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.
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.
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.
Stop spewing this claptrap as copium for your own mortality. Everything is natural and «part of life» till it isnt, like cervix cancer was like syphilis was like rheumatic fever was.
You die because your DNA gets damaged and your cells lose the ability to repair themselves.
You werent «programmed» to get alzheimer cancer artherosclerosis dementia and embolism. It’s not supposed to happen.
gtfooh
Do we currently have the ability to do targeted methylation or de methylation at sites in cells?
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.
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.
more specifically the lack of more failsafes seen in some other mammals are a reaction to something besides happenstance
Discussion: https://news.ycombinator.com/item?id=49832938
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
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.
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.
[0]: https://www.forbes.com/sites/tracybrower/2024/09/15/how-bein...
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.
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.
Ignorance is bliss
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.
Relevant video by Kurzgesagt – In a Nutshell: https://www.youtube.com/watch?v=Mo1A45ShcMo
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.
In other news, widows outlive their husbands.
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.
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.
In fact there is very little talk about new limit. But what they are doing seems impressive and important.
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.
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.
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.
Yes, and proteinopathies, and likely lots else besides. We probably don’t even understand the failure modes that aging protects against.
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.