The strongest evidence we have of the reversibility of epigenetic aging, as well as its limitations -- are embryos which undergo an epigenetic reset.
After fertilisation, the embryo strips the father's DNA of its age-linked chemical tags and swaps its packaging, destroys his mitochondria, rebuilds telomeres, and clears damaged proteins, though it can't undo the DNA mutations sperm gather as men age.
(those that result in an non viable embryo result in miscarriage.)
> Do we currently have the ability to do targeted methylation or de methylation at sites in cells?
No, and you probably wouldn’t want it if you could. You don’t know what mutations are lurking in the genes that have been switched off or the consequences of turning them back on.
I’ve thought about this a bit, and what resetting the methylation map really requires, in addition to actually resetting that map, is resetting your genome to a known good state.
That’s pretty radical, but to selectively switch methylation on and off with precision you’re already talking about science beyond anything we have, featuring custom engineered constellations of proteins that unwrap your chromatin from around histones and then walk along it changing methylation state, then pack everything back.
And doing it for each cell type, without applying the wrong map anywhere.
And knowing what all the cell types and their correct methylation maps actually are.
And assuming that methylation isn’t used anywhere, for example in the brain, in a way we don’t expect.
And methylation isn’t the only kind of epigenetic modification.
So, if we’ve solved all of those problems, rebuilding your DNA to a clean, mutation free state at the same time should be a breeze.
We really do need AI for this if any of it is going to be remotely feasible.
Cancer is the price we pay for complex multicellular life. It’s not a failsafe, it’s the failure of all failsafes to regulate cellular growth within an organism.
Evolution doesn't care about individual organisms, it's all about reproduction. Our lifespan is enough to raise a few children and pass genes on, so, from the evolutionary point of view, it's adequate
There's the grandmother hypothesis that holds we could just not have menopause and reproduce more, but we don't because there's greater evolutionary advantage for having the elderly provide support to their kin. Maybe this type of kin selection is bounded by consanguinity though, and that limits the advantage? Or maybe population pressure discourages family units from getting too large?
Evolution doesn't care at all, its just environment pressures and whatever organisms do within it. It can very well lead to some dead ends and sub-optimal long term choices.
There will come time when we will grok all this 100% and then can setup whatever we want (its just a bunch of molecules acting predictably), but we are very far from there and there is no point discussing this even for our grandchildren. We will have cyberpunk implants way sooner.
I understand, I'm equally frustrated when people including scientists say that something evolved for an environmental specialization, instead of the evolution being happenstance that may have incentivized more viable mutant offspring surviving until reproduction in that environment, but was not "for" anything.
and yes, so I understand that with human cancer, it tends to happen or advance after reproduction has already occurred so therefore those traits are not selected against. it's impossible to weed out with human mating strategies
I would just like to believe the cancer itself is an adaptation preventing something worse, but you're right, it doesn't work with the natural selection theory and so we just had a dead end to our survivability baked in, not so different than how the opposite phenomenon of senescence in cephalopods ends their lives
> wondered whether cancers in humans are a failsafe
I don't think so, but in the context of theories that are more-interesting than "stuff just breaks sometimes", I'd like to suggest the atavistic aspect.
Some cancers resemble a return towards unicellularity, as if "newer" multicellular rules have broken down. Not in any remotely-effective "our genes shall survive the dark times as goo" way, though.
> We really do need AI for this if any of it is going to be remotely feasible.
Would you give your life into the hands of AI skynet slop?
I understand your rationale, of course, but I for one don't want big fat mega-corporations dictate over our life here. Naturally, all of this hinges whether AI can even solve this problem. I assume it can, but I doubt it can do so initially - and the legal implications are still enormous. I really am not ready to turn my hands to claude's gene therapy slop.
AI is an amazing Rorschach test in this regard. In the way that two people will look at it -- not just AI in general but in a specific implementation of it (coding, vidgen, etc). And one will feel deep dread and knots in their stomach while the other is filled to the brim with hope and optimism.
I think the former group almost certainly outweighs the latter group at least in the Western hemisphere, but I know the Western hemisphere has been steeped in a deep malaise of anti-optimism for several decades preceding AI to begin with. That it's almost a game to identify all the ways anything new might be bad, rather than celebrating the obvious ways they are good. And this penchant invariably biases their developing opinions of all new technology, be it AI or anything else.
What if I'm super optimistic about most technology but also scared of AI?
Space, nuclear fusion, advanced fission, the internet since about 1993, blockchain, anti-aging, I've been a big fan of all of it. But I've read the AI safety arguments and seen what a lot of researchers say about it, and I'm seriously worried.
AI would be much easier to be optimistic about if it were in the hands of people I like and trust. Its in the hands of people who appear to be complete psychopaths instead.
On the other hand I'm amazed at how flat access is. Access to the best models available is incredibly inexpensive relative to technology in the past, and everyone in the world with at least a smartphone has access to an LLM of some sort now.
Second, the technology is very open. It's not as if the ONLY way to access an LLM is to pay a toll to Sam Altman. Models that are very good can run on my Macbook for the price of electricity and they're only getting better.
Sure if you work in anthropic / openai or several connected / similar places future is exciting. And that's about it for the list, over-represented on HN but not really out there in real world.
Literally everybody else, all white collars including, feels they could be replaced in 5-10 years. Just talk to people ffs, its not that hard. Literally everybody is worried, doctors (know plenty from all parts of medical care), lawyers, bankers, tons of various bureaucrats, ALL are afraid in one way or another. Its also sort of helpless worry you have 0 control of, not very nice place to be 24/7 in the back of one's mind. Double that for parents with non-teen kids.
I use nature to relax and recharge and it works wonders. But reality is as it is and I have 2 small kids, I don't expect to hold the job I have in next 5 years, maybe due to llms maybe not. But I will have big issues finding another job on over-saturated market at that point, thats completely on llms. Thus as any sane person, hating the tool destroying my/our future while using it from time to time (in minimal fashion, code churning is really not a bottleneck in any decently large company and certainly not mine but I can imagine code sweatshops doing various cruds and eshops all day can be much faster now).
It makes me concerned on many levels, but perhaps also more hopeful. It was inevitable that we would eventually develop AI if we didn't go extinct first, and while there are myriad risks and challenges, there is also massive potential, which seems like it could be a source of hope. As the earlier comment said, the only way that therapies like these could be remotely viable on any kind of near to medium timeframe would be with AI assistance, and this is just one example.
What about Xanax or medication. Hypothetically ignoring the ill effects of the drugs themselves will chemical stress relief have the same anti-aging benefits?
Most of it is oxygen. Oxygen is highly reactive so the same thing that makes it a good as source of fuel, also makes it poisonous. It is a double-edged sword.
Yes we can do targeted (de)methylation at cells via a system called CRISPRon/off. It’s a CRISPR with the DNA cutting part deactivated but retaining the DNA binding part. They then attach a protein that adds methylation (DNMT3A) or removes it (TET1). So it’s a huge protein machine and it has only been tested in a petri dish (maybe mice, not sure).
There’s a lot left to figure out. Delivery is hard. It would be hard to get it inside the right set of cells in a real person, you usually would only want to demethylate in a subset of cell types. There’s pretty steady progress being made in that area, but I think it will be several years before we fully solve that. Existing methods for doing this include hijacking a virus to deliver the DNA of the CRISPR system but those are one time only treatments because your immune system recognizes the virus and destroys it after one treatment. We use these viral delivery systems for some gene therapy treatments in real patients now. It presents a pretty terrible conundrum for patients who have to choose taking their one shot on an experimental treatment which may not work. Brave people!
Anyways, yes it is possible but it’s quite early in development.
I just don't understand. Wouldn't we have evolved in an environment with constant stress? Constant fear of disease, starvation, predation, attacks by neighboring tribes? Why would our body's natural response to our environment be to immediately grenade itself.
I'm no biologist, but it's pretty easy to imagine a plausible mechanism.
Stress doesn't cause your body to "immediately grenade itself", it causes gradual problems over an extended period. But you can imagine that evolutionarily speaking, a stressful situation would frequently be a situation involving imminent danger. A response that prioritizes short-term survival (e.g. releasing adrenaline and cortisol) regardless of the long-term consequences could easily improve evolutionary fitness.
I suppose the stress was running away from a lion, not having the all-eating thought of meeting deadlines, a bad boss, backstabbing coworkers and so on, i.e. intense, but short, not persistent and chronic.
Considering that aging only happens later in life, it wouldn't have much of an effect on how efficient humans produce offspring, so it wouldn't be selected against. It is the same explanation for why Huntington's and Alzheimer's are still around.
The idea that pre-agricultural societies are subjected to constant stress reflects modern biases somewhat. I remember years ago I saw a talk from Spencer Wells where he described how pre-agricultural life might have been like in Anatolia. Fields and fields of wild wheat stretching across the horizon. Long periods of seasonal abundance. Occasional periods of hunger and privation where families would often have to rely on the help of friends and acquantainces, with the understanding that one day the debt would be repaid if similar ill circumstances befell your neighbors.
You can see some of how life might have been like in modern Papua New Guinea. War is nothing like modern warfare with artillery and guns. Its two groups of people firing arrows at each other from stand off distances while shouting at each other with minimal casualties. If you look at casualty rates from some of the early Greek warfare during the hoplite era, it's also surprisingly low.
Also note that in this post, and from research, caloric restriction counteracts some of these inflammatory effects. In many ways modern life can be stressful in its own ways, especially as we remove ourselves more and more from the active lifestyles that necessitated survival in previous eras.
You only need to get to reproduction once, regularly, for a gene to keep getting passed on.
Other mitigating factors: not eating much of the ultra-processed garbage we have today, regular high-intensity exercise, and a vastly-more interconnected community. Multigenerational homes make it easier to dump the kids off with grandma and go for a long hike with the wife or a party with the village or whatever. Etc. etc. etc.
Were safer and healthier, but I don’t think we’re necessarily happier.
Yes, we damage ourselves with lack of exercise and bad food choices, likely much more stress (I guess fear of getting eaten by an animal is less than our modern stress about our quarterly reviews?). But also, because we can fix ourselves or repair or prevent/recover from many illnesses, we live vastly longer on average than earlier humans did.
I don’t think humans evolved under chronic stress conditions. I think we evolved under momentary stress conditions. Also stresses are heavily mitigated by community and our current society is generally one of chronic stress and low social connections. Inducing a moderate level of stress in your employees is literally the primary “motivational” tool for management in most places.
> Wouldn't we have evolved in an environment with constant stress?
Well, humans did not reach an old age if you look back to history.
Only in recent times, say, 2000 years or so, or, if you want to be
strict, the last 100 years, did humans reach very old ages. Back
in older days, 30 years was considered old. Then 40 or so.
I heard that is mostly a myth due to misunderstanding what life expectancy means. It's an average over populations, pulled down mostly by enormous infant mortality. If you made it to 15 then there was a good chance you'll make it to 60.
> So chronic stress is one of the main contributors to aging.
I remember seeing a documentary on that some two decades ago, so we’ve known it for a while. I haven’t watched it since so can’t say if it holds up, but to this day still remember the explanation of telomeres and the story of the baboons.
It’s been uploaded to YouTube if you’re curious. For future readers, in case the link is dead, it’s called “Stress: Portrait of a Killer”.
These papers simply present the accumulated damage hypothesis with new window dressing. They do not account for the known facts.
The article about these papers does not present a mechanism that would account for the Hayflick Limit.
Nor does it explain why dogs, for example, age and die more quickly than humans. If there is a mechanism of epigenetic drift that would explain this, I do not see it in the article.
The obvious answer to senescence is that we are programmed to do it. Cells die when they are supposed to die; if they don't, we have a problem.
Likewise, mammals die when they are supposed to. It takes less time to train a puppy to survive on its own than it takes to train a human. Hence, dogs are optimized to age and die more quickly. It's better for the species.
If we were not programmed to get old and die, evolution through natural selection would not work. We would never adapt to changing environments and our species would fail.
Aging and death is not an accident or a deterioration from damage or a drift away from a correct instruction set. It is an absolute hard necessity, without which we would all be long gone.
Stop wasting your time on nonsense articles like this and seek the mechanism that provides us as a species with the flexibility to adapt. Until we see aging and death as an core mechanism, we're going to be looking in the wrong place.
A lot of fallacies and assumptions in this comment.
First of all there is nothing in biology or evolution where the "good of the species" has any kind of bearing on natural selection. This is the group selection hypothesis that has numerous counterexamples. If anything selection happens at the gene level over the long run.
There is also no clear reason we know of yet as to why a human being couldn't simply reach sexual maturity and hunting age faster. In fact, there might be at least some evidence other hominids did reach sexual maturity faster. It is not fully understood why humans take so long, but in animal kingdom terms we take roughly as long as the Asian Elephant to reach reproductive maturity. Almost certainly a tradeoff for achieving greater brain development and intelligence, but this could also simply be the consequences of being intelligent (e.g. it's easier to evolve for bigger skulls once ape intelligence surpasses a threshold where the apes are capable of committing to greater early childcare such that natural selection in absence of intelligence is weakened).
If dogs were optimized to age and die more quickly for the betterment of the canine species, then you could make the same argument for humanity. That's simply not what's going on. Human ancestors in the past who traded generation time for greater intelligence, likely selfishly outcompeted those who did not, and those other hominids either died off or represent a much smaller allelic contribution to the extant human gene pool.
For evolutionary biologists, aging and death similarly likely represent evolutionary tradeoffs. After reaching sexual maturity, as the probability of producing more offspring declines, so too does natural selection as alluded to in the article. Women are born with their entire compliment of ova and the rate of errors increases dramatically as they get older. Men have similar but more subtle issues with sperm generation. These error rate absolutely can be driven by mechanical stresses over time, and I would imagine could be driving much of the selective pressure that puts a cap on human longevity in the long run.
>Aging and death is not an accident or a deterioration from damage or a drift away from a correct instruction set. It is an absolute hard necessity, without which we would all be long gone.
Not buying this at all. This view is completely at odds against multicellular organisms that can literally clone themselves.
Everything we know about aging so far points towards the deterioration of renewal mechanisms that keeps our system functional. Cells die due to a host of reasons besides programming. For example, they may become non-functional and eliminated by the immune system.
> If we were not programmed to get old and die, evolution through natural selection would not work. We would never adapt to changing environments and our species would fail.
An arbitrarily long-lived organism can not only keep reproducing (think trees), thus increasing its share of the future gene pool, but can care for its descendants, increasing their survival and further amplifying its genes. Besides, even without senescence nothing would live forever: accidents, fights, and disease would take their toll. Avoiding these would just be an even stronger selection pressure than they are currently.
On a long enough timescale, things with a small chance of occurring become a virtual certainty. This includes the best of the human experience and the worst, which can get pretty dark.
There is a vast amount of difference between growing old and dying by 100+ and living until the heat death of the Universe trillions of years from now. Surely something in between, say centuries or millenia without death from the ravages of old age would be ideal. Life is too short and tends to end in a bad way, would be nicer if it was a bit longer and more open ended without the decline until something fails.
There are giant tortoises that live longer than humans. I don't think they require a prolonged childhood for training to become successful adults. Perhaps the "programmed to die" is just an artifact of different evolutionary branches for some other biological reason.
This webpage is a great example of why AI-generated illustrations are counterproductive. They make your webpage look flashy to somebody just scrolling by, but contribute almost nothing to the actual content.
I suspect that epigenetic aging is adaptive; a deliberately programmed sequence wherein genes more likely to contribute to age-related mortality are shut down progressively. This being in response to random genetic damage accumulating at a predictable rate.
What we think of as aging then becomes primarily the epigenetic response to the problem of DNA damage, much like the symptoms of a virus are mostly the result of the immune response rather than the virus’s direct effects.
There's a lot of indirect evidence for this from the fact that some naive attempts at stopping aging give you cancer, like turning telomerase on indiscriminately.
Almost everything in nature has multiple functions or causes, but one cause of aging is probably an evolutionary compromise between longevity and not getting cancer.
One option, I guess, would be turning the guard rails off and just getting incredibly good at treating cancer or inventing some extraneous cancer detection and killing mechanism.
It’s rarely such a simple tradeoff that only two things are being optimized. Modern humans live way longer than wolves for example despite being of similar body mass. However that’s fairly new in our evolutionary history as wild chimps for example cap our at ~63.
Cancer is extremely rare as a cause of death in wild animals. Again is more common but late enough that reproduction has produced multiple offspring.
Energy expenditure isn’t something we’re concerned with but drives a great deal of evolutionary optimization.
We all get cancer every day, and our body destroys it. When it finally fails to identify one, you get a tumor. If we’re doing something that massively increases cancer rates, we’d likely need a daily pill of some kind, or we’d be getting screened for cancer twice a year or something.
Can you state which genes these are that do that? Because I don't know of any.
Plus, many genes have pleiotropic effects. There is no specific aging gene.
On top of that, aging is a word that combines to many different factors. For
instance, progeria was called accelerated aging. Well, turns out you have a
mutation in lamin A. So, it is about cytoskeletal structure that is defect, rather than aging in itself. Of course the effects that this has, looks like an older person then, so it is related to aging. But one can not say it is "accelerated aging" as such. People having a normal lamin A allele still age nonetheless. So the whole term is problematic. And you can find many more such descriptions where xyz is about aging. Well, most of that it is about damage rather than aging. The Hayflick limit, though, is not about damage; that's just that cells fatigue for some reason when their telomeres shorten, but I have not yet read a sound explanations about why that is the case - after all there must be a mechanism in place.
I’m a bit mystified by the authors of the papers and the blog ignoring circadian rhythms. Three timescales, and there’s one daily oscillation in the middle that clearly integrates these shorter signals and is known impact aging… why is that not part of this picture?
The strongest evidence we have of the reversibility of epigenetic aging, as well as its limitations -- are embryos which undergo an epigenetic reset.
After fertilisation, the embryo strips the father's DNA of its age-linked chemical tags and swaps its packaging, destroys his mitochondria, rebuilds telomeres, and clears damaged proteins, though it can't undo the DNA mutations sperm gather as men age.
(those that result in an non viable embryo result in miscarriage.)
Hmmm seems high stakes
What a perfect metaphor for modern societies.
That's why knees hurt in old age? They forgot they were knees, decided they were sentient cheese?
I think knees also just wear out.
ah, the famous cheese knees disease
Somebody call Dr. Mario!
So chronic stress is one of the main contributors to aging. I hope I make it to my 40s.
Do we currently have the ability to do targeted methylation or de methylation at sites in cells?
> Do we currently have the ability to do targeted methylation or de methylation at sites in cells?
No, and you probably wouldn’t want it if you could. You don’t know what mutations are lurking in the genes that have been switched off or the consequences of turning them back on.
I’ve thought about this a bit, and what resetting the methylation map really requires, in addition to actually resetting that map, is resetting your genome to a known good state.
That’s pretty radical, but to selectively switch methylation on and off with precision you’re already talking about science beyond anything we have, featuring custom engineered constellations of proteins that unwrap your chromatin from around histones and then walk along it changing methylation state, then pack everything back.
And doing it for each cell type, without applying the wrong map anywhere.
And knowing what all the cell types and their correct methylation maps actually are.
And assuming that methylation isn’t used anywhere, for example in the brain, in a way we don’t expect.
And methylation isn’t the only kind of epigenetic modification.
So, if we’ve solved all of those problems, rebuilding your DNA to a clean, mutation free state at the same time should be a breeze.
We really do need AI for this if any of it is going to be remotely feasible.
Is “at the same time” a hard requirement?
in my futile searches for meaning I’ve wondered whether cancers in humans are a failsafe to something else or preventing something worse
more specifically the lack of more failsafes seen in some other mammals are a reaction to something besides happenstance
Cancer is the price we pay for complex multicellular life. It’s not a failsafe, it’s the failure of all failsafes to regulate cellular growth within an organism.
Larger mammals with many more cells have additional protections against cancer
Such as longer and more numerous telomeres
Hence why the human situation stands out to me and can’t be reduced to “it just is“. Some other mammals have it worse though
Evolution doesn't care about individual organisms, it's all about reproduction. Our lifespan is enough to raise a few children and pass genes on, so, from the evolutionary point of view, it's adequate
There's the grandmother hypothesis that holds we could just not have menopause and reproduce more, but we don't because there's greater evolutionary advantage for having the elderly provide support to their kin. Maybe this type of kin selection is bounded by consanguinity though, and that limits the advantage? Or maybe population pressure discourages family units from getting too large?
Evolution doesn't care at all, its just environment pressures and whatever organisms do within it. It can very well lead to some dead ends and sub-optimal long term choices.
There will come time when we will grok all this 100% and then can setup whatever we want (its just a bunch of molecules acting predictably), but we are very far from there and there is no point discussing this even for our grandchildren. We will have cyberpunk implants way sooner.
I understand, I'm equally frustrated when people including scientists say that something evolved for an environmental specialization, instead of the evolution being happenstance that may have incentivized more viable mutant offspring surviving until reproduction in that environment, but was not "for" anything.
and yes, so I understand that with human cancer, it tends to happen or advance after reproduction has already occurred so therefore those traits are not selected against. it's impossible to weed out with human mating strategies
I would just like to believe the cancer itself is an adaptation preventing something worse, but you're right, it doesn't work with the natural selection theory and so we just had a dead end to our survivability baked in, not so different than how the opposite phenomenon of senescence in cephalopods ends their lives
Was actually a great article on this last week: https://dynomight.substack.com/p/liver
Discussion: https://news.ycombinator.com/item?id=49832938
It's the other way around. Aging is the failsafe and cancer is the failure mode.
> wondered whether cancers in humans are a failsafe
I don't think so, but in the context of theories that are more-interesting than "stuff just breaks sometimes", I'd like to suggest the atavistic aspect.
Some cancers resemble a return towards unicellularity, as if "newer" multicellular rules have broken down. Not in any remotely-effective "our genes shall survive the dark times as goo" way, though.
> We really do need AI for this if any of it is going to be remotely feasible.
Would you give your life into the hands of AI skynet slop?
I understand your rationale, of course, but I for one don't want big fat mega-corporations dictate over our life here. Naturally, all of this hinges whether AI can even solve this problem. I assume it can, but I doubt it can do so initially - and the legal implications are still enormous. I really am not ready to turn my hands to claude's gene therapy slop.
why do we need ai for this? Yes, it's hard, so is laying out millions of gates in a cpu, later billions. We did it with software, not necessarily ai.
Good news! Research shows that hope reduces stress! [0]
[0]: https://www.forbes.com/sites/tracybrower/2024/09/15/how-bein...
Sadly, AI just made many of us lose all hope.
AI is an amazing Rorschach test in this regard. In the way that two people will look at it -- not just AI in general but in a specific implementation of it (coding, vidgen, etc). And one will feel deep dread and knots in their stomach while the other is filled to the brim with hope and optimism.
I think the former group almost certainly outweighs the latter group at least in the Western hemisphere, but I know the Western hemisphere has been steeped in a deep malaise of anti-optimism for several decades preceding AI to begin with. That it's almost a game to identify all the ways anything new might be bad, rather than celebrating the obvious ways they are good. And this penchant invariably biases their developing opinions of all new technology, be it AI or anything else.
What if I'm super optimistic about most technology but also scared of AI?
Space, nuclear fusion, advanced fission, the internet since about 1993, blockchain, anti-aging, I've been a big fan of all of it. But I've read the AI safety arguments and seen what a lot of researchers say about it, and I'm seriously worried.
What AI if is the only means for having those in your lifetime
AI would be much easier to be optimistic about if it were in the hands of people I like and trust. Its in the hands of people who appear to be complete psychopaths instead.
On the other hand I'm amazed at how flat access is. Access to the best models available is incredibly inexpensive relative to technology in the past, and everyone in the world with at least a smartphone has access to an LLM of some sort now.
Second, the technology is very open. It's not as if the ONLY way to access an LLM is to pay a toll to Sam Altman. Models that are very good can run on my Macbook for the price of electricity and they're only getting better.
Sure if you work in anthropic / openai or several connected / similar places future is exciting. And that's about it for the list, over-represented on HN but not really out there in real world.
Literally everybody else, all white collars including, feels they could be replaced in 5-10 years. Just talk to people ffs, its not that hard. Literally everybody is worried, doctors (know plenty from all parts of medical care), lawyers, bankers, tons of various bureaucrats, ALL are afraid in one way or another. Its also sort of helpless worry you have 0 control of, not very nice place to be 24/7 in the back of one's mind. Double that for parents with non-teen kids.
I use nature to relax and recharge and it works wonders. But reality is as it is and I have 2 small kids, I don't expect to hold the job I have in next 5 years, maybe due to llms maybe not. But I will have big issues finding another job on over-saturated market at that point, thats completely on llms. Thus as any sane person, hating the tool destroying my/our future while using it from time to time (in minimal fashion, code churning is really not a bottleneck in any decently large company and certainly not mine but I can imagine code sweatshops doing various cruds and eshops all day can be much faster now).
>one will feel deep dread and knots in their stomach while the other is filled to the brim with hope and optimism.
Ignorance is bliss
It makes me concerned on many levels, but perhaps also more hopeful. It was inevitable that we would eventually develop AI if we didn't go extinct first, and while there are myriad risks and challenges, there is also massive potential, which seems like it could be a source of hope. As the earlier comment said, the only way that therapies like these could be remotely viable on any kind of near to medium timeframe would be with AI assistance, and this is just one example.
You spelled SI wrong.
Sometimes I like to close my eyes and dream of electric sheep.
Thanks, Obama
What about Xanax or medication. Hypothetically ignoring the ill effects of the drugs themselves will chemical stress relief have the same anti-aging benefits?
They are not talking about stress in the "mental health" setting, rather the metabolic one.
In most cases they are the same thing.
Most of it is oxygen. Oxygen is highly reactive so the same thing that makes it a good as source of fuel, also makes it poisonous. It is a double-edged sword.
If you believe that HRV is inversely correlated with stress then Xanax has the opposite of your intended effect.
Yes we can do targeted (de)methylation at cells via a system called CRISPRon/off. It’s a CRISPR with the DNA cutting part deactivated but retaining the DNA binding part. They then attach a protein that adds methylation (DNMT3A) or removes it (TET1). So it’s a huge protein machine and it has only been tested in a petri dish (maybe mice, not sure).
There’s a lot left to figure out. Delivery is hard. It would be hard to get it inside the right set of cells in a real person, you usually would only want to demethylate in a subset of cell types. There’s pretty steady progress being made in that area, but I think it will be several years before we fully solve that. Existing methods for doing this include hijacking a virus to deliver the DNA of the CRISPR system but those are one time only treatments because your immune system recognizes the virus and destroys it after one treatment. We use these viral delivery systems for some gene therapy treatments in real patients now. It presents a pretty terrible conundrum for patients who have to choose taking their one shot on an experimental treatment which may not work. Brave people!
Anyways, yes it is possible but it’s quite early in development.
I just don't understand. Wouldn't we have evolved in an environment with constant stress? Constant fear of disease, starvation, predation, attacks by neighboring tribes? Why would our body's natural response to our environment be to immediately grenade itself.
I'm no biologist, but it's pretty easy to imagine a plausible mechanism.
Stress doesn't cause your body to "immediately grenade itself", it causes gradual problems over an extended period. But you can imagine that evolutionarily speaking, a stressful situation would frequently be a situation involving imminent danger. A response that prioritizes short-term survival (e.g. releasing adrenaline and cortisol) regardless of the long-term consequences could easily improve evolutionary fitness.
There always has been a lot of stress, but there used to be relaxed moments as well. The issue is that we don't calm down anymore.
Relevant video by Kurzgesagt – In a Nutshell: https://www.youtube.com/watch?v=Mo1A45ShcMo
I suppose the stress was running away from a lion, not having the all-eating thought of meeting deadlines, a bad boss, backstabbing coworkers and so on, i.e. intense, but short, not persistent and chronic.
Considering that aging only happens later in life, it wouldn't have much of an effect on how efficient humans produce offspring, so it wouldn't be selected against. It is the same explanation for why Huntington's and Alzheimer's are still around.
There are 2 stages. Growth, till ~20 and then it switches to aging.
> Considering that aging only happens later in life,
In other news, widows outlive their husbands.
The idea that pre-agricultural societies are subjected to constant stress reflects modern biases somewhat. I remember years ago I saw a talk from Spencer Wells where he described how pre-agricultural life might have been like in Anatolia. Fields and fields of wild wheat stretching across the horizon. Long periods of seasonal abundance. Occasional periods of hunger and privation where families would often have to rely on the help of friends and acquantainces, with the understanding that one day the debt would be repaid if similar ill circumstances befell your neighbors.
You can see some of how life might have been like in modern Papua New Guinea. War is nothing like modern warfare with artillery and guns. Its two groups of people firing arrows at each other from stand off distances while shouting at each other with minimal casualties. If you look at casualty rates from some of the early Greek warfare during the hoplite era, it's also surprisingly low.
Also note that in this post, and from research, caloric restriction counteracts some of these inflammatory effects. In many ways modern life can be stressful in its own ways, especially as we remove ourselves more and more from the active lifestyles that necessitated survival in previous eras.
> If you look at casualty rates from some of the early Greek warfare during the hoplite era, it's also surprisingly low.
Didn't Genghis Khan wipe out entire cities? Like, every person inside, kind of thing. Women/children/etc included.
Genghis Khan did not live in a hunter gatherer society. His time was only 800 years ago... a time when gunpowder and intracontinental trade existed.
Could arguably say the same of aLexander the Great and the classical era when casualries and army sizes balooned
When humans evolved you'd have to be an incredibly lucky outlier to have lived long enough for stress to kill you.
You only need to get to reproduction once, regularly, for a gene to keep getting passed on.
Other mitigating factors: not eating much of the ultra-processed garbage we have today, regular high-intensity exercise, and a vastly-more interconnected community. Multigenerational homes make it easier to dump the kids off with grandma and go for a long hike with the wife or a party with the village or whatever. Etc. etc. etc.
Were safer and healthier, but I don’t think we’re necessarily happier.
Yes, we damage ourselves with lack of exercise and bad food choices, likely much more stress (I guess fear of getting eaten by an animal is less than our modern stress about our quarterly reviews?). But also, because we can fix ourselves or repair or prevent/recover from many illnesses, we live vastly longer on average than earlier humans did.
I'll take today.
The stress has always been about food. Worrying about prey or a paycheck is the same thing.
I don’t think humans evolved under chronic stress conditions. I think we evolved under momentary stress conditions. Also stresses are heavily mitigated by community and our current society is generally one of chronic stress and low social connections. Inducing a moderate level of stress in your employees is literally the primary “motivational” tool for management in most places.
> Wouldn't we have evolved in an environment with constant stress?
Well, humans did not reach an old age if you look back to history. Only in recent times, say, 2000 years or so, or, if you want to be strict, the last 100 years, did humans reach very old ages. Back in older days, 30 years was considered old. Then 40 or so.
I heard that is mostly a myth due to misunderstanding what life expectancy means. It's an average over populations, pulled down mostly by enormous infant mortality. If you made it to 15 then there was a good chance you'll make it to 60.
> So chronic stress is one of the main contributors to aging.
I remember seeing a documentary on that some two decades ago, so we’ve known it for a while. I haven’t watched it since so can’t say if it holds up, but to this day still remember the explanation of telomeres and the story of the baboons.
It’s been uploaded to YouTube if you’re curious. For future readers, in case the link is dead, it’s called “Stress: Portrait of a Killer”.
https://youtube.com/watch?v=eYG0ZuTv5rs
Yet, people who have had 100% stress-free lives get old and die like everyone else.
These papers simply present the accumulated damage hypothesis with new window dressing. They do not account for the known facts.
The article about these papers does not present a mechanism that would account for the Hayflick Limit.
Nor does it explain why dogs, for example, age and die more quickly than humans. If there is a mechanism of epigenetic drift that would explain this, I do not see it in the article.
The obvious answer to senescence is that we are programmed to do it. Cells die when they are supposed to die; if they don't, we have a problem.
Likewise, mammals die when they are supposed to. It takes less time to train a puppy to survive on its own than it takes to train a human. Hence, dogs are optimized to age and die more quickly. It's better for the species.
If we were not programmed to get old and die, evolution through natural selection would not work. We would never adapt to changing environments and our species would fail.
Aging and death is not an accident or a deterioration from damage or a drift away from a correct instruction set. It is an absolute hard necessity, without which we would all be long gone.
Stop wasting your time on nonsense articles like this and seek the mechanism that provides us as a species with the flexibility to adapt. Until we see aging and death as an core mechanism, we're going to be looking in the wrong place.
A lot of fallacies and assumptions in this comment. First of all there is nothing in biology or evolution where the "good of the species" has any kind of bearing on natural selection. This is the group selection hypothesis that has numerous counterexamples. If anything selection happens at the gene level over the long run.
There is also no clear reason we know of yet as to why a human being couldn't simply reach sexual maturity and hunting age faster. In fact, there might be at least some evidence other hominids did reach sexual maturity faster. It is not fully understood why humans take so long, but in animal kingdom terms we take roughly as long as the Asian Elephant to reach reproductive maturity. Almost certainly a tradeoff for achieving greater brain development and intelligence, but this could also simply be the consequences of being intelligent (e.g. it's easier to evolve for bigger skulls once ape intelligence surpasses a threshold where the apes are capable of committing to greater early childcare such that natural selection in absence of intelligence is weakened).
If dogs were optimized to age and die more quickly for the betterment of the canine species, then you could make the same argument for humanity. That's simply not what's going on. Human ancestors in the past who traded generation time for greater intelligence, likely selfishly outcompeted those who did not, and those other hominids either died off or represent a much smaller allelic contribution to the extant human gene pool.
For evolutionary biologists, aging and death similarly likely represent evolutionary tradeoffs. After reaching sexual maturity, as the probability of producing more offspring declines, so too does natural selection as alluded to in the article. Women are born with their entire compliment of ova and the rate of errors increases dramatically as they get older. Men have similar but more subtle issues with sperm generation. These error rate absolutely can be driven by mechanical stresses over time, and I would imagine could be driving much of the selective pressure that puts a cap on human longevity in the long run.
>Aging and death is not an accident or a deterioration from damage or a drift away from a correct instruction set. It is an absolute hard necessity, without which we would all be long gone.
Not buying this at all. This view is completely at odds against multicellular organisms that can literally clone themselves.
Everything we know about aging so far points towards the deterioration of renewal mechanisms that keeps our system functional. Cells die due to a host of reasons besides programming. For example, they may become non-functional and eliminated by the immune system.
> If we were not programmed to get old and die, evolution through natural selection would not work. We would never adapt to changing environments and our species would fail.
An arbitrarily long-lived organism can not only keep reproducing (think trees), thus increasing its share of the future gene pool, but can care for its descendants, increasing their survival and further amplifying its genes. Besides, even without senescence nothing would live forever: accidents, fights, and disease would take their toll. Avoiding these would just be an even stronger selection pressure than they are currently.
"because they're supposed to" isn't a meaningful statement who is doing the supposing here? is this just an appeal to intelligent design?
>The obvious answer to senescence is that we are programmed to do it. Cells die when they are supposed to die
More handwaving like this and we'll name the hurricane after you.
On a long enough timescale, things with a small chance of occurring become a virtual certainty. This includes the best of the human experience and the worst, which can get pretty dark.
Why do people want to live forever?
Fear, fear of the unknown, fear of death
There is a vast amount of difference between growing old and dying by 100+ and living until the heat death of the Universe trillions of years from now. Surely something in between, say centuries or millenia without death from the ravages of old age would be ideal. Life is too short and tends to end in a bad way, would be nicer if it was a bit longer and more open ended without the decline until something fails.
There are giant tortoises that live longer than humans. I don't think they require a prolonged childhood for training to become successful adults. Perhaps the "programmed to die" is just an artifact of different evolutionary branches for some other biological reason.
This webpage is a great example of why AI-generated illustrations are counterproductive. They make your webpage look flashy to somebody just scrolling by, but contribute almost nothing to the actual content.
Also, they signal that AI was definitely involved in the process, which can mean the writing itself is generated garbage.
No mention of new limit.
In fact there is very little talk about new limit. But what they are doing seems impressive and important.
I suspect that epigenetic aging is adaptive; a deliberately programmed sequence wherein genes more likely to contribute to age-related mortality are shut down progressively. This being in response to random genetic damage accumulating at a predictable rate.
What we think of as aging then becomes primarily the epigenetic response to the problem of DNA damage, much like the symptoms of a virus are mostly the result of the immune response rather than the virus’s direct effects.
There's a lot of indirect evidence for this from the fact that some naive attempts at stopping aging give you cancer, like turning telomerase on indiscriminately.
Almost everything in nature has multiple functions or causes, but one cause of aging is probably an evolutionary compromise between longevity and not getting cancer.
One option, I guess, would be turning the guard rails off and just getting incredibly good at treating cancer or inventing some extraneous cancer detection and killing mechanism.
It’s rarely such a simple tradeoff that only two things are being optimized. Modern humans live way longer than wolves for example despite being of similar body mass. However that’s fairly new in our evolutionary history as wild chimps for example cap our at ~63.
Cancer is extremely rare as a cause of death in wild animals. Again is more common but late enough that reproduction has produced multiple offspring.
Energy expenditure isn’t something we’re concerned with but drives a great deal of evolutionary optimization.
> one cause of aging is probably an evolutionary compromise between longevity and not getting cancer
Yes, and proteinopathies, and likely lots else besides. We probably don’t even understand the failure modes that aging protects against.
We all get cancer every day, and our body destroys it. When it finally fails to identify one, you get a tumor. If we’re doing something that massively increases cancer rates, we’d likely need a daily pill of some kind, or we’d be getting screened for cancer twice a year or something.
This assumes there are genes that:
a) contribute to age-related mortality, and
b) shutting down helps combat aging.
Can you state which genes these are that do that? Because I don't know of any.
Plus, many genes have pleiotropic effects. There is no specific aging gene.
On top of that, aging is a word that combines to many different factors. For instance, progeria was called accelerated aging. Well, turns out you have a mutation in lamin A. So, it is about cytoskeletal structure that is defect, rather than aging in itself. Of course the effects that this has, looks like an older person then, so it is related to aging. But one can not say it is "accelerated aging" as such. People having a normal lamin A allele still age nonetheless. So the whole term is problematic. And you can find many more such descriptions where xyz is about aging. Well, most of that it is about damage rather than aging. The Hayflick limit, though, is not about damage; that's just that cells fatigue for some reason when their telomeres shorten, but I have not yet read a sound explanations about why that is the case - after all there must be a mechanism in place.
The two papers:
* https://www.nature.com/articles/s41586-026-10955-0
* https://www.cell.com/cell/abstract/S0092-8674(25)00853-0
Neither is open access. A sad state of affair in 2026
I’m a bit mystified by the authors of the papers and the blog ignoring circadian rhythms. Three timescales, and there’s one daily oscillation in the middle that clearly integrates these shorter signals and is known impact aging… why is that not part of this picture?
Furthermore - I am stunned that the authors seem to have completely eschewed the Krebs cycle!