs in tissues that have high expression of lamin A AND low expression of lamin Bs AND are subject to high physical forces. This just so happens to be tissues like the heart, bones, and skin. So when progeria patients present with weak bones, wrinkly skin, and eventually die of infractions, we interpret it as aging, but it's somewhat just a coincidental overlap of affected tissues.
Interesting idea. I would think nuclear membrane ruptures would trigger apoptosis mechanisms even before you got to the point of damaged DNA, but I don't know.
These were my same conclusions after spending 4 years doing a PhD that involved the basic study of aging at the genetic level. "It's all just random," a fairly prominent gerontologist on my committee told me about halfway through the project. This is still my main takeaway.
Further, a cure for aging would be one of the hardest things to actually test and get approved as a drug. Aging itself is not classified as a disease, so the FDA could not approve a drug for that unless this situation changed, which would get very political.
Even if you found a workaround for that issue, how would clinical trials ever work? They would take multiple generations to do safely. I will be dead before any such drug is approved, even if everything else goes right.
Ultimately, I realized that studying aging will almost certainly bring no personal reward to me or billions alive today. Even if it was a tractable problem even in theory, which I no longer believe it is. One of several reasons why I abandoned academia and now am just a boring old ER doc.
Presumably any good life extension drug would also reduce some of the symptoms of aging, so the most likely work-around is that as long as the safety profile is good enough (and wouldn't it need to be if you are giving it to the entire population of old people?) it will just get approved for treating some random secondary marker that it improves. "reducing the risk of heart disease" or even just "treating grey-hair". No political fight or multi-generation clinical trials needed there.
Some of these things aren't even needed as drugs per se, right now. Fisetin is thought to be a potent senolytic and widely available over-the-counter, for those who wish to take the risk. (Bioavailability is a major problem with the oral kind, though.)
I understand the strategy. It's been a strategy since at least 2000, around the time Aubrey de Grey and SENS became well-known.
Have there been any notable advances by SENS and allies since 2000?
The point of "it's all just random" is that things that treat secondary markers generally do just that... treat secondary markers. It's like repainting the one-hoss shay, when in reality the only thing that could "cure aging" would be to basically build a new shay.
Don't get me wrong, I'm not trying to discourage whoever wants to study this stuff. (Although in a sense I deprived myself of my 20s in order to do it just the way I wanted.) I want to return to studying this stuff whenever I can FIRE. It's fascinating and aging is the cause of so much human suffering. But, I suspect there is no solution to it. I'm just a guy who enjoys tilting at windmills.
I'm fairly ignorant of the details of FDA regulation so I have to ask: if ageing isn't a disease, then wouldn't there be no need for FDA regulation? Is it really a drug if it doesn't treat a disease? How does the FDA define a drug anyway?
I guess that word "FDA" was a distraction here. My main point was really about, like, actual personal safety for you.
Suppose some guy came up with a drug he says will make you not age. What conditions would have to be true to make you swallow this pill every day for the rest of your life?
If FDA does not regulate this, would you risk your personal safety by taking it? What if it's, like, the next DNP and there's a 1/10,000 chance it will make you spontaneously combust? What if it's so new that no one knows that?
If FDA does regulate this, well, then we need clinical trials eventually. What is the bar for a successful clinical trial in this case? Delayed death, really.
If "this" is just a cure for baldness and is approved by the FDA for that indication, sure, go ahead and take it off-label. It's probably safe and probably no combustion for you. But what makes you think it will delay your aging?
My main point is that my life is pretty good right now, I accept that I am mortal, and so the bar for me personally to take such a pill would be really, really high. It's OK if your bar is different though.
Aging isn't classified as a disease yet, but there's growing pressure to, and I think we're on the way. A couple years ago the WHO added a code in the International Classification of Diseases for "aging-related diseases".
https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f459275392
I don't think it would get that political, due to the simple fact that everyone faces this. There would be political problems resulting, to be sure, but we always have them.
Clinical trials? People are actively working on that. It would get approved by using quicker metrics of aging with things like the various biological clocks, like Horvath's using DNA methylation. There are some aging clocks using blood markers, too, if I recall aright. In any case, the FDA's hand might be (probably would be) forced by medical tourism.
Oh, I'm 80% sure it would get political if there was a big move up-front to classify aging as a disease. Think of all the FUD that came out about GMOs 5--10 years ago. Now add in all kinds of narratives about class, the elites sucking young blood, etc.
In the popular imagination, with just a tiny bit of spin, immortalists are Voldemort. Many, many sides have many things to gain by attacking this straw-man.
(Full-disclosure: I'm anti-GMO because Precautionary Principle.)
I'm not sure most people would realize the implications if they classified aging as a disease. For many months now I've been telling friends, family and acquaintances the things I've been learning about this amazing science and the nearly weekly breakthroughs it seems to have, and they're invariably reacting with something like, "I had no idea!"
But as I pointed out earlier, everyone is facing this. Not only is the AARP a potent political force, but your average member of Congress is in the physical-decline part of current life- and healthspans, giving them a strong incentive aligned with that of the AARP and the most reliable voters, retirees. By contrast, I don't see a strong potential coalition to line up against them.
People were making the same arguments you just made 20 years ago when I got into gerontology. Indeed, that's part of the reason I got into it. I genuinely hope this time this will happen.
Fertility span is more relevant than lifespan. An asocial geezer who no longer reproduces is irrelevant to evolution, except as a competitor for resources to those who are still reproducing. A social geezer however might contribute to the chances of offspring reproducing, and this is I think a typical proposed explanation for longevity (though would seem to be only necessary as an explanation in those species for which longevity/fertility is unusually large).
I think this is thinking about evolution as acting on a species level. Evolution can't design creatures to die off so that they stop competing for resources with the rest of the species, it doesn't act on that level. The closest you could get to an evolutionary advantage of dying off would be leaving more resources for your children, but your children are only half you, and you are all you, so it would be better, from a relative gene expression point of view, to stick around and continue breeding, even if it means competing with your children (every child you have is another 50% you, every child your children have is only 25% you).
Evolution doesn't care about how many rolls on the mutation table it gets, because it doesn't work on that level. It's just the understanding that an entity that replicates more will be more prevalent than one that replicates less. This *ends up* as a search for good replicators, but it is not a goal. And a replicator that dies off is going to replicate less than one that sticks around and continues to replicate.
It seems unlikely for evolution to select for eventual death (it also seems unlikely for evolution to select for eventual infertility), simply because things that stop replicating... stop replicating. Therefore, it's more likely that death and infertility are just problems that evolution failed to solve yet. Which does still end up suggesting that these things are difficult to solve, but for different reasons.
It gets subsumed in replication. A thing that can't escape predators dies and fails to continue replicating. A thing that can't manage to feed itself dies and fails to continue replicating. Successful replication requires those additionals.
I wish I could claim to mastery on this, but one thing I do understand is that evolution is not a force. It doesn't actually push in any direction. Evolution is something that falls out of the math that if you have two things growing exponentially, one growing at x^t and one growing at (x+1)^t, at some future point the second population will vastly outnumber the first. Draw in complications like portions of the population dying off, and it won't affect the core conceit.
From a empirical standpoint, evolution actually selects against mutation. Polymerase has an exceptionally low error rate, and this doesn't seem to be an accident. It makes sense: In evolution, the "populations" aren't of organisms, they're of genes. The organisms are just housings for those genes. Mutations just mean that some of your replications aren't actually replications, so in terms of increasing your population number, you can get better results by decreasing mutations, and thereby increasing replications.
If organism A doesn't create more organism A, but instead creates copies of organism B, in the future you should expect to see a population that contains mostly B, and very few A. A has been selected against.
No reason for false modesty, you can claim mastery on this. You avoided the classic traps of goal and group selection, and got kin selection right.
Death or aging will not increase the genes copy you can output, so it is not evolutionary selected for. It's a byproduct of other things selected for, the result of a trade-off. But such trade off are super common, because short term benefit is so much more important than long term ones (earlier gene copies are amplified because they coupound faster) , and accidental death ensure there is a quick diminishing return for late copies.
Not necessarily; there are serious arguments that longevity is selected for in part because there are natural selection pressures on society, too. That is, societies with older individuals helping take care of the kids can work sufficiently better that longevity gets selected for.
One thing worth noting is that older men are much more likely to be fertile than older women, which may be because of the high rate of mortality from childbirth.
>I think aging might be one of the hardest conditions to reverse or cure. Death is a significant driver of evolution.
But we're talking about AGING, not death. These are two different subjects: it's possible to grow old without dying, and possible to die without growing old.
I don't understand your logic. How does dying faster help a species evolve? How is having 2 offspring and then dying at 40 better than having 2 offspring and dying at 80?
In most premodern societies, older people serve a function. They provide childcare, and act as carriers of tribal knowledge (which is important when you can't read or write). You don't want them to die off as fast as possible.
My own theory of aging:
Mankind evolved in an environment where there was a high chance you could suddenly die from disease, starvation, predator attack, and so on. For this reason, evolution never had a reason to "crack the code" of aging, because it wouldn't have benefitted anyone. By age 70 something probably would have killed you.
Greg Cochran had a cool metaphor: it's like inventing a type of car paint that never rusts or fades...and putting it on a car that's about to enter a demolition derby. It's just a waste of money. The car will be scrap metal long before the eternal paint can pay for itself.
I've heard pop-culture anecdotes that some ethnic groups age slower/better than others ("black don't crack", and so on), but no strong evidence. It doesn't seem to be something evolution strongly pushes towards.
Not having researched this at all / just off the top of my head, the "black don't crack" phenomenon may be due to high levels of melanin giving protection against skin damage from sun exposure, which is known to contribute to skin's appearance of age (wrinkles etc.) If so, this probably wouldn't have much effect on actual lifespan, just on how young one looks.
True; there are many DNA stressors besides UV rays.
> Mankind evolved in an environment where there was a high chance you could suddenly die from disease, starvation, predator attack, and so on. For this reason, evolution never had a reason to "crack the code" of aging, because it wouldn't have benefitted anyone. By age 70 something probably would have killed you.
By age 3 something probably would have killed you. But if you made it past that, you'd most likely live into what we call middle age, which is old enough for aging to be a problem and probably a contributing factor to your death. Aging is a clear negative; one that only sticks around because evolution can't fix it without breaking something else.
That seems a lot like group selection, and it seems unlikely to me that something as long term as evolving more slowly would have a huge effect.
My impression is that lifespan has a lot to do with not being easy prey. Longevity correlates with size, group living, flight, poison, and armor. You can't maximize all of these at the same time.
This doesn't mean that speed of evolution is irrelevant, but is older members of the species still being around (and still fertile, presumably) a major factor?
I'd thought that progeria could be a big clue because it suggests that aging is a well defined syndrome which can possibly be blocked. I'm not sure whether a drug for one type of progeria argues against the premise.
Your logic assumes that conditions are continuing to change relatively rapidly that must be adapted to or the organism will die. That doesn't seem to be the case. In any case, there are a fair number of organisms that are effectively immortal-- certain hydra and jellyfish are the most famous-- which by your logic should not occur.
https://en.wikipedia.org/wiki/Biological_immortality
They're much less complex than primates, that's true, though I'm not sure more evolution inherently means more complexity.
It's early days yet with our knowledge of the kinds of evolution, so I'm not sure anyone knows why immortal species exist. My point is only that they can. In particular I'd like to know where they fit in with the theory that longevity goes along with a lack of external causes of death, like predators, such that species with many predators, like mice, select for fast and fecund breeding rather than for long lives the way even closely related but safer species, like bats, do. I wouldn't think hydras were particularly safe from predators or disease, after all.
Well, it's not pairings for most predators or prey. Mice can get eaten by a lot of different things, for example, so how are you going to evolve to defend against one without potentially opening yourself up to vulnerability to another? Against flying creatures versus ground creatures, say. Evolutionarily they're being attacked on several fronts at once. And, too, there's probably only a certain range of potential traits for evolution to create, limited by things like the nature of chemical bonds.
I don't think, furthermore, that cancer is thought of as a circuit-breaker to enforce anything. Cancer seems to be an accident-- the result of a certain kind and number of mutations-- which we have evolved to deal with, like our two-classes-of-cells arrangements by which somatic cells "intentionally" die off after hitting the Hayflick limit, to be replaced by new somatic cells produced by stem cells that live a lot longer using telomerase. In any case, again with the examples from nature, there are animals that appear to be effectively immune to most cancer, like the naked mole rat, and if your theory were correct that shouldn't happen.
I'm still not sure why you think species that have evolved less could be immune to these things where more-evolved ones are not. Less complex species, sure, that's possible, but as I mentioned I don't see a necessary link between complexity and more evolution. But if cancer were a way of limiting lifespans to the optimal level for evolution it would kind of assume the species that don't get cancer need to evolve so rarely that there is no optimal period of lifespan for evolution. I don't see how that could happen over millennia.
The most obvious counterargument to this logic - I'm surprised nobody seems to have mentioned it - is that there is in fact quite a few species which do not age, i.e. for which the chance of dying per year doesn't increase over time: https://en.wikipedia.org/wiki/Negligible_senescence#cite_ref-FinchLSG_1-1 Obviously those all are products of evolution. So whatever the mechanics are, it's just a matter of fact that aging does not follow from evolution inevitably.
Also, there's no such thing as "evolutionary left behind". Many of organisms living today are not meaningfully different from what they were hundreds of millions years ago. It's a common misconception that evolution is a steady progress from more primitive to more advanced, but it's not exactly true, there's plenty of room for sticking to "tried and true" and even going backwards (in some sense).
More centrally, the natural selection does not work "for the good of the species". The only factor determining which genes are going to propagate more is - which are more likely to replicate? If some organism could live forever while flooding the world with its offspring, that would create a ton of copies of their genes, each making new copies. The problem is in the "live forever" part, for most organisms the mutations allowing for extremely long lifespans are not particularly useful because they're likely to die from disease or predation too early to make use of them, so most don't evolve negligible senescence.
Why-- perhaps I mean "by what definition"-- do you think apex species would be different?
Well, greenland shark is the apex predator in its ecosystem and is reasonably complex. But it lives in extremely cold waters and has very slow metabolism so I guess you can make an argument it doesn't count. Bowhead whale is basically as complex as an organism can be and is extremely long lived, although it does age eventually.
But it doesn't really matter, because even if true I don't fully understand how it supports your point that that primates have "many different and de-correlated defense mechanisms against longevity". In the model you describe below, longevity is connected with the evolution rate solely through the reproduction rate. And that is something we can observe directly, and see that primates and other apex species (btw the only primate to be the apex predator is human) generally have slower reproduction rates and longer generations for their size. Which apparently doesn't stop them from being very evolutionary advanced, and there's in fact quite a few known and proposed mechanisms for how that might work.
I think the best critique of this logic is to look at the natural world, where species lifespans and rates of aging vary incredibly widely, and there doesn’t seem to be any kind of limit associated with a need to adapt.
I think the most useful definition of aging for this discussion is the statistical one: how long it takes your risk of death to double with age. For humans, this mortality rate doubling time is about eight years. For mice, it’s a few months. For animals with what’s called negligible senescence it’s infinite: their risk of death is constant with time. We know of quite a few species with this property—some tortoises, salamanders and fish, naked mole-rats, hydra, and I guess quite a lot more that we’ve not found yet. They also don’t seem to degenerate appreciably in terms of physical frailty, reproductive capacity etc with time, so in that sense they seem quite literally not to age, which your logic would suggest is impossible. In fact, there are even some creatures with _negative_ senescence, whose risk of death _decreases_ with time.
The distinction between aging, the diseases it causes, other diseases (most of which become more likely to kill you with age) and other causes of death from an evolutionary perspective also isn’t that clear-cut. The spectrum of diseases different animals die from varies widely too—for example, naked mole-rats were thought until recently to be entirely immune to cancer, though the discovery of a few tumours in them now shows that they’re in fact merely highly resistant. Cancer therefore isn’t a circuit-breaker for them, or many other species.
Basically, evolution will do whatever it needs to do to lifespan and ageing rate to maximise the chance of genes being propagated to the next generation. Ageing evolves in certain scenarios due to evolution only caring about you up to reproductive age and, after that, allowing deleterious mutations to kill you (aka https://en.wikipedia.org/wiki/Mutation_accumulation_theory) or, worse, optimising your body to reproduce more effectively in ways that kill you in the long run (https://en.wikipedia.org/wiki/Antagonistic_pleiotropy_hypothesis).
Those Wikipedia pages are a good start, but another good place to read about how aging evolved—and more on what we can do to treat it—is my book! https://andrewsteele.co.uk/ageless/
Incidentally, I agree with Scott’s assessment of progeria and its lack of significance to normal aging—it only gets one mention in the book, and that’s to ask the ethical question of why we consider these premature forms of ‘aging’ a disease, but are sanguine about ignoring these symptoms when they occur at what’s currently the ‘normal’ time…
I agree, there could be some complex, high-level meta-selection going on from the species up to the ecosystem or even Gaia level (!) but I think the consensus in evolutionary biology is that it’s far weaker than individual-level selection. Immortality actually confers a disadvantage at the individual level too—the protective mechanisms necessary come at significant energetic cost, and that energy could be more profitably invested in eg bigger muscles to outrun predators, or simply having more babies more quickly for many organisms. That’s the essence of antagonistic pleiotropy theory, and its descendant disposable soma theory.
So yes, there probably are second-order effects, but I think they’re probably much, much smaller than the effects on the individual organisms, which are sufficient alone to explain (most of) what we observe. :)
Some of the hydras, jellyfish etc. actually revert their cells to juvenile status to undo aging, if I recall correctly. Which is something we can now do with the Yamanaka Factors.
We’ve certainly got a foothold! We can’t go full jellyfish and revert to a stem-like state to refresh our tissues, but the good news is that the ‘reset biological age’ and ‘reset cell identity’ levers appear to be somewhat distinct, and the Yamanaka factors activate them in a favourable order. It’s definitely one of the areas which I’m most excited about!
"primates have many different and de-correlated defense mechanisms against longevity"
No, we are extremely long lived for a mammal of our size (we outlive elephants!):
https://i.stack.imgur.com/eUu1c.png
We seem to have evolved specific anti-aging mechanisms (even trading off against disease): https://en.wikipedia.org/wiki/Urate_oxidase#Significance_of_absence_in_humans
If this was the case, evolution would select very strongly for short-lived species with extremely high rates of reproduction.
In real life, we see numerous species - humans included - which actually live for a very long time and reproduce relatively slowly. In fact, humans age abnormally slowly - humans live an extremely long time for animals of any size, let alone the size they are. Lifespan generally increases with size, but humans outlive every mammal except maybe baleen whales.
But the logic is more obviously flawed, as it relies on incorrect notions about group selection.
Evolution will happily select for longer lifespan, because more babies = more genes passed on = more offspring with those genes. Being able to produce offspring forever is great.
The reason why animals are limited in life expectancy is likely simply that most animals *don't* live very long. There's no reason to select for a mouse that lives to ten years of age when most mice die inside a year due to predation. Longevity thus gets selected for in species that are really good at avoiding predation and living a long time - which is why you see very large animals that live for a long time, because they're not terribly vulnerable to it as adults. Humans, by being able to avoid predation, likely underwent the same process. It's likely that humans have gradually been selected for longer life expectancy and longer reproductive years.
Indeed, the fact that men can reproduce to a greater age than women can is likely due to exactly this - women used to die a lot more frequently in childbirth, whereas men did not. As such, there was stronger selective pressure for older men to still be able to reproduce than older women.
Lorfarinib is a farnesyltransferase inhibitor, and those have some pretty bad side effects, since many important proteins are farnesylated. I wouldn't want to take it unless I had no other choice.
Gene editing for progeria is coming along quite well, there was a mouse paper recently published and the scientists involved are already working on moving into clinical trials. https://www.nature.com/articles/s41586-020-03086-7
Gene therapy may also be more generally useful for anti-aging. See https://www.nature.com/articles/s41586-020-2975-4 and https://www.pnas.org/content/116/47/23505
And more on the topic of lofarinib side effects (in cancer patients, originally it was a chemotherapy but it failed): https://pubmed.ncbi.nlm.nih.gov/18641985/
"astrointestinal toxicities (diarrhoea, nausea and anorexia) and myelosuppression were the major side effects. Other toxicities included infections, fatigue, increase of liver enzymes, arrhythmia and skin rash. One patient died of infection, and the treatment was stopped in one other who developed atrial fibrillation. Doses were reduced in all but one patient treated with more than one course of farnesyl transferase inhibitor. Responses were assessable in 12 patients. A partial response in one sAML patient and a very transient decrease of blast cell count with normalisation of karyotype in one MDS patient were observed. No relation between improvement of marrow parameters and detected Ras mutations was observed. Lonafarnib alone, administered following our schedule, has shown limited activity in patients with MDS or secondary AML. Gastrointestinal and haematological toxicities appear the limiting toxicity in this population of patients."
Have you had a chance to read the book Ageless yet?
Agh just realized I made a bunch of spelling errors. Oops.
That is a very impressive paper! Gene editing live mice to more than double their lifespan!
I have virtually zero expertise in this area, but my understanding is that a common problem with lifetime extension research in mice is that it turns out that humans are already doing most of these tricks (and that's part of why we live so much longer than mice). Is this an exception?
Can you give examples of tricks known to the human body but not to mice? My understanding was that lifespan is fairly predictable based just on size (1/4 power rule). There are also some theories trying to explain the 1/4 exponent. See “allometric scaling of lifespan”.
It's actually not just size. Compare for example bats and mice, which have comparable sizes - bats live about an order of magnitude longer than mice. One theory about why is that bats are generally better at escaping from predators, meaning it's made evolutionary sense not to have them die after two years, on the premise that the longer they live, the more they can make more of themselves. Mice meanwhile, in the wild, are fairly unlikely to survive longer than that anyway, so evolution hasn't "bothered" to remove cruft that makes them short-lived -- all of their evolutionary fitness is optimised for getting as much out of their lives before they get eaten. Very simplified: The fewer things eat you, the longer you (eventually, if evolution is given the time to improve your lifespan) live.
Beta amyloid plaques are definitely a symptom of Alzheimer's. They just don't seem to be part of the disease mechanism.
For anyone else interest in this thread: I've read that they might be an immunological response of the body's and Alzheimer's is "just" your brain's immunological response going into overdrive and starting to do damage. Struggling to find a good and succinct paper to link to right now, but this was an early find in my searching process - https://www.intechopen.com/books/exploring-new-findings-on-amyloidosis/is-alzheimer-s-associated-amyloid-beta-an-innate-immune-protein - In any case, I've heard the hypothesis that it may be outright counter-productive to try and reduce the beta amyloid levels directly, because the body'll just produce more to compensate, although I don't at all know if that's true. I don't think it necessarily follows, anyway. (Though I do think it follows that one should try figuring out what's causing the immune response in the first place. The book "The End of Alzheimer's" argues one should try drastically reducing carbohydrate intake, amongst other things, to reduce inflammation levels. See also https://memory.ucsf.edu/sites/memory.ucsf.edu/files/CanWeTrustTheEnd2020%280420%29.pdf for miscellaneous book criticism.)
Would make most sense for there to be a reason for immune system attacking there. Usually immune system overdrives mostly hurt young people with effective immune systems, underdrives old people with non-effective immune systems.
Carbohydrate connection would make most sense if it was a bacteria or mushroom, getting food from them.
Remember someone writing they found some species of small bacteria in brains of some dead patients (though of course they could get there after death aswell).
You might be interested in looking at the other progeroid syndromes, Bloom Syndrome and Werner syndrome. Both are caused by mutations in helicases, responsible for unwinding DNA during replication. Their absence leads to DNA damage due to stalled replication forks.
Excited to see a post related to longevity here (and would be even more excited to see more in the future)!
It's worth noting that many substances that help to remove senescent cells do appear to sometimes be able to extend the lifespan of several organisms, although the only higher-quality data we have for this is generally in mice (as one expects). See https://pubmed.ncbi.nlm.nih.gov/33555034/ for a recent example, although there's tons of other interesting substances and papers out there by now, just search pubmed or google scholar.
I personally believe that some of this mechanism of action applies to humans as well as most of what is involved appears to be pretty evolutionarily conserved (although even if correct, this doesn't implicate that the drug this post is about would be beneficial at all!). I am lately finding longevity to be a pretty exciting area and now consider it one of the most important fields of the next decade and beyond (along with machine learning and biotech). The unfortunate side to this is that, in general, we have little idea what we're doing, and doing proper longevity RCTs on humans is very difficult and slow, so we are lacking the data we'd want in almost every area).
I'd guess that the most one could hope to gain from the above would be around 1-15 years in lifespan. The good news there is that this is an absolutely amazing prospect, even if it ends up being on the lower end (which is perhaps likely, or perhaps it is even negligent), especially when contrasted with the fact that curing cancer would only extend the average human lifespan by around 3-4 years (see https://news.usc.edu/55969/delayed-aging-is-better-investment-than-cancer-heart-disease-research/, the short answer being that if cancer doesn't get you, something else will only shortly afterwards on average, as you are still fundamentally aging). For a great introductory paper that tries to give a rough outline of what some root causes of aging may look like, also check out the hallmarks of aging: https://pubmed.ncbi.nlm.nih.gov/23746838/)
I'll probably manage to resist posting all of the other weird things that I think might notably extend human life span, but I'll read about progeria now for a bit which I haven't learned much about, so appreciated this post.
Correction to last link, here is the full text rather than abstract: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/
One thing I'm not sure people fully appreciate is that if you slash mortality in half, you only end up increasing mean life expectancy by about 8 years. Aging is an exponential process, and it's often hard to get a grasp on just how strong that is.
According to the SSA's period life tables, you have around a 1/1000 chance of dying during your entire elementary school years (around ages 5-12).
At age 25, you have the same chance of dying just that year alone (not preconditioned on your sex... at this age in particular it's much worse for males than females).
When you're 50, it's around 3 months.
At 65, one month.
80, a week.
And lastly, when you're 100, you have a 1/1000 chance of dying every single day -- the same as your entire time in elementary school.
When you're dealing with an exponential like this, quite large changes in chance of death end up having relatively little effect on life expectancy, because the rise catches up quite fast. I'm hopeful that more work can be done in the future on therapies that can actually slow down the process (and "flatten the curve", if you will), which would have a much larger downstream impact in the end.
I didn't fully appreciate this, thanks for the reality check!
That assumes, I think, that mortality is the same clear through. But I think different forms of aging probably compound at different rates. Slash the correct half of mortality, such as senescent cells whose emissions not only spread disfunction but encourage other cells to become senescent, which is the single most obvious form of compounding in aging, and it's likely to be a different story. And senolytics are one of the geroscience therapies that we're most advanced at, so we may see what the numbers actually are pretty soon.
Thanks Nearcyan - good links but from 2013 so ageing fast 😉
The future post on longevity I'd be *most* excited to see is the one posted in 2121.
>"except that in doing this research I kept finding people saying that maybe some of aging is caused by this one weird mutant protein..."
I suspect this might be a general phenomenon; anybody who studies an aging-adjacent disease or molecular process will say that it might also be implicated in normal aging, whether the case is strong or weak; otherwise, why should anybody else pay attention / for that matter, why are they themselves studying it? It also helps (or hurts) that despite the progress that's been made, aging is still mysterious enough that anyone can say anything *might* be involved, and it's hard to say they're wrong.
When gerontologists who don't specialize in that specific disease also start saying they think it's implicated in normal aging, that's when I'd give it extra weight.
Here's an exchange between some biogerontologists on whether accelerated-aging models like progeria are or aren't useful for understanding normal aging (Miller's a skeptic):
Miller, R. A. (2004). ‘Accelerated aging’: a primrose path to insight? https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9728.2004.00081.x
Hasty, P. and Vijg, J. (2004). Rebuttal to Miller: ‘Accelerated aging’: a primrose path to insight?’ https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9728.2004.00087.x
Ah: I'm looking now at the papers Scott quoted, and they do seem to have a specific link in mind, not just general handwave-y speculation. Looking more closely now
>"All of this suggests lornafarnib shouldn't help prevent normal aging. After all, normal aging is caused by lots of processes including gradual expected accumulation of DNA damage - not just the downstream effects of one weird mutant protein.
...except that in doing this research I kept finding people saying that maybe some of aging is caused by this one weird mutant protein..."
Ok so from looking at stuff, it looks like: they're not claiming that normal aging is caused *just* by this one weird mutant protein, they're just claiming that of those lots of processes, lamin A is involved in one or some of them (as opposed to none, with progeria just bearing a superficial resemblance to aging).
Progerin (the truncated version of lamin A) is also found in normal old people's cells, not just the cells of people with progeria: https://genomics.senescence.info/genes/entry.php?hgnc=LMNA
Dermal fibroblasts respond to increased support by literally becoming younger because of mechanosensory signaling pathways.
Part of the marketing of those usually awful fillers- but your fibroblasts will be like extra old once they dissolve.
https://www.pnas.org/content/117/19/10131
You're pretty much designed to get old and die- we wouldn't be here if that wasn't our inherent actual purpose. You can make random interventions which usually are a winning tickets for cancer, but your CNS is going to reach thermal equilibrium sooner or later.
lol the former- https://m.youtube.com/watch?v=B0egWbwErRQ
We're not /designed/ to get old and die; that's just a tradeoff evolution has decided for us. We may have lots of genes that have a short-term advantage (e.g. better fitness in our teens and twenties) but end up killing us in our 80s. Staying alive long enough to nurture your grandchildren and great-grandchildren has /some/ genetic advantage, but one generation more and the effects are too dilute, and evolution stops having any reason to keep us alive. So, all the tradeoffs where we get an early benefit but pay the price in old age are greedily selected for, and everyone who could easily live to 100 but can't pop out more babies in their 20s gets kicked out of the gene pool.
Absolutely. There's no advantage to my body slowly becoming weaker. Evolution would not preserve that trait unless it were accompanied by some greater benefit.
I've seen this argument before and I still don't completely understand the reasoning. If non-aging organisms of both sexes remained fertile indefinitely and kept producing new offspring, how could that *not* be a selective advantage?
It's an advantage until conditions change and the old version doesn't fit the world very well.
Like famine or war?
Think of evolution as an editor that can only correct some errors. An error that kills you at 80 will be far less important to correct than one that kills you at 20. Because of DNA copy errors that happen in reproduction, there will always be significant errors. If all errors could be corrected, evolution would work to increase the complexity of the creature creating more opportunity for errors. The error correction mechanism is creatures with fewer errors having more kids.
To expand on this (in case the framing I'm about to give is a better framing for someone else reading this thread) - It's really worth noting that evolution doesn't care very much if individual animals die, as long as they die *after spreading their genes* - so genetic cruft that kills you very slowly can accumulate over time.
This is especially true if there are predators that would put an "unnatural" (extrinsic, really) end to your lifespan, where it's unlikely you're even going to live to your then-"natural" (intrinsic) lifespan.
I assume you're talking about menopause, which is not what I meant exactly, so I'm not sure the same argument holds. Rather, assuming equal lifetime fertility, the offspring who grow up to be stronger, more resistant to disease or starvation, etc. in their 20s will outcompete the others. If evolution can find genes that improve those traits, those genes will propagate, even if they also make you decrepit by the time you're 80. This matters a lot more to humans, who reproduce slowly. A young mother who can devote all her resources and attention to her first child is going to outcompete an old mother who has 10 children vying for her attention. The earlier you can gain an advantage, the better.
I'm imagining that a healthy woman who can have ten children (not all at once) is founding a clan. If the work is done competently, there will be a lot of mutual aid. In the real world, older children (possibly mostly daughters) help take care of younger children.
True, but all of that is (somewhat) secondary to how their genes propagate. A woman with 10 children is very successful, but even so her genes can get outcompeted. It's been a while since I read up on this theory but I remember early life fitness being considered the decisive factor.
Direct offspring is not the only way to help your genes propagate. A woman with 10 children will gain some extra gene propagation by birthing an 11th kid, but perhaps she can also get much more gene propagation by facilitating a good life for their 10 children so that they each get one more healthy kid; and for social animals like humans, someone who's "non-reproductive" (for whatever reason) can definitely help their genes propagate by helping their siblings, nieces and nephews who, especially in a close-knit clan, are pretty much the same genes anyway.
That brings up an interesting thought related to the earlier comment you replied to (about organisms that just live a long time with reproductive ability, like tortoises or something). Human reproduction is an inherently risky endeavor. Even _if_ we had genes that would let us be reproductively capable for 100 years, for women at least, the odds of continuing to have children without _ever_ dying from complications (in the pre-historical, evolutionary context) is practically zero. So genes that give you an early advantage and make the odds of your first few children being successful, are _even more_ advantageous because anything that gives you a chance to have more children on the downstream end are less likely to ever come into play at all.
Does anyone have numbers for the risk of death or serious injury for the mother in childbirth in the ancestral environment?
Could we even get those numbers?
> If non-aging organisms of both sexes remained fertile indefinitely and kept producing new offspring, how could that *not* be a selective advantage?
Immortal parents would end up competing with their children for resources, so this selective pressure would drive low fertility. Low fertility means low mutation rate, and if the enviroment changes, old cells may not be well suited to the new environment and your whole species might suddenly go extinct.
Not to mention that immortal multicellular organisms are resource hungry on their own. For instance, a lot of energy in computers is spent on signal fidelity and keeping the voltages within tight tolerances. If computations were robust against a certain error rate so these tolerances could be relaxed, computers could be considerably more energy efficient.
That's more like what organisms with sexual reproduction are like: computations that can tolerate some error rate but that will eventually crash due to accumulated errors, but that can spawn a new set of computations using considerably less information, ad infinitum.
Parents aren't competing with their children any more than they're competing with everyone else. It's still worth it to have children because that's the definition of inclusive genetic fitness. So selective pressure wouldn't "drive low fertility".
Think of an animal whose fertile period is 2x normal, then 3x normal, and so on. In each case the optimal thing is to have as many kids as possible during the fertile period (or at least as many as you have the resources for), while surviving yourself as long as you can. An immortal animal is just the limit of this.
> Parents aren't competing with their children any more than they're competing with everyone else.
Parents and offspring are necessarily in the same geographical area and thus are necessarily competing for the same finite resources. "Everyone else" are not necessarily in the same area, and thus, not necessarily competing for the same resources.
> It's still worth it to have children because that's the definition of inclusive genetic fitness. So selective pressure wouldn't "drive low fertility".
Parents that live alongside descendents are competing for finite resources, ie. food, water, etc. That's just a fact.
Organisms with no check on their populations inevitably destroy their habitat; we have ample evidence of this, and humans are doing this right now with climate change.
If you extend lifespan to "immortal" and fertility does not go down, they will destroy their habitat and go extinct. Only those populations that don't destroy their habitats with out of control reproduction will survive. Therefore, in surviving *immortal* species, fertility will necessarily be lower than non-immortal species.
Fertility will not be zero of course, because even immortal organisms will have accidents or natural predators, but it will definitely be lower than the fertility rate of species with a shorter lifespan.
Successful groups get more resources by expanding their territory.
It can be a *negligibly small* selective advantage, because by the time you reach 80 you've most likely been eaten by the lions or cholera or something. And for this mutation to fixate, at least some of your children must reach 20, and some of their children and so on for quite a long while.
In the natural world, there are many things that can kill you, not just aging. For example, mice typically only live for a few years before being eaten by predators. Consequently, there is no selective pressure for long-lived mice. Even if a mutation appeared that might have caused a mouse to be healthy and fertile for decades, it wouldn't be more likely to be passed on, because the mouse would be eaten by a hawk long before then.
In the absence of selective pressure, there is no reason for DNA/senescence/cell repair mechanisms to evolve past the bare necessity. Without repair mechanisms, damage accumulates over time. So every species on the planet tends to die of old age shortly past the time at which it would ordinarily die of other non-age related causes.
Species which don't have predators (e.g. Sequoia trees) can and do live and reproduce almost indefinitely.
So I gather you actively disbelieve the theory of antagonistic pleiotropy? 'Cause that directly contradicts your "designed to get old" theory.
https://www.merriam-webster.com/dictionary/believe
https://en.m.wikipedia.org/wiki/Common_misunderstandings_of_genetics
Links are not arguments.
Cephalopods. Now they're designed to age and die.
After mating and brooding, their optic gland triggers endocrinological changes and they quickly stop eating and start to deteriorate. Remove the gland and they live significantly longer.
Human senescence is weaksauce compared to this.
I'd like to know how progeria is explained by the Information Theory of Aging. By that theory, actual aging occurs when your cells progressively "forget" what sort of cell they're supposed to be as a result of damage to your epigenome, the "analogue" information that controls which parts of your "digital" DNA get expressed and how much. Progeria is cellular damage, but from the sound of it, not the same mix of cellular damage as aging.
https://www.fightaging.org/archives/2019/06/progerin-acts-in-normal-aging-as-well-as-progeria-but-is-it-important/
Why do you people not want to get old and die? Trust nature.
Preventing aging is a terrible idea for several reasons, but "trust nature" isn't one of them.
As a pantheist, I trust Nature.
Doesn't Nature include human inventiveness?
Sure, but it is a ridiculous subject on which to focus our resources. Let's make the next generation better off and stop worrying about ourselves. There's one big soul not a bunch of small ones. Almost everyone is behaving like solipsists even though most reject that label.
I don't fear my death (maybe because It's probably still a decent ways off, but I don't think so). But I enjoy being alive and would rather not have death thrust up on me. Maybe I would eventually get to a point where I didn't enjoy being alive, in which case I would like to be able to choose death. But I would much prefer that choice to be in my own hands than in the hands of some stochastic process. I find it unlikely that, presuming a decent level of health, that I will have wrung all the enjoyment and happiness that is possible out of life by the time I'm 80ish.
No one person is ever going to wring all the enjoyment and happiness that is possible out of life. The good news is that there are billions of people on the planet, billions and billions more to come, and trillions and trillions of other creatures. Let's wring all the enjoyment and happiness (and pain and sorrow) out of existence together. The best anti-aging technology is sexual reproduction.
Ever read The Magic Mountain by Thomas Mann? Written just after WWI. There is a great scene where the protagonist has a brush with death and has an experience of his small soul joining the great soul. There were an awful lot of German writers of that period putting forth ideas cribbed from Vedic Cosmology. Even Erwin Schroedinger talks about how each of us is “God Almighty” in the Hindu sense. That is in the afterword of his What Is Life lectures.
I've read it. Not a huge Mann fan but he has his moments.
Okay, that's a nice pretty sentiment and all, but *what if you're wrong*?? What if there's no "one big soul," and there really are just trillions of tiny isolated souls, and every time any one of us dies, something precious and irreplaceable actually is gone forever? On that premise, surely the existence of death is doing an incalculable amount of harm.
So, how sure are you about your "one big soul" assumption? 50%? 90%? Even if you're 99.9999999% sure that you're right, isn't even the 0.0000001% chance that you're wrong worth taking into account, considering the staggering moral implications of that possibility?
Bear in mind as well that assuming on the basis of religious convictions that the suffering of large numbers of beings doesn't really matter is not an attitude that's led to terribly positive results, historically speaking.
And, by the way, the belief that trillions of unique and irreplaceable beings and/or souls exist and are worth preserving is literally the exact opposite of solipsism.
Not at all likely IMO. It’s part of the South Asian take on the unknowable. To me it’s much more appealing - as metaphor - than the angry bearded guy that Bronze Age pastorals came up. It’s poetry and a philosophical way to get by in a cruel world.
Do you wear shoes?
Only when society makes me.
I'll grant that this can be internally consistent, but also speaks as to how society ought to treat your engagement with heavy machinery.
And exactly what those would be?
I have a rather moderate case of getting older, and it's unpleasant even so.
How old are you?
I'm over 50. I was happier when I was younger. I'm just glad I'm going to die. I'd hate to extend my life.
My feelings about life and age and all that vary quite a bit. I'm probably less depressed than I was.
You may be imagining your life just getting worse. Decent longevity tech would presumably restore your earlier happier self.
A lot of this is probably because of the aging process. If you were just as healthy as you were when you were 20, you'd probably be less into the whole dying thing.
And if you even then would still have qualms against living forever... well, that's fine, it should be optional. Doesn't change the fact that aging is by far the biggest public health crisis facing humanity.
Also in case you haven't read this: https://www.nickbostrom.com/fable/dragon.html
So don't.
I’m just 2 years shy of my allotted 3 score plus 10. Maybe I shouldn’t even mention this but I’ve never been happier. My wife is a year younger and her daily level of joy is up there with. It’s the old happiness is a choice thing I guess.
Yeah I kind of regret the previous post already. I know that there are biological reasons that people can’t just choose happiness.
And it did take several years of Theravadan meditation for me to get to this point.
Because it's a problem to solve, and humans are natural problem solvers? What is unnatural about humans, a species that evolved on this planet, using the natural resources of this planet to challenge aging anyway? We're not an alien species, and we're not bringing in materials from outer space/another dimension or using magic here. It seems to be natural for the primate species homo sapiens to seek to manipulate and change itself and its environment, and this is just another example of this. Like it or not, humanity and our environmental manipulation is a major part of the nature of this planet, and seeking to challenge the progress of aging is just a normal human behaviour, like eliminating Smallpox or treating wounds.
If you found out that you have some deadly disease, but fortunately there's a cure available, would you take the cure or let nature take its course? If your hip went bad and you needed a hip replacement, would you take the surgery or crawl around like nature intended for you? Do you use fluoride toothpaste or let your teeth rot and fall out at nature's preferred schedule? If you happen to have bad eyesight, do you grope around with the half-blind eyes nature decided to give you, or do you uses glasses or contacts or even laser surgery to correct them? If, as you get older, your doctor advises you to take certain vitamin supplements, does that count as not trusting nature?
Where is the boundary between using technology to fix a problem with your body, and "distrusting nature" in the way which you apparently consider bad?
I'm all for improving the quality of individual lives just not the length of them. One should outlive their parents. Beyond that the length of life should not be a priority.
I don't mind dying, but ageing is pretty horrible. >50% of your life is spent getting weaker, enduring more pain, sleeping less and less well, and being more prone to various illnesses.
Why trust an accidental process?
Aging is a horrible thing if you cut away the cultural fluff.
The definition of "nature" is unclear here. After all, modern lifespan is considerably greater than it was in 20,000 BC. Should we eschew antibiotics, clean water, wheelchairs, indoor living, because these things extend lifespan beyond what was "natural" for Mitochondrial Eve?
What some people hope is that similar technological tweaking will establish that if humans not only live indoors, have clean water, have antibiotics for disease, avoid breathing radon and plant smoke, and....use some as yet unknown therapy for some as yet unknown problem -- then we will find that the "natural" lifespan of human beings is, say, 250 years instead of what we currently view as "natural" (80 years).
Then our great-great-great-grandchildren, once they have become habituated to lifespans of 250 years and write anguished odes to the finiteness of life, will get to have the argument all over again.
I don't think this cycle would continue forever, though. If people were somehow able to live for Graham's number years, I don't think that they would write paeans at the end about life is far too short for them; on the contrary, if I lived for that many years, I would probably be scared and lonely and bored for all but the first ~million. (C.f. https://waitbutwhy.com/table/how-long-would-you-live-if-you-could-choose-any-number-of-years)
Hard to say-- what are the odds of good solutions for boredom and depression?
It's possible that if you want new experiences, you're going to need some sort of augmentation eventually.
It seems unlikely to me that augmentation could supply endless new experiences at the scale of my earlier comment though. Purely based on a rough estimate of the number of ways that quantum particles could possibly be arranged to form this universe and taking this as a rough upper bound on the number of possible experiences therein gives a rough upper bound of 10^10^10000 different experiences, which, though very large, is *much* smaller than Graham's number.
Maybe. Human beings are notoriously adaptable, and seem to reach the same set point regardless of their situation. It's often assumed that people with severe handicaps would be generally much less happy than those who don't, but they aren't. The rich aren't, in fact, significantly happier than the poor. Those who live in countries with high life expectancies aren't way happier than those who live in low. (Way more people in Japan kill themselves than do in Nigeria, just for example, and Japanese on average live almost 30 years longer.)
So a priori I think it very likely human beings would psychologically adapt to whatever new lifespan they got. The first generation or so that got to live an extra 100 years would be ecstatic, but by the 5th generation it would be taken for granted, and people whose lives were "cut short" by being allergic to boosterspice would feel as tragically wounded as someone today who is diagnosed with fatal cancer at age 25.
What would happen if lifetimes were really long, like a million years? The only noticeable change I can imagine is that we would become very, very careful about accidents, because over that lifespan accidents are the major determinant of lifespan. (IIRC average lifespan for Americans if accidens were the *only* way to die would only be of order 1000 years, I believe definitely less than 10,000.) So that would be a little weird. But a million years is actually not that long by cosmic standards. If you were born a million years ago, the Earth wouldn't be all that much different than it is now. Most of the same species would be here, although many would have changed a bit. You'd have experienced Great Winters (Ice Ages).
But the universe doesn't become more boring when you experience it on a much longer timescale. It's just that we're *unaware* of events that happen on much longer timescales, because thinking about them is existentially uncomfortable (or pointless), so we are unaware of the ebb and flow of events on multi-thousand and million year timescales that would be interesting, if you could live long enough to see it.
So
Not sure about not aging meaning you get extra careful about accidental death. It's a common sf theme, immortals turning into paranoiac cowards so obsessed about accidents that they do not really live anymore, and it's logical... Except it does not works like that in real life, it seems fear of accidental death and illness is only slightly affected by a rational risk benefit analysis and more under instictive control, probably largely hormonal: when you get old, you get more and more afraid physical risk, more concerned about health issues,while you obviously have less and less to lose. You can say it's experience, but why are women much more careful on average than men at the same age? I guess it's largely testosterone and adrenaline-controlled. I am much more physically cautious than when young, and it's not experience (my assessment of risks is more or less the same) not confidence in my physical abilities (although it play a role). It's just a less adventurous mood, i evaluate risk the same but i am morr averse to it (physical ones for sure, but i think it's general). So my guess is that immortals that stay physically fully young will maybe get a little bit more cautious than teenagers or young adults... But far less than middle aged or old people.. .
Let me suggest that instinctive control is merely a rational risk/benefit analysis that your DNA (assisted by 40,000 years of natural selection) have already done for you.
I almost fully agree : my dna didn't do it for me, it did it for him (it?). It's obviously adaptive to engage in high risk activities to gain early advantages, social status and impress mates, because it maximize amount of offspring. The risk/benefit is not in term of lifespan, it's in term of fitness...
This still say something about possible immortals: their risk aversion will not be affected by their extended life expectancy much, but by their (likely edited, because that's will be needed for immorality anyway) genome. You can get careless violent immortals that do not die later than nowadays, although society will certainly opt for the opposite (select tameness)
Thanks for the reply; I think that I feel better about the Graham's number longevity hypothetical.
(Also, your comment seems cut off, merely ending with "So". Is it a length limit thing? If you were going to write more about it you could finish your thing below.)
Are you sure the modern lifespan is considerably greater than it was in 20,000 BC? Life expectancy is surely shorter, but couldn't pre-historic man also live into their 80s or 90s? Do we know?
Not sure what you're asking. Are you asking: is it possible for *somebody* to have lived to age 80 in 20,000 BC? The answer to that is obviously yes, but it was almost nobody. And the average matters, it's why we compute it. In 20,000 BC most bad bone fractures meant prompt death. Now it doesn't, because we have splints, casts, surgery, wheelchairs, and a civilization that let's you hang out in a safe place, completely immobile, for 8 weeks while you heal. Even in historical times death during childbirth was a major risk factor for women -- old graveyards are full of twentysomething women buried next to their newborns. That is no longer true, because we have ultrasound to diagnose problems, and can intervene surgically. There are many people who died in their 50s from heart disease circa 1900 who would live into their 70s or 80s if their physician had been able to prescribe statins for them, or they had been able to get an implantable cardioverter.
In principle any technology life-extension method or drug falls into the same philosophical category. Someone from the perspective of 2200 AD could look back and say, gee, almost nobody in the 2020s lived to the "natural" lifespan of 150 that you get if you go on foobarbazib 5mg once daily at age 50, what a primitive period that was.
When we *get* to the point where Method X promises to extend lifespan *indefinitely* then we can have the genuine philosophical discussion of whether immortality is a good idea. But at present, at best we're talking about quite modest extensions, at best letting us live as long as Galapagos tortoises, nowhere near bristlecone pines.
"a civilization that let's you hang out in a safe place, completely immobile, for 8 weeks while you heal"
You don't need a civilization for that? Where hunter-gatherers unable to provide for their sick and injured? Isn't your tribe's camp a pretty safe place? I was under the impression there was even evidence of neanderthals taking care a permanently disabled member of their tribe.
I don't want to die. I'm more okay with getting old, though.
(Also, according to a lot of people, nature isn't responsible for people getting old and then dying - some kind of deity is.)
Nah, I think I'll rage, rage against the dying of the light. YMMV.
Few things terrify me more than the thought we will one day prevent aging.
There are already more people living on this planet than it can reasonably support. If new births are no longer balanced by deaths from old age we will arrive in a dystopian nightmare scenario very rapidly.
Any effective anti senescence technology will reveal that we have a moral obligation to die anyway.
I sort of agree with you, but I don't think it's quite as bad as you think. Certainly if you snapped your fingers today and completely cured ageing, that would be terrifying, but if we gradually slow it over the next few decades, other technological changes are going to be relevant as well. The world could support more of us if we all lived sustainably, and I hope that will become easier with better technology.
Also, I think if people have longer to live (and no menopause to think about... I guess I'll hand-wave that away as part of ageing for now) they'll have children later, so the birth rate will fall. Even if they don't, states could enforce lower birth rates, and they wouldn't have population pyramid problems down the line because old people are still working.
The saddest thing about all this in my opinion is that the older we live, the fewer children there are in the world. There was an almost throwaway comment about this in a Banks book (possibly State of the Art) and it hit me quite hard.
Unless people scale up their child-bearing in proportion to their lifespan, this will not happen. The rate of child-bearing will slow to match the lengthened lifespan.
The evidence already suggests that people do *not* scale their child-bearing in proportion to their lifespan. In fact, if anything, the correlation goes the other way rather: the average lifespan in the Nigeria and the US is 53 and 79 years, respectively, and their total fertility rates are 5.4 and 1.7 children/woman/lifespan. That is, longer lives lead to *fewer* children per lifetime, not more.
I can imagine that most people don't want to have many children, but a small proportion really *like* producing large families. That would be an interesting future, and it's certainly a good enough premise for science fiction.
I hope you're right, but I'm doubtful. I suspect the different lifespans and birth rates in the US and Nigeria reflect differences in economic development. There's no reason to think directly extending lifespan will have the same effect on birth rate.
Besides, if it is possible to extend life indefinitely, no amount of reduction in the birth rate will prevent a population explosion.
The richer countries get, the lower the birth rate. This is well-known.
That is basically the point I am making. Carl Pham claims that longer life leads to fewer children. I disagree; I think the economic factors driving increased life expectancy also happen to reduce birth rates.
There is no reason birth rates should fall when life expectancy is altered by a different mechanism, like life extension technology.
You're assuming that fertility will extend along with longer life. I'm not at all sure that's the case-- 80 being the new 50 is still going to have the fertility of 50, for women-- but in any case I think the extra years are going to be under the control of science, which is not the case at present, so I think the question of extra fertility is going to be more within our grasp than the standard period of fertility is.
Yes there is. There are people in Nigeria who are rich (at least by Nigerian standards) and they *still* have lots of babies. Furthermore, you have only to look at the advancing age of first birth that you see in developed countries. Why do so many women put off childbearing until their 30s? Because they can. Because they can count on living to age 75. If their realistic horizons were more like 50-60, as they once were, they would not.
A simpler way to put it: how many children did Queen Victoria have?
> There are already more people living on this planet than it can reasonably support.
I read somewhere that the world produces more than enough food calories to feed everyone on earth (https://www.huffpost.com/entry/world-hunger_b_1463429 ?), so to me world hunger/etc seems a lot more like a logistical/political issue than an issue of supply. Even if there are way too many people, we might have interplanetary populations and food supply systems, so it might not be that bad. Also, in the premise of the serialized web fiction 17776, the death rate drops to zero, but the birth rate also drops to zero, making for a stable population.
Well, perhaps we could support a population of 100 billion if everyone ate processed insects and lived in ten-foot-square boxes... but would we want to?
I'm being flippant obviously, but the absolute maximum number of human beings isn't what I had in mind. A better target would something like the optimal population for human flourishing, which I suspect we have exceeded already.
In any case, we have yet to solve the political and logistical problems you mention.
There may be technical solutions but there are too many "ifs" for me to be reassured at this point.
What about the incredible burden that an aging population has on our economy, in the form of costs of medical treatment, long-term care for people who can no longer care for themselves, and palliative care? How many deadly car accidents do geriatrics get into per day? How many sharp, inventive minds are dulled by dementia at a point when they have so much more to give us? If we didn't have these problems, what strides do you think we could make towards a better world?
The status quo is often more terrifying than your imagined future dystopia, if you stop to consider it.
+1
I agree that there is a very large burden of aging and related diseases. I would be very glad if this burden could be reduced. But we'd need to do it without eliminating death, which is challenging.
In what world is aging harder to solve than DEATH?
If they cannot work, care for themselves, drive a car safely, etc, then they're going to die soon enough and you won't have to worry about it. You can't plausibly hope to "treat" aging by patching together geriatric bodies every time they stroke out or whatever; that problem increases literally exponentially on a roughly eight-year timescale. If there's a treatment (really, set of treatments) for aging, it can only plausibly work by preventing 40-year-old bodies from turning into 80-year-old bodies.
Which incidentally means being as capable of working, driving a car, and generally taking care of yourself as any other forty-year-old, even though you happen to be eight. Or eight hundred. This happening any time soon is a medical long shot, but it's at least theoretically plausible. The struldbruggian horror of being trapped forever in an increasingly decrepit body makes for nifty drama in fiction, but it doesn't work in reality because increasingly decrepit bodies increasingly die no matter how cleverly you try to save them.
Might as well try to run your car forever by letting it rust and the superglueing the rust flakes back into place as they fall off.
The problem of overpopulation is something we can deal with. More importantly, let's stop people shriveling up and dying.
A continually increasing population on a finite planet doesn't sound to me like a problem we can deal with. I'd be interested to hear your suggestions.
Better technology, heavily reduced fertility, more planets, brain uploading
It wouldn't be a dystopian nightmare any more than today's world is, just a different one to get used to. We've had clashes of human beings about everything. Why should this one be avoided particularly? Eventually a new equilibrium would be reached. Certainly I think that it can't be avoided any more than the people railing against the A-bomb succeeded in getting it uninvented.
You go ahead and die if you wish. I don't think much of your "moral obligation" talk.
If nobody dies, the "equilibrium" we arrive at will be one where finite resources are shared between an extremely high number of people. This will not be a pleasant world to live in.
You sound like Thomas Malthus. It's not as though people won't still die; they destroy themselves in all manner of ways. But your objection boils down to a matter of timing and nothing else. Population is growing as it is, we are going to have to find ways to deal with more people, no matter what, and we might as well find it out sooner as later. But Norman Borlaug came along and genetically manipulated crops came along. I don't think there's going to be any way to rationalize not saving people, most especially in a democracy where some will call you a murderer for that, on the assumption that nothing else will come along.
Would you support a policy of killing everyone at the age of 50 in order to free up the planet? If no, how's killing everyone somewhere around 70-90-ish morally different?
I thought we were supposed to kill everyone at twenty-one, unless we don't read in which case we do it at thirty.
I'm more concerned about static hierarchies (the people at the top don't age out) than overpopulation.
I think that the real danger is developing anti-aging technology before we engage in mass genetic engineering of humans to greatly increase IQ, health, and similar things.
It'd be a bad idea to make probably close to 98% of the population today immortal, simply because they would continue to create problems indefinitely.
Once you have increased those traits to high levels, there's no particular reason to worry about it; there's no reason to replace old people with new ones at that point.
It looks like you actually can, and people are wanting you to, try something very much like this drug! I first went to learn about lornafarnib, which is a farnesyltransferase inhibitor, actually spelled Lonafarnib? which got me to read about Progerin, which lead to Progerinin, which pointed the way to [0].
Quoting from the study:
In the LmnaG609G/+ mouse model, improved morphology such as status of coat hair and body size, increased body weight and extended life span for about 16 weeks was noted following Progerinin treatment. In addition, Progerinin can suppress muscle weakness including the heart muscle. Safety pharmacology studies did not indicate any Progerinin-related effects on vital organs and systems including respiratory, cardiovascular and central nervous system.
Prior to studies in the disease states, this study PRG-PRO-001, an initial first-in-human study, will be conducted in healthy volunteers to assess the safety, tolerability and pharmacokinetics of Progerinin.
[0]: https://clinicaltrials.gov/ct2/show/NCT04512963
Lamina is so important because it touches multiple basic mechanisms that lead to aging.
Here's a list of hallmark of aging: https://marlin-prod.literatumonline.com/cms/attachment/ea35bd24-f55b-43ea-acf0-1157c60c6bfe/gr6_lrg.jpg
Which of those are connected with lamina?
1) DNA damage - as mentioned in this post, lamina defects stop DNA repair
2) Telomeres - lamins serve as anchors for telomeres, which preferentially locate to nuclear periphery, and lamins are needed for telomere repair (review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916877/).
3) Epigenetics - without lamins, nuclear architecture is messed up and genes are not read correctly (review: https://www.karger.com/article/fulltext/357206)
4) Proteostasis - lamina is needed for clearing damaged proteins (review: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400325/)
Would lamina treatments help with "normal" aging? To the extent lamins are defective in regular old people, maybe they can slow it little. But aging has many causes, and in some sense it's a self-causing problem with many feedback loops. So what I would like to see are complex treatments that address multiple causes at once.
John Wentsworth makes a point on LW about how while DNA damage certainly seems to be part of the mechanism of aging, pure accumulation of DNA damage over time (as opposed to an increase in the rate of such leading to such accumulation) doesn't make sense as a reason for aging: https://www.lesswrong.com/s/3hfjaztptwEt2cCve/p/d4DvqS88Q29ZaJAj3
He's got a whole series on aging-related stuff and the question of what the root causes are (https://www.lesswrong.com/s/3hfjaztptwEt2cCve), which I'll admit I don't really know enough to evaluate, but it's pretty interesting at least.
I find the essay to be a good demonstration of the fact that pure reasoning is not an effective way to produce knowledge in biology. Frankly the central argument, that ageing has a root cause, is simplistic (it assumes that dna repair is perfect) and the proposed mechanism for this root cause (transposon) is highly improbable.
Ah, and the arguments at the beginning of the essay to explain why he has an interesting theory of the origin of ageing whereas academics are wrong, are quite comical: "Most overviews of aging suffer from multiple problems: [...] They are usually written by working academics, who are shy about telling us when their peers’ work is completely wrong." Hum, no, quite the opposite in fact.
The entire reason empirical science exists is because we discovered in the 1600s that pure reasoning is not an effective way to produce knowledge in *any* field of natural philosophy. It is, nevertheless, fascinating how the errors of Scholasticism are rediscovered, over and over again, as the centuries roll by, no matter how often they are shown to be errors. Feynman argued that it was just inherent in human nature.
That is inherent in human nature seems plausible to me, we love to make sense of stuff, even if the story we tell is wrong!
I would expect that reasonig is less efficient in biology than for example physics, because biological process are frequently very "messy" due to their gradual origin by evolution, but this may be just because I know almos nothing about physics.
Ha ha no, physics also has alas a long history of beautifully argued theories that were, empirically, just wrong, starting with geocentrism and Ptolemaic epicycles and moving right up into the luminiferous aether.
I grant you that biology may be a special realm, or at least has been, because we all *experience* biology just living.[1] That is, because everyone inhabits a "biological system" (his body) he kind of assumes he has some kind of built-in natural expertise, because he can query his own experience to derive wisdom. That was no doubt true in physics in the 1600s, which is why people could have fierce arguments about whether inertia existed or not, on the basis of how "obvious" it was to them from their experience with forces and motion.[2]
But once physics moved into realms far beyond daily experience -- quantum mechanics and relativity -- people stopped thinking their daily lived experience was a source of wisdom. *Maybe* that is starting to happen with biology, as it has become increasingly complex and removed from daily experience. How do you mine your daily lived experience for insight into the function of retrotransposons? Difficult.
I'm not a biologist by training, but I have had increasing occasion to learn it over the past 10 years or so, and the one constant is that the more I learn about it, the less I trust my native instinct and/or sense of how it "ought" to be. It's....weird. A system designed by Hieronymus Bosch and Rube Goldberg in collaboration. Elegant, but...weird.
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[1] My experience is that the same is true of economics. Because everyone lives a live as an "economic unit" they will argue freely with their economics professor in a way they won't with their physics professor.
[2] There's a fascinating historical tale one can ponder of how people labored long to dismiss the evidence of inertia that came from observing heavy ships in water. Yet another example of how man is more the rationalizing animal than the rational animal.
"I'm not a biologist by training, but I have had increasing occasion to learn it over the past 10 years or so, and the one constant is that the more I learn about it, the less I trust my native instinct and/or sense of how it "ought" to be. It's....weird. A system designed by Hieronymus Bosch and Rube Goldberg in collaboration. Elegant, but...weird."
Il love it! A common metaphore is that evolution is a tinkerer not an engineer, but this description is so much better!
"But once physics moved into realms far beyond daily experience -- quantum mechanics and relativity -- people stopped thinking their daily lived experience was a source of wisdom. *Maybe* that is starting to happen with biology, as it has become increasingly complex and removed from daily experience. How do you mine your daily lived experience for insight into the function of retrotransposons? Difficult"
Indeed, some domains of biology, molecular biology for example, are not connected at all to our daily experience, but but other fields of biology like evolution seem (wrongly!) to be possible to intuit from our daily experiences. There is a rich tradition of "Darwin was so wrong" essays from both laymen and scientists from fields other than biology, math in particular I think.
Reasoning has its limits, but where else are you supposed to get your hypotheses from?
Making assumptions is fine, but coming to a conclusion without involving data is a bad idea!
Inspired guesswork, largely. Hypotheses by definition cannot come from deductive logic, they are efforts at induction -- attempts to create brand new axioms from which future implications can be deduced. So people just guess. It's a weird process of blue-sky imagination, and some people are much better at it than others, and it has nothing at all to do with intelligence. Very smart people can rarely come up with interesting and useful hypotheses, and by contrast people who aren't very smart can sometimes be founts of creativity.
It's certainly true we use deductive logic to prune dumbass hypotheses from consideration early on. Few people will take seriously a hypothesis that violates Conservation of Momentum, unless they need to. But this is not part of the origination -- it's already part of the vast machinery of pruning and winnowing that constitutes the bulk of empirical science.
Perhaps this criticism applies to the short version. But after reading the much more elaborate variant of the same argument here, I disagree with the criticism:
https://www.lesswrong.com/posts/ui6mDLdqXkaXiDMJ5/core-pathways-of-aging
I don't see how this is based on "pure reasoning". It doesn't make up anything, it gives a summary of what Wentsworth has extracted from the existing literature. I don't even think he claims that it is "his" theory.
On:
"They are usually written by working academics, who are shy about telling us when their peers’ work is completely wrong."
I can absolutely confirm this point for neuroscience. I have come to this field as an outsider. A problematic issues is that a lot of papers are wrong, and a lot of labs are not reliable. The way I have found to deal with this issue is to directly ask my colleagues who do experiments themselves. They can tell me which lab to trust, and which papers just to discard. But they would never write this knowledge in a research article, it's more like gossip. If I am very lucky, I find hints in reviews, but most of the time not. I think it is really hard to get this knowledge without talking to experts in private.
Also, it seems you misread the main point: The short article says that imperfect DNA repair does happen and *is* a possible candidate for a root cause.
" It doesn't make up anything, it gives a summary of what Wentsworth has extracted from the existing literature. I don't even think he claims that it is "his" theory."
I disagree. The essay contain short syntheses on various points that are indeed based on the existing literature. But the main idea, the big idea, is that the field lacks "high-level picture" , and the author has one, namely that ageing has “root causes”, and he has identified this root cause (transposons). Both points, the existence of a root cause, and that transposons are important in the ageing process are based on reasoning and not experimental data (and I am pretty sure the are incorrect).
"they can tell me which lab to trust, and which papers just to discard. But they would never write this knowledge in a research article, it's more like gossip. "
Indeed, this kind of gossiping ('I think this lab is crap') has no place within a research article. But if someone can disprove an established theory, it is usually highly publishable. Not so much if it is just a non replication, though.
I don't understand what you mean that there might be no root causes.
I could understand if Wentsworth and you disagree about *which* root causes are more or less likely. You seem to prefer accumulating DNA damage as explanation(?), while he prefers transposons and/or mitochondrial mutations.
But you explicitly say that you do not believe in root causes at all. What do you mean by that? It won't be that there is no reason at all for aging? That there is a very long cycle causal pathway so that it doesn't make sense to talk about "upstream causes" and "downstream causes"?
The current scientific model (the one of these shy academics!) is that ageing is a multifactorial accumulation of damage at multiple levels (DNA, proteins, cells, etc.) whose rate was modulated by natural selection during the evolutionary history of a species and is strongly related to the ecology of the species.
The idea that there is a "root cause" of ageing, ie a unique cause of ageing that, if fixed, would suppress ageing entirely, is an old idea that is not well supported by data in my opinion.
Hm, but that has nothing to do with the article.
The article defines "root causes" as "causally upstream". Not as "unique cause". The article explicitly says that there might be several ones. There is even a section which discusses whether it's more likely to have a single or several ones.
With respect, but are you sure that you understood correctly what the article said? If you have conflicting terminology about the core concept of the article, then you may have got a lot of the arguments wrong as well.
Re root causes: what do you think of Sinclair's information theory of aging, if you're familiar with it? The theory does propose a single root cause, but it's more along the lines of "this whole complex mechanism breaks down" than "this one protein/gene is the problem".
My impression was that this theory was quite focused on epigenetic changes, which I do not think is a probable main factor of ageing.
But "this whole complex mechanism breaks down" does seem very correct to me. I'd just add the caveat that organisms could avoid the breakdown, several species show negligible ageing, but humans and mammals in general do not, very probably due to our life history.
With apologies for the self-promotion, commenters on this thread might enjoy my book! https://andrewsteele.co.uk/ageless/
It breaks down the aging process into hallmarks based on the 2013 ‘Hallmarks of Aging’ paper https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ (but I have added and combined some, ending up with ten hallmarks overall), and examines how they impact the aging process and what we can do about it.
I think DNA damage and mutations are a really interesting case where new evidence is making us reevaluate their contributions—there’s accumulating evidence that mutations leading to cells that expand when they shouldn’t (though don’t necessarily go on to become cancers) may be the primary mechanism by which mutations contribute to aging.
I did enjoy your book, and can recommend it to everyone here!
What do you think of Dr. Sinclair's "Information Theory of Aging"?
Thank you! :)
I think it’s probably at least partly true—the fact we can reprogram the epigenetic clock and seemingly reverse aging, and that clones are born young are both good evidence that there’s lots going on in our epigenome! But I don’t think it can explain everything, eg I don’t think there’s much resetting the epigenome would do about mutations in the ‘digital’ copy of the code as he puts it, ie the DNA itself, and the idea of non-cancer clonal expansions makes me worry that this is a relevant potential cause of aging too.
Like everyone with a nice narrow theory of aging, I hope he’s right—but I think we should be going after every plausible cause of aging, and trying to build models to understand how they all link together, just to be on the safe side!
I quite agree! Speaking of the "digital" DNA, I have noticed in my reading a fair amount of evidence that having duplicate copies of the coding for certain proteins is often correlated with longer lifespan, which, IIRC, is speculated to be because DNA damage to one copy doesn't keep your cells from producing the protein using the others. I think women living longer is said to be related to this-- the extra X chromosome. Have there been to your knowledge any papers or serious talk about changing DNA "on the fly"-- that is, in already-living beings? I know there are tens of trillions of cells, but I would think that if they could just target DNA alterations to stem cells alone, it would be a smaller task, and we could then steer somatic mosaicism the way we want, with more and more somatic cells over time being daughter cells of the altered stem cells.
(Thanks, by the way, for the opportunity to geek out about this and ask questions. It's a privilege.)
That’s certainly one theory why women might live longer—in birds, where it’s the females who get the smaller, mismatched sex chromosome, the trend is reversed, and evidence from clonal expansions seems to show you need both copies of a gene to be disabled before there’s a problem.
The good news is that there’s a lot of work into somatic DNA editing, though actually I don’t think this is how we’ll solve this problem (of course I could be wrong!). I think the clearer path to success is finding a way to kill the mutant cells rather than editing their DNA, and letting daughters of non-mutant stem cells take their place. The more futuristic approach could be to extract some cells, create stem cells from those with intact DNA, and use those to aid repopulation. Possibly directly editing DNA will be useful for particularly common mutations in certain cell types though—I guess we’ll have to see!
And you’re very welcome, always happy to geek out. :)
Symbolism pedantry: the cover picture shows the personification of Death being pushed away by a figure holding a caduceus (wings and two snakes) rather than a rod of Asclepius. So the latter figure is a personification of Commerce rather than of Medicine? That would fit just as well.
Or Americans are just idiots: https://en.wikipedia.org/wiki/Caduceus_as_a_symbol_of_medicine
It might be a great metaphor for our stupid commercialized medical system though.
Apollo didn't realize exactly what he was forfeiting when he gave the caduceus to the patron of thieves.
Perhaps that's Plutus holding the caduceus!
> After all, normal aging is caused by lots of processes including gradual expected accumulation of DNA damage
In case you haven't seen it, I recommend the LW essay "Core Pathways of Aging" here: https://www.lesswrong.com/posts/ui6mDLdqXkaXiDMJ5/core-pathways-of-aging (which itself is a follow-up to https://www.lesswrong.com/posts/d4DvqS88Q29ZaJAj3/homeostasis-and-root-causes-in-aging )
Even though the specifics may not be entirely accurate, I felt significantly less confused about aging than before I read the essay.
Key quote from the Homeostasis post:
> "a root cause of aging cannot be a higher or lower value of any parameter subject to homeostasis on a faster timescale than aging itself...
> DNA damage (as opposed to mutation) is normally repaired on a timescale of hours - sometimes much faster, depending on type. “Accumulation” of DNA damage cannot be a root cause of aging; either the rate of new damage has increased or the repair rate has decreased...
> Note that the homeostasis argument does not mean the factors ruled out above are not links in the causal chain. For instance, there’s quite a bit of evidence that DNA damage does increase with age, and that this has important physiological effects. However, there must be changes further up the causal chain"
Oops, I didn't see Sniffnoy's comment.
I did not find the essay good. For me the author mixes well-established knowledge with wild speculation, without seeming to differentiate well between the two. And I think that the substance of his argument, the existence of a root cause for aging, is incorrect, as is his hypothesis that transposons cause aging.
What do you think of the specific claim that DNA damage is normally repaired on a timescale of hours, so an increase in DNA damage over time must be caused by some other slower change(s)?
I think this is true, DNA damage is normally repaired quickly. This does mean that in a small percentage of case, it is not repaired quickly, or repaired but with a mistake.
"We can prevent young people from being old, but preventing old people from being old sounds also sounds useful."
I think there might be one "sounds" to much. But im not a native speaker.
As a native speaker, I can confirm that you're correct. This is a typo.
I googled but couldn't find any reference to experiments treating normal mice with lornafarnib (mice with 'a mouse model of progeria' have been treated, and seemingly it works.) But the drug is new, and I assume somebody will do the experiment before long.
The Scaffidi and Misteli paper is a less conclusive than it might at first seem. If you dig into it, one thing that is very strange is that they find that the amount of abberrant lamin A does *not* increase with aging. So it can't be as simple as that the abnormal splicing *itself* is causing aging, because the rate of those mistakes does not increase with age. Rather, what they observe is that in younger cells the abnormal protein doesn't get localized to the nuclear envelope -- it has a much wider distribution. So there has to be some (as yet unknown) mechanism that localizes the abberant protein to the nucleus where it can interfere with DNA repair. Arguably it's *that* mechanism more than the abnormal splicing itself which is more central to the problem. They did show that preventing the splice reverses signs of aging, which is pretty cool (and probably why the paper was worth writing), but this only says the bad splice is *part* of the problem. The unknown localization mechanism is also key.
This seems like as good a place as any to bring up a thought I've been having on aging research: why does the focus seem to be so confined to humans? Obviously the end goal is extending human life and health span, no argument there, but in the short term it feels like there are easier options. It is often stated that extending life in mice, rats, and other small mammals is much easier than doing so in humans, so what about pets? I know I would pay hundreds of dollars a year for a treatment that would let my cat stay young and healthy for an extra ~5 years on average, lots of other people would too and it would get way less push-back from the "you're playing god!" types than work directly on humans. If a cheap enough treatment were found it might even be economical to use it on farm animals that are not intended for meat (Dairy-cows, egg laying chickens, wool sheep etc) to allow them to remain at peak productivity for longer and not have to go to the expense of raising new ones as often.
https://loyalfordogs.com/
I think there are several others as well. No idea what sort of share of overall anti-senescence research this is.
Neat. I'll have to look into that more.
Here's another dog startup https://www.rejuvenatebio.com/
I'm don't remember hearing of any others (besides loyalfordogs), but the overall idea is out there. And if you're serious about the cat, the "good" news is that most of the research is done in mice anyway, and it presumably should generalize to nearly all placental mammals (or even all eukaryotes in some cases). So you can take the numbers for the mice and scale up or for humans and scale down, with the help from some openly-minded veterinarian.
Using it for farm animals is an... unorthodox proposition for sure. I've never heard of anyone even thinking of it. But it might be trickier and potentially impractical, because at the end of the day the metric a farm is trying to maximize there is produce per life, not lifespan, and those might be at odds. E.g. the best proven longevity intervention is caloric restriction, but I'm sure applying it to farm animals will cause them to produce less or none at all of whatever they were supposed to be producing.
Others have thought of this too. There's the Dog Aging Project. They've been approaching it from a scientific standpoint rather than a commercial or emotional one-- the argument being that dogs are closer in size and so on to humans than mice or yeast are-- but it's still the same sort of thing.
https://www.fightaging.org/archives/2019/11/the-dog-aging-project-forges-ahead-with-a-large-study/
I think human aging comes from loss of degeneracy in the complex systems of an individual’s biology. The examination of edge cases, such as progeria or cystic fibrosis, provides changes in the surfaces of the examined parameters that are within the resolution of the tools we currently have available to examine them. As the complex system gets closer to the failure cascade— moves from the “flat part” or “healthily living” part of the response surface to the curved surface— our existing tools can start to measure parameters that tell us something new about the many possible control mechanisms involved in healthy aging. I don’t think the tools and methods currently available have the resolution or detection capabilities sufficient to see a way to extended lifespan-- yet. They can give us some insight to extending health span but I think it’s safe to say learning how to extend life span (healthy life span because otherwise why?) is beyond our current tool capability. Good to know people continue to work on more capable tools.
Table 1 “Degeneracy at different levels of biological organization” in this paper: https://www.pnas.org/content/pnas/98/24/13763.full.pdf
starts a list of ways degeneracy plays into biology from genetics to social structures.
A paper with definitions of degeneracy, redundancy and robustness as considered in biology along with an explanation of different hypotheses for why doi:10.1186/1742-4682-7-6
I also seriously doubt there is a single mechanism (excluding things such as a catastrophic accident or obviously unhealthy habits like smoking tobacco) that lead to the failure cascade toward death. This means there isn’t a single chemical/pharmaceutical that extends healthy lifespan.
The idea of different pathways to aging, “ageotypes”, is gaining some visibility and quantification. See, for example, https://www.livescience.com/four-types-of-aging-revealed.html. Knowing my ageotype gives clues to things I can do to aim for healthy aging. All I can do is try and wait for better tools to change my hypothesis.
Have you seen the Information Theory of Aging?
https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/
Thanks for pointing out a potentially more easily read book on the topic. I'm not surprised it exists. From the review in the hplus link, the list of mechanisms is part of the list shown in Table 1 "Degeneracy at different levels of biological organization".
IMO, it is valuable to furthering what is known and actionable to combine different knowledge domains with similar mathematical underpinnings. Complex systems have a math mechanism with applicability in biology, information theory and linguistics (at least-- see, for instance, doi: 10.1073/pnas.96.6.3257) More recently, I've been actively seeking simplifications in information theory math that might have actionable application in biology. It really hits the "need for cognition" itch.
You're welcome. I think Dr. Sinclair's work is one of the best out there, and I've read quite a few by now. (Andrew Steele's book, that he linked to elsewhere here, is up there in the top few, too.) Sinclair, as I recall, specifically cited Claude Shannon's work on information theory as a strong influence on this line of thought.
"After looking into this more, I find some evidence *the* the answer is no, but also some reasons why maybe it's less clear cut than that?" Should be 'that'
Incidentally, "Reason", who writes the FightAging blog that covers this topic well (I rely on his newsletter to keep up on the latest), has noticed this discussion and weighed in.
https://www.fightaging.org/archives/2021/06/thinking-of-progeria-as-accelerated-aging-only-produces-confusion/
Good resource. Thx for sharing.
The recent observations in mice are fascinating, as is the discussion about derivative anti-aging indications for Lorfarinib, but... I'm still intensely skeptical about the societal and political implications of life extension. With all due respect to Aubrey de Grey and a host of VC's that get lathered about the possibilities, it seems quite probable that the emergence of a legitimate life extension protocol would be intensely toxic for human societies.
My conclusion is based on a few simple assumptions. A practical life extension technology:
A) will be very expensive. (Even if the pharma production and therapeutic costs are modest, the pricing power would be so asymmetric that enormous price gouging is certain).
B) will be very limited in availability (because it is expensive).
C) will, therefore, accelerate economic and social inequality at unprecedented rates.
Difficult to see how such a technology could be deployed without fracturing every industrialized society, whether democratic or authoritarian. The perception that elite privilege suddenly includes the addition of an extra 20-30-50 years of active life would be so politically toxic it isn't hard to imagine revolutions sweeping the globe.
What am I missing?
The part where "potential for tremendous social and political fractures" is not a good reason for condemning literally everyone to literally certain death. And the part where human societies got through equally drastic changes (see: neolithic revolution, industrial revolution) and eventually came out of them better off on the net.
Agreed!
I think that argument is actually the most interesting topic in re life extension. Utilitarianism a la Mills would suggest that the greater good (societal stability and reduction of wealth asymmetry) should prevail over benefits granted to a few elites (i.e. 10% of humanity living an additional 20 years).
Are you actually suggesting that there wouldn't be friction when a minority of the wealthy suddenly has access to life extension, or simply that it is worth the risk of social upheaval for some folks to have access to a longer life?
First of all, where do those numbers come from? If we do start to prolong human lifespan, nobody knows where's the limit and if there's one. And whatever technologies we discover along the way, they'll be gradually spreading until they're available to almost all of humanity. If we don't work on longevity, literally everybody literally dies, which is not considered a good outcome in most non-religious moral frameworks I'm familiar with.
Secondly, longevity and access to medical technologies is already correlated with income. And top 10% includes most people on this forum, and most likely yourself if you live in the US, Commonwealth, or Western Europe. "the elites getting to live extra 20 years" sounds all so evil and sinister, but "my grandma gets better medical care than some poor schmuck from Uzbekistan" not so much.
To your question, of course there will be a friction. As there is and there always has been and it always increased during great societal changes. But a *temporary* increase in this friction is a worthy trade off for a *permanent* increase to (eventually) everyone's life expectancy, and for the first step to even further increases.
And if you want to argue that it won't eventually spread to be available to everyone, could you please give an example of one major technology that stayed restricted to the same % of society for e.g. last 100 years?
Some good points raised.
Unfortunately, there is no rational way to analyze the probability of ubiquitous distribution of life extension technology without further insight into the nature of the drug / treatment protocol. Those factors will have an outsized influence on the degree to which mfg. at scale can reduce costs, or not.
I don't have a perfect counter example for the ubiquity of distribution question, but lets use neonatal incubators. Introduced to market roughly a century ago. Relatively inexpensive. Enormous impact on infant mortality. And yet, still a meaningful skew in access based upon individual and societal wealth. Multiple reasons why, including design lock and bundling practices of the medtech companies that mfg. them. Design lock refers to difficulty in repair. Studies show that many incubators - often donated via Western Aid programs - in African / Middle East hospitals sit unused because when they break the facilities do not have sufficient funds to contract the mfg. for repair, and they are often engineered to hinder third party repairs. Differential access also occurs within relatively wealthy countries based on variations in insurance coverage schemes, geographic isolation, and other factors.
Surely, a technology that saves the life of an infant is even more beneficial, morally defensible and economically justifiable than a technology that helps adults extend life? And yet, access to incubators is not universal, even after a century of deployment.
To paraphrase William Gibson, "the future is already here, it's just unequally distributed."
FWIW My numerical examples were simply for illustrative purposes.
As a general thing (and probably worth bringing up in an open thread), is there any way to make maintaining a thing as prestigious as starting that thing? Or at least more prestigious than it is now?
>Unfortunately, there is no rational way to analyze the probability of ubiquitous distribution
For the record, I disagree with this statement - there's a rational way of analyzing it, there are entire fields of study devoted to judgement under uncertainty. But if you believe it is true, how exactly do you go from saying "we have no way of knowing what the probability is" to saying "the probability is precisely 0%"?
>neonatal incubators
So they were spreading over the last 100 years from being available to the very reach to being available to most people in the developed countries and many people in the undeveloped world. How exactly does it prove that technologies do not spread? Are you claiming that there's some evidence that spread of this particular technology has just stopped and is not going to continue long term? Otherwise, my point never was that any technology is guaranteed to spread to 100% population in 100 years, just that it will spread to the most of the world *eventually*.
>Surely, a technology that saves the life of an infant is even more beneficial, morally defensible and economically justifiable than a technology that helps adults extend life?
Not terribly important for the argument but I very much disagree with that. Saving a life of a premature born infant adds around 70 years of life per person and affects only a fraction of the population (most people are born on schedule). Completely solving aging adds hundreds if not thousands of years per person and affects 90% of the population (most people die of age-related diseases).
You can make more money from a small profit on a very large number of sales than from a large profit on a very small number of sales.
If anti-aging tech can be made cheaply, I think it will be.
Your argument ignores the recent examples of PharmaBro Martin Skreli and other documented examples of 'repricing plays' by PE firms and generic drug portfolio owners. Repricing of commonly used drugs with relatively low manufacturing costs is a documented pattern of behavior. It appears to be a way for patent holders and orphan drug producers to beat the algorithms used by PBM's and insurance companies. If there is a compelling example of, or case to be made for, industry pricing restraint I am not aware of it.
https://www.washingtontimes.com/news/2019/sep/16/prescription-drug-price-gouging-must-stop/
You have a point, though I think small-scale manufacturing will become cheaper and harder to control.
Those drugs are not widely used because the market is limited. There is no way they could pull that off with something as widely used as say a statin. Apart from the political and public backlash, it would be a bad business move. The loss in number of sales would overwhelm the increased profit per sale.
Well, for one thing, you're missing the fact that our current systems against the accumulation of wealth are predicated on current average lifespans. Politics would simply adjust.
Not true is if access to life extension is asymmetric. Longer life would certainly imply more wealth accretion for those with access to the protocol. But if limited access mirrors existing disparities in wealth, healthcare, political clout, etc., it would seem logical to assume that introducing life extension technologies would simply increase social friction and generate new vectors of instability.
Lifespan is already asymmetric, not only from some being able to afford better health care, but from some people being smarter and more able to think abstractly. They're more likely not only to accumulate wealth more but to take better care of themselves with personal habits. And they're more likely to believe in science, with the current asymmetric situation with regard to vaccines a contemporary example. We wouldn't have refrained from the development of the COVID vaccine if we knew in advance that richer people were more likely to take it than poorer ones. My point is, we already have political and economic responses to differences like that, and I don't know why they wouldn't operate similarly to encompass life extension too.
At least in developed countries, even poor people have access to expensive cancer treatments that were created through multimillion dollar trials. There would a massive public push to make effective anti aging treatments similarly available to everyone.
And from a purely cynical standpoint, it is in the best interests of the wealthy to allow for widespread access. That will allow for faster and more thorough testing of the technology. And insurance companies will certainly pay for any treatment that reduces all of the other costs of aging to zero.
I don't think preventing normal aging would be a sustainable thing to do, given the current overpopulation problem. Besides, it won't give you immortality, as from the statistical point of view some accident would inevitably happen sooner or later that will give you a very painful and violent death, as opposed to peacefully dying in your sleep at 90+ years of age. I personally would never want that.
What makes you think dying peacefully in your sleep is the expected outcome? What about your body slowly being ravaged by cancer, or your mind by dementia, or pneumonia choking you to death?
I think instead of preventing normal aging, medicine should concentrate on treating age-related diseases, so that dying peacefully in my sleep would in fact become an expected outcome. It certainly is a possible outcome, and we should work on making it the default one.
Do you see how this sounds like saying "I think instead of preventing car accidents, we should concentrate on treating car-related injuries"?
Maybe. But I still prefer that way of dying to, say, burning alive in a fire. You may have different preferences, but I just wanted to remind about the downsides. Besides, you haven't addressed my point about overpopulation.
I'm not disagreeing on your preference to die sleeping. I'm just saying that, out of all the age-related causes of death, the ones that are quiet and painless are a tiny minority, and no matter which one kills you, it's probably going to cause you immense suffering in the lead-up. You're assuming that preventing aging makes you /more/ likely to suffer, which is obviously false.
And if I had to address every overpopulation argument here I'd be here all day. Suffice it to say, every prediction that we'd suffer catastrophic worldwide famine as a result of overpopulation by this point has been proven false, so I'm not convinced by the ones that predict it now.
It's interesting to me how the second part of your statement kind of argues against the first. The first assumes that everyone will prevent normal aging, but since right now a lot of people accelerate their own aging with fat, too much sunlight, smoking, drugs, et cetera, or wind up killing themselves either deliberately or negligently in accidents, that's not likely to be the case, even aside from the question of whether they can afford anti-aging processes.
So, to be clear. Imagine your natural lifespan is 200 years, accident statistics are exactly the same. Would you take a pill to die peacefully once you're 90, just to avoid dying of accident?
(Of course "dying of age peacefully" is mostly a comforting lie, but lets assume it for the sake of the argument.)
I probably wouldn't want to commit suicide, even through peaceful means, because my instinct of self-preservation would prevent me from doing that. But it won't prevent me from not trying to prolong my lifespan artificially.
So if you're sick you're not going to a doctor? And what about the lives of your older relatives, when they die of age do you genuinely feel happy for them that they didn't live longer to eventually be hit by a car or something?
Of course I will go to the doctor. It's just that with biological immortality, I imagine I will live in constant dread, constantly awaiting violent death to suddenly come after me.
So your logic is that you need to die in order to escape the fear of death? Hmmm I feel like there might be some miscalculation involved here. Also, do you live in constant dread now? If no, why *lowering* your chance of dying at any given moment should create the dread?
Because despite everything I still may hope for at least a small chance of painless natural death. Whereas if I didn't age, I would be not only 100% sure I'll die someday (statistically speaking), but I also would be 100% sure it will be an unnatural, violent death. OK, I admit, violent death can also be painless, if I'll die instantly. So for better calculation I need to know what are the chances of dying instantly in an accident vs. dying painlessly of old age.
Did you just recommend NOT looking at a person because they have a genetic condition? For what reason, the privacy of the child or the perceived disgust of the viewer? If the second, that strikes me as a very odd and judgmental comment from someone who works in healthcare.
I'd suggest the work of Dr. Loren Fong and Dr. Stephen Young at UCLA. They're building a compelling case that a defective nuclear lamina leads to literal nuclear membrane ruptures which in turn causes DNA damage which leads to cellular death. Some have already been published and expect more in coming months.
In the context of progeria, this occurs in tissues that have high expression of lamin A AND low expression of lamin Bs AND are subject to high physical forces. This just so happens to be tissues like the heart, bones, and skin. So when progeria patients present with weak bones, wrinkly skin, and eventually die of infractions, we interpret it as aging, but it's somewhat just a coincidental overlap of affected tissues.
Here is a review in Nucleus from Dec 2020:
https://pubmed.ncbi.nlm.nih.gov/32910721/
Interesting idea. I would think nuclear membrane ruptures would trigger apoptosis mechanisms even before you got to the point of damaged DNA, but I don't know.
I would be interested in an article about fasting as a way of reversing or stopping cognitive decline and other kinds of aging.
Subheading has an error with two ‘sounds’: “being old sounds also sounds useful.”