We can prevent young people from being old, but preventing old people from being old sounds also sounds useful.
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
Beta amyloid plaques are definitely a symptom of Alzheimer's. They just don't seem to be part of the disease mechanism.
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.
>"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
>"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.
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.
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.
Why do you people not want to get old and die? Trust nature.
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.
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 .
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.
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.
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
> 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"
"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.
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 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.
"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.
What am I missing?
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.
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:
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.”