Fight Aging!

''One might also suspect that the exceptional familial longevity of some Ashkanazi Jews is simply too much for good lifestyle choice to explain, though there no single variant really stands out after many years of assessment.
The commentary here notes recent research into rare variants and life span that, once again, fails to find a sizable contribution to longevity or its inheritance. At some point, we must accept that genetics is most likely not a direct and easy path to enhanced human longevity. It is an important tool in the toolkit, enabling therapies for a range of uses, but the goal of a modest adjustment to a few genes that produces an altered metabolism that yields significant gains in longevity (with minimal side-effects) may be a mirage. Time will tell. ''

Hi there! Just a 2 cents. I am happy your health is good and your website going. Covid is the bane for gero/reju (well, not entirely, because it made FDA be in accelerated mode (and it should be like that for everything else in biogerontology/therapy approval for public use)...if only it could stay that way when normalcy comes back; doubtful, because it will go back to slow_mo-de).

I agree that it seems pointless to do genetic tinkering if it will yield small results (once again) related to metabolism changes (which always give small yields in terms of lifespan gain)...like, CR/fasting or exercise. But, I think they should not stop doing epigenetic tinkering because it is where the 'nexus' of aging happens. Rejuvenation therapies have little to do with the epigenome and that is concerning. We hope that reduction of damages would be enough that we Would see epigenetic reversal; like removal of lipofuscin Should reverse epigenetic aging (because it is an ubiquitous aging pigment present in all 'end of stage' cells (at hayflick)). We think that solving mitochondrial oxidative function would make longer life (because rebuilding mitochondria) but I do not think that (so far) any of the therapies have the power to reverse aging (slow it yes (possibly by 50% not much more; Certainly not by 100-500%, aging by many times less speed - this Has to show in telomeres/genome/DNA otherwise no we are not 'Not aging' ,we are aging still), and are not reversing it); becaus aging is 100% in the epigenome (those other new clocks are nice...but nowhwere what epigenome clock is), epigenome is about the stuff that relates to disease like progeria (HGPS) which they show accelerated aging; might not be the same aging (as regular healthy aging in healthy human), but still a form of premature aging nonetheless; which is driven by ROS/epigenetic changes. And, in their case, Lamin A/histones...histones/chromosomes are Definitely the whole epi/genome territory; so are telomeres; thus, DNA. If we do not see it any changes to our DNA, epigenetic changes in our DNA; I don't see how this add up; if some damage repair does indirectly repair DNA (by allowing continue DNA repair ...to continue/anew/again)...then I'm for it...but so far, I am puzzled as what that would be (mitochondrial genes? lipofuscin removel? stem cell rebuild whole thing? telomerase en mass? redox maintenance (we need it)? senescent cell removeal (that one is 100% health aging improvement, not reversal aging, replicative senescent cell will continue accumulating but their numbers are small but they are inflammatory; replicative problem/hayflick is the problem (cell division arrest/crisis after time passed), not really sescent cells or SASP; which they contribute to disease; but I'm sure if we remove all senescent cells we still die on time/same thing around MLSP)? At a certain point, we have to face reality, if we want to defeat aging; what is it going to take.

Just a 2 cents.

PS: I think the genetic component eludes the researches because it's so complicated (understandably), and so they will say : 'genetics have Nothing to do with lifespan'....which I believe is a bit 'out there/in the field'...the 'epigenetic field - we're lost'...in order words, genetics Do have a much stronger say than we think. With that said, it's still ambiguous as to What/specifics of genetics are truly causal; but they are there. Ashkenazi/supercentenarians' offspring show reduction of aging speed...it's like what more we need to get it, that, indeed, DNA/epigenetic is behind it all; and in these Lucky children that inherited this perk...they will live just as long as their long-lived parents, if they remain overall healthy/helthy diet/lifestyle....they age, slower (as seen on telomere shortening and redox maintenance). So (I believe), yes, genetics Absolutely have a say in lifespan. As they say with a collection of many micro genes/effects that make an Overall effect of longevity (metabolistically) - still, does not change anything about wondering being there or not/saying genes have nothing to do with it (which is baloney that you can see in thousands of studies; it all goes back to that, the genes on/off with time); It's there. Just much more elusive/transparent than they can 'pin it down' to 2-3 genes. And, more specifically, epigenetics; the whole gene silencing/activation is so behind aging; because these genes are what make so many processes happen/or not, in the first place. When you turn on/off, some of the processes appear/disappear. I am amazed that researches think (epi)gene silencing/activating/expressing is like...not important or let's say unconsequential...it is the backbone 'program' of DNA.

PPS: It has to become much more 'normal' to talk of Eternal life with your famile and people you care...oviously we only talk of virus/diseases like covid because that is pressing world matter - But so is Aging/Death (covid is all about death, So is Aging). In the short time, defeat virus, (after) now we have chance of defeating aging. I so want people to talk of extreme lifespan and not freak out 'you are extreme/outlandish martian thinking rejuvenations works..you will die like everyone else (so don't be afraid, just embrace it)', (like...what is there to embrace? About death/aging - the finitness/bittersweet end - 'the end' we have one?...that'S about it, I think not much to embrace but more despise) this long lifespan is for all (not selfishly/egotistically but altruistically), so that we can say ''we beat covid, and now we've beat aging''. Like your website (fightaging).
Covid/virus must trigger conversations of aging and diseaese/like virus....to get people to 'wake up' and make themselves realize that they succomb to a virus or any disease...but Worse than that, they will die with Absolutely certainty, of aging in the next few decades (which may seem 'veryyy far' for them; but it should not be and they should understand that it will come; so they should focus on defeating/talking of defeating aging Right now so that the Funds go towards research/building therapies - instead...of later when they are gone/dead).

The problem I think is, that with things like the high metabolism brain, nature had to essentially create solutions that would provide for indefinite longevity, once age of first reproduction was pushed far enough. Even in mice we already see that some high metabolism cells can last over two times as long as the mice themselves do without dividing. But those mechanisms had to be limited lest the lifespan be indefinite(which could create genetic havoc with inbreeding, gene pool stagnancy or decay, etc ).

What I believe happened is that after developing sufficient maintenance and repair for indefinite lifespan, a series of genetic checks evolved alongside keeping agelessness from easily evolving and limiting those maintenance mechanisms. Like cancer which requires multiple mutations to occur, these checks would necessitate multiple mutations to break. But since they are all over the body, the mutations would likely have to occur in the fertilized egg before division or most organs wouldn't get it and their failure would doom the organism. The likelihood of multiple mutations occurring at such a point is so remote as to be basically impossible.

That said the maintenance mechanisms exist. Even in humans neurons last over 115+ years, while the average lifespan is in the 70s. And it isn't the failure of neurons that kill the oldest. Keep in mind that the support tissues of neurons do age as they have dividing cells. The aging of the support tissues does mean neurons do experience issues themselves. It is likely the repair and maintenance of human neurons isn't too distinct from other species. Some researchers have hinted that neuron lifespan might be indefinite if provided with appropriate support. Just like mice neurons last over twice as long upon transplantation, it is conceivable human neurons could last over 160+ years in the right species.

Another thing to keep in mind is that you have two positions, either the longer lived a species is the more mutations it needs to extend lifespan to reach a biological immortal state, or you believe the longer lived a species is the fewer mutations are needed to reach the biological immortal state. While multiple mutations occurring in the fertilized egg is unlikely, it is conceivable that a drug cocktail could target different areas and together achieve similar results to multiple mutations.

Hi Darian! Just a 2 cents.

That is a really great and insightful take on it. When we look at animals that live much longer than us, then we realize quickly that aging is defeatable (which changes); in my POV, the only way for an extreme lifespan is to maintain a young body; there is no other way. I know that there is a risk of cancer with 'forever living' as mutations accumulate; but cancer is 100% of the epigenome control, these mutations can be stopped despite high cell proliferation. Cancer can definitely be solved and destroyed, continuously to remain 'quiescent/benign'. Like, I researched about skin aging and saw that mutation burden means appearance of moles/nevi; yet, it also shows higher proliferation and also, higher telomeres (in general, nevi mole counts correlated to telomere length in skin ecm fibroblast; more moles meant taller telomeres, when it seems the inverse that skin mutation would mean smaller telomeres; in fact, it means High Proliferation and is a driving element Behind Telomerase (like skin telomerase) - which cancers hijack to keep telomeres in the 2KB region 'frozen' there); meaning, 'keeping young' and body that is epigenetically aging will surely cause 'mutation overload' (and I saw this with aging, like more moles and stuff on back), oxidative stress (like UV tanning of skin) can cause deleterious mutations/oxidative lesion/DNA SSBs DSBs, skin pigments (like drusen/lipofuscin/liver spots) and prepare for mutation 'rogue cell formation/(cells turn) cancer cell'..while Extreme proliferation, such as in stem cells Also promotes cancer formation ('stemcellness = cancerness'; it is a double-edged sword catch22 (like everything in evolution); too much and you make mutations (deleterious 'errors'); too little and no more division = cell arrest) because stemcells can divide rapidly like cancer cells; they say that cancer cells acquire 'stem-ness'. Which, basically, means that the cells 'become younger/smaller/spindle-like' (instead of flat, large and full of crap/aged/senescent), and *mmortalize/transform (to stay *mmortalized they must keep a 'young' profile - not Continuously age; because then they will not be able to continuously proliferate and after, the tumor mass, to mestatasize..this needs/involves high cell division/activity. Sometimes, I think there are 'forces' out there that don't want to solve the problems, but only make money from your dying body (and that's really sad, because once the cure is found = no more money to make of your old body; you now Live Too Much Healthy = 0 money (aka big pharma)). I am obviously generalizing and simplifying it, because trillions of dollars have been poured to defeat cancer. Yet, we're still at square 1. (I digress).

Animals live some of the longest lived ones, bowhead whales, groenlander sharks, cold adapted mollusk clams from Iceland...tell us a lot, of what is possible; ok, not many are mammals (but, the mechanisms are Close) - these animals Liver Much longer than us; up to half-a-millenia. Why. We live a long life but compared them, no, not really. Statistics say that on animal chart we should live '25-35 years' max...but we reach 122....so something is telling. You have people who die at 15 years old * as 'premature adults' (HGPS hutchison gilford sydrome) havin progeria. Yet, you have people like Ashkenzi people who live 115 years old: 15 vs 115...something is going on. That is nearly 10-TIMES the different between two same HUMANS. It goes to show, our potential for Much longer lifespan as not been YET tapped. Animals live 500 years, why human just 115. Bristlecone pine live 5000 years. And everyone of these animals who live extremel lifespans have Extreme Slowed Aging (oftenly extremely slow metabolism). Such as giant sea turtles (galapagose tortoise) that live 175 years or ara blue parrots that live 111 years old. It is telling. We have to slow - dramatically - our aging, and only then do ahve chance of living 400+...reversing aging is something we hope to achieve, if we can't, then we must 'freeze it', slow it to a nearltotal halt - which is exactly what is happenign in these animals. How so? Well, epigenetically, they have great DNA repair but it'S not really that...it's because they acquire mutations and epigenetic chances MUCH less than us; obviously this 'acquiry of phenotypic 'changes' in epigenome causes to 'change' (aka age). So we approach the cell death when it can'T work anymore. Tehy don' do that, they continuously keep their cells 'young'. For centuries. Neuron are a good example, they could do far longer that 150 years;;;all cells in our body do could do 500 like those clams. But for that it needs change. A great study is one called 'A heart beating for 500 years'...it's revealing and shows that in clam, their heart beats 500 years and everythinh A-OK.

''Some researchers have hinted that neuron lifespan might be indefinite if provided with appropriate support..human neurons could last over 160+ years in the right species.''

100% d'accord. Albeit, right now, I am not sure it is indefinite; it is more finite and that is due to loss of neuron spine and tangles/damages that cause neuron death. But, not only that, they too probably lose telomeric/DNA content over time; it's undefetable, they will end and face apoptosis at some point if there is no maintenance of DNA content (it'S not jus quality and efficiency, it's the actual content 'being there' or not anymore, if the content disappears (like there is global demethylation/loss of cytosine/guanines/quads/histone changes/loss/end termini telomeric DNA TTAGGG loss/chromosomal havoc)...no more content; no more DNA/epigenomic content = no more cell). Pruning of brain is problem with age, neuron loss too. If an animal like groenland shark lives 450 years and has a brain, has 'some' neurons in there and it sure maintained them all this time to swim around/eat/hunt/think (sort of)/live (likewise for the heart and every other organ). Neuron could last 1000 years if kept/well-conserved (like cryogenization-conservation/hermetic conservation (no O2 ROS/no PUFA loss (by peroxidation)/no hydrolysis)). WE talk of this like it's a scifi movie on ScIFi ChanNel...but it is not anymore and should not be.

''Another thing to keep in mind is that you have two positions, either the longer lived a species is the more mutations it needs to extend lifespan to reach a biological immortal state, or you believe the longer lived a species is the fewer mutations are needed to reach the biological immortal state. While multiple mutations occurring in the fertilized egg is unlikely, it is conceivable that a drug cocktail could target different areas and together achieve similar results to multiple mutations.''

Exactly, that is what I fear, the mutations - the must be rendered futile; I believe that we can reduce their burder and maintain young body that though has high mutational burdern due to 'living forever'; but a young body can defeat aging (immune system) it's that touchy position where you think you are 'young enough' to beat cancer, despite you are aging (chronologically I mean), not biologically. When I see problems of old people, like what you said that people of old age do not die like of neuron loss, but of something else, like transthyrethin in the heart...than it means that being 'old' and having accumulated lots of detritus/junk is incompatible with continued life - it will mess up down the line. So we have to keep a young body - as young/intact/pristine. This is why these animals live so long, they are not OLD ever...simple as that, they are young ALL along. By biological age you can tell tehy are Much younger than their Chronological age; there is a discrepancy between their bio-age and their chrono-age. The less bio-age and the MORE chrono-age; the Longest lifespan they will have.

And, yes, possibly, targetting directly in the egg could stop these mutations are the very start. It may mean that only later children that re not born yet will obtain this benefit; for us, stucj with this mutation problem, we have to render them futile/inconsequential; because their burden rises and at soem point, their cumul will be sufficiently consequential to end us. Probably, cancer once more or organs failing. We have characterize these mutations and find ways to amke them bening and 'forever sleeping' like a dormant virus (some virus 'wake up' 30,000 years later (when exposed after ancient ice melt with 'bubble airs of 30K years'), that's a good sign; it should take this long for mutations to be of any relevance/concern).

@CANanonymity
I would dismiss the Greenland sharks and turtles and they have much slower metabolism. There you can just say that they live "slower". The ARA however, are more interesting. Their metabolism might be even faster then ours, they are smart , so have to maintain relativity large and expensive brains. There is little that can be translated directly to humans from them but they office that aging in principle can be slowed down even with high metabolism.

@Darian
The idea of programmed "intentional" dead is over simplistic. In fact, it would be to easy to hack those death switches. Alas they are not that obvious. I wild be gladly return wrong, though. The sad fact is that our species historically didn't need to lover longer than 40 years. If the rite of passage in adult Hood is attend 13 years 2-3 generations of lifespan. More then enough for the brutish lives out andesite ancestors lived. The coming of agriculture made that time even shorter as having faster generation turnover helped to adapt to there new infections and food. Then higher population density meant other daughters dangers like wars and famine. If your chances are high to die not full old age, then your best bet is to procreate more and don't invest to much resources to lover much longer. In fact, we already love much longer than 40 years.

Now, one thing in favor of the programmed death is that start 110 everything in the body starts failing precipitously. Three are valid questions for why at this time. Why not much slower.

Hi Cuberat! Thanks for that. Just a 2 cents.

Metabolistic speed is definitely an important element to longevity, and since these ultra-long-lived animals (like cold water sharks, turtles and clams) have a basically 'nill' metabolism, it makes sense to say, as you said, that it can't translatable/applicable to humans. But, as you said also (after), if ara Parrot birds can live so long and have increased metabolism (well about the same ours...theirs is faster...but birds use clever 'sleep hibernation' where their bodies metabolistically slows down quite a lot during their sleep; it happens in humans too during sleep but not as drastic; this means they 'compensate' for their daily fast metabolism by slowing it at night; so it ends up with an 'average metabolism speed' about equal to a human - and why, a Parrot could live nearly 115 years or possibly more if he even 'slowed things' even more in his life (probably, a Lab Raise ara, would live 130 or more; of course, we would have to raise it for 130 years (way too long) in labcaptivity (but with minimal stress/human-tempering and 100% all resources the animal needs for a long life) to see if indeed it passes the 122-130 MLSP, as like in humans)). I guess it would because studies in bird showed that aviary mitochondria have a 'base' mitochondrila emission that substantially lower than humans; as suchl there is just Less ROS to begin with in them, than humans; that is due to needing a 'Fast/powerful/compact body and strong muscle wings - and fast beating heart' to pump blood in the wings/make flight of the bird. Like toucan birds beaks acts as a 'temperature' moderating element; their 'nose' literally controls (like thyroid) the body temperature (like a 'heat sink' on a CPU/a 'cooler' or 'warmer' depending ambient temp), and thus, toucan metabolistic speed. They live long, though nowhere as long as ara/parrot birds. The fact parrots 'talk' like humans...is a testtament of high inteliggence ad brain cognition; brain intelligence, overal, is quite related to longer longevity. But, not always, like galapagos tortoise, we think they are intelligent, but can't even talk (no vocal cords) as like a parrott. Yet, they live up to 175..as you said, they slower metabolism. Like their was one study that research on seatortoise fibroblasts and showed that the hayflick limit in their skin cells is Much longer; from the start...so this means they preserve DNA and have very extended 'cell replication rounds' (before hitting cell crisis hayflick). For them, it was also about 1 PD (bio) = 1 YEAR (chrono); thus, their fibroblast made about 150-200 PDS (population doublings); while humans' skin fibroblast make 65-95 PDS;...yet, when we combine that with NAD+/Niacin/Nicotinamide/B3 there is slowed aging and the fibroblast can reach 125 PDS; but still senesce around that MLSP (120 PDs = 120 Years lifespan). Fibroblast are a good 'overall' surrogate of how long we'll live (excluding areas 'Damaged' by extrinsic oxid. stress. UVs...etc tanning...). IT is even measurable by glycation/AGEs/ALEs; like pentosidine accumulates several folds more (in short time) in mice skin vs human skin. They, thus, live only 2-4 years.

One Russian 1980s study showed that there is Clearly a loss DNA Proportional to lifespan (and this reaches telomeres and mutations acquiry in DNA), like mouse lost DNA 50-100x times faster than humans, cows lost it 1.5x faster, dogs lost it 5-10x faster, ...I would bet/wager, my whole savings that it is the same for Any animal; we lose this important program 'matter/stuff' and thus, we live less longer. For me, the fact that Arra birds live 110+ years, and have overall faster metabolism and it 'still works'....it means, that metabolism is Not the Be All end All, and there can be 'workaroudns' around it so that even a faster metabolism - which is suppose to die quicker - could liver longer. Like, for example, Bats have faster metabolism (although they do lots hibernation so they compensate), same for squirrels, very fast metabolism (But again ,do hibernation (slowed metabolism) to compensate metabolistic high speed), these animals live quite long despite so. We humans, live quite long, despite so. We can maintain, I am sure, the possibility of function of 'this speed of metabolism', and thus could live as long as these animals - despite not having a metabolistic speed as low as them; it is possible, metabolism can Be Decoupled. Yes, a faster metabolism = faster aging = faster Junk accrual; but, it's more subtle, the body can find workaroudns: ex. parrots have high levels of bilirubin and uric acid (this means they probably have high purine turnover/they produce more DNA synthesis than us; this ends up as uric acid excess), uric acid (and bilirubins/biliverdins/biles) is a 2-faced oxidant - and - anti-oxidant. It is extremely quenching of ROS but causes uric acid stones/renal failure and causes Uracil Mismatches Purine/Pyrimidine Formation/incorporation in DNA; which is extremely toxic (almsot more than methylation or methionine (a toxic amino acid that evolution did its best to not incorporate the most possible; you need some (for redox) but methionine causes havoc by increasing homocysteine in redox transulfuration pathway). So, clearly, animals, like birds, found ways - be it Quenching ROS/Consuming mitoROS.... - there are ways...the body can adapt the situation and it is why a faster metabolism animal may still a longer life. WIth that said, in general, faster metabolism leads to faster aging/damages etc...so its catch22; we can't Slow Down until we are Zombies....we have to find alternate solutions to maintain our speed while being able to reduce the aging process - despite the faster metabolism - not helping.

I believe that why the body falls apart more towards 110 years old, is that we reach the Hayflick limit, is really is that; End Replication Problem. No More Cell Division Left...No More 'Telomere Left'...a 115 year old woman with short telomeres in her immune leukocytes - says it all. No more 'room left', it's the maximum end of the cell - the VERY maximum, no more. After that , M1 Crisis, M2 Crisis, if it bypasses M1 checkpoint/death, the cell will go on to replicate a little bit more, like 15 PDs extra... (in replicative 'half-senescent' state) but then it will completely Stop, at M2...last checkpoint; there it will Transform into mutational/rogue cell 'try to become 'stem cell' again to 'survive some more'); it will late harbor cancerous properties or turn full cancer cell to for a tumor. This transformation may/often be accompanied with '*mmortalization'....the cell will replicate forever after that (it will not lose Anymore DNA/telomeres hijacked/ nor accumulate lipofuscin...like our somatic cells do).

Just a 2 cents.

I agree with you CANanonymity, but I don't think human lifespan is 110 or 115.
Only extremely rare people live that long and their body is falling apart for a long time before that age.
Human lifespan is about 85 to 90 (without rejuvenation) anything longer than that and your body is so weak and fragile I wouldn't call it a life, more like vegetating (again without rejuvenation or slowing down aging).

@basinc
What you are talking is actually the current life expectancy which is between 78 and 88 in different oeced countries. Event regifted maximum human lifespan , of I remember correctly, is 122. 115 is rare but not unheard of. By tweaking the metabolism and cleanup/restore mechanisms or loving in perpetual calorie restriction we might be able to push the median expectancy to 98 or even 115 with some medical advances. That will do almost nothing for the maximum lifespan, though. So it will not really slow down aging but simply letter more people survive it longer. Extreme calorie restriction might even slower it down to some extent.

And there's a way to measure it even if we don't have good markers of effective age. From statistical point off view we can look at the curves of modularity, she and survivorship.

So if the survival curves become more "square" it would mean that we don't show down aging but rather cope better with it due to better medical and social progress. If in the other hand, the shape of the curve is the same but it got stretched a decade or even a couple of years that would mean that there is a genuine slows down in aging for the whole population. That would not only mean shifted all cause mortality but also later onset of morbidity. And if we have working reinvention therapies the treated cohort would show a bump or dip in their curves against the control. So even a small effect can be seen if we have enough people.

Of course, until we have mass application of Senolytics and CR mimetics all this is pretty speculative.

It seems that metformin has statistically significant albeit not impressive effect. Rapamycin has much stronger effect but due to its died effects is not used widely, not is recommended.

@CANanonymity
In your post you have brought several concepts worth of their own articles.

What is amazing with Senolytics is that it seems that even in deep old age there is a reservoir, albeit small of cells that still have good enough telomeres and DNA. If we start doing regular senescence ablation we might eventually run out of available pristine cells. However, that stage is well above 115 years old. Let's bump from that bridge when we get there, though. By then we might be able to replace the stem cells with engineered ones. We already can do it for some cell types like nine marrow. So I can see a plausible protocol of periodic Senolytic ablation after forty-something. And say after 65-75 the ablation can be followed by stem cells injection to provide more youthful and capable steel cells to replace the missing ones.

Speaking of senescence, Dr Harold Katcher has finally published: "The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus." "Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging."

https://www.biorxiv.org/content/10.1101/2020.05.07.082917v1?fbclid=IwAR2_bT2NW7MpcoMT2kQwiV0zhzciNpSQnphgxVJ86s995rwOftp_405iJfE

@John S
Half of the abstract is about markers, which might not have clinical significance by themselves. Think of reversing the odometer on an old car.

However there is a spacious claim: "... The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions..."

This will require a reproduction if the effects are large enough...

Re Cuberat

I think I have aging figured out now, ..it was even more subtle, ambiguous and complex than I thought...

I guess it is because studies oftenly don't distinguish, or do but it is an after thought, between in vitro and in vivo.

Intrinsic Aging, with actual progressive bodily changes/transformation, is clearly a manifestation of loss of chromosome compaction (decompaction), in turn, this creates LAMIN a changes, seen as formation of progerin (same thing in HGPS disease, or lesser so, in Werner Syndrome or Trisomy 21/Down's Syndrome), this progerin is said to be immature and non-farnesylated, not mature, as such it cannot correctly go on to make correct chromosome arrangment.
Healthy people STILL have progerin, albeit much less so, accumulating with age; so it's not just HGPS people who get it, Werner, Down's, you and me, and Everyone Else are getting progerin. Albeit at different rates.

It is a manifestation of chromosome problems with age. Chromosomal decondensation/decompaction; where the (DNA) coils (of chromosome) unravel and 'let genetic matter be accessible' (making gene unsilencing by demethylation).

And, it's a proof, that it is aging; for healthy people too, just slower...

'Fragile Syndrome X' people are basically HGPS people BACKWARDS....you know like that film 'Benjamin Button'...aging backwards...well not really; but these 'Adults'..never become Adults. They 'Stay Children'. And this is the kicker...their DNA methyl clock/epigenetic age does not advance/or very little. Yet, they suffer complications from not 'growiing up'...not becoming adults/maturing. This causes skeletal problems and they look an infants...one of these adults are 40 YEARS OLD - my age - and look *5 years old/like babies*...no kidding.

(While HGPS people, at 15 years old, like 80 Years old...)

The FS-X forever-child/ultra-neotenous people die around 20-40 years old from problems of 'making this work'...so both being ultra-old (HGPS) or ultra-young (FS-X) causes chromosome problems, which lead to death at some point; earlier than regular 'healthy growing/aging'.

I would wager that FS-X people have little or not accumulation of lipofuscin and have tall telomeres (in the 12-16kb region, just like at near birth), have very little to no progerin (even less so than us healthy people).

But, it is incompatible; probably, before death, there complications in 1 or several organs; and then there would be appearance of 'Accelerated HGPS' in these people's 1 or 2 organ; 1 or 2 organ failing can be Enough to kill/die suddenly 'sudden death'.

Epigenetic Aging is more complex than I thought....epigenetic aging is Rather, a Tab Counter....and is DIFFERENT than Telomere Aging; Telomere Shortening is responsible of Cell Cycling Rounds/Division Dynamics...but it is Irrespective of Epigenetic Clock Age...

It was proven where cells that becase replicatively senescent and *mmortalize STILL AGE after...even after *mmortalizing....and they can replicate Infinitely and AGE Infinitely (by the Horvath or Hannum epiclocks).

You could have a 5000 replication rounds cell that is equal to 5000 Years to replication...it is still viable and replicating...it IS 5000 years old on the epigenetic clock. In terms of 'epi-Tabs'.

So epigenetic aging is just Tabs (like a Calendar that memorizes the cell's age).....but, that is In Vitro Cell Culturing.

In Vivo...it's more complicated but is the same...Phenotypical/Organismal Aging characterized by physical manifestations: Wrinkles, Gray Hair, sagging/leathery collagen-empty skin....etc is because telomeres are shrinking and there are less bouts available; and because 'Function', in vivo in humans, is in that Epigenetic Age Clock (meaning you need certain elements of chromosomes to keep it working Right), the Clock Can Continue On...but in humans, it leads to cell arrest/replicative senescence/Hayflick.

Our cells could age infinitely and be 1000 years old...in perfect function....Except, there would be problems on the telomere function and the epigenomic content would be emptied (loss of 5-metc, cytosine, decompaction of chromosomes...especially, histone changes, loss of histones; these histone changes contribute to SASP/SAHF (Senescent Associated HeteroChromatic Foci);; the HF part is the important one; this means histone/chromosome foci forming. Which will make progerin/LAMIN a appear/cause chromosome problems. And we remember that Telomeres ARE on the chromosomes. Pointing it all to DNA - in the telomere/sub-telomere/centromere - In/On - the Chromosome. SAFH is complete incompatible it will cause histone/chromosome decompaction/G-Quad loosening/Coil Uncoiling.

Fragile Syndrome X (neotenia/juvenia) is like Trisomy 21/down's; it is problem at the Chromosome 21. Again very closely to HGPS (gerontenia/progeria); also problems at those chromosomes.

So, in humans (at least), When there is Reversal of Epigenetic Clock Age (DNAm / DNA methyl age by Horvath), the actual Chronological Age is Reversed, such as iPSCs reversed by Yamanka factors (Oct Sox Nanog c-Myc Ras) 'reprogramming/erasing age-identity of cell'. These iPSCs (induced pluripotent stem cells) have nearly 0 Age by the DNAmethyl clock. And they Proliferate anew - BECAUSE - their telomeres were ReLengthned. IF, the telomere would Not Be Relenghtened; they would resume aging and would senesce from that point. They saw that when they made these reversed iPSCs to 'differentiate again' in new Young cells... it worked...the only problem thy saw was that their immunne response was reduced VS 1st timers/original cells derived from normal pluripotent stem cells that were never reversed in epiclock. I think it kind of reaches what you said...that *mmortalized or reversed epiclock cells can harbor weaker immune responses (loss immune memory/erased due to losing near-completely cell identity during reversal); and it is why it may incompatible (aka...Eternal living animals would develop problems iwth immunity...they would never adapt anything to new diseases; they would succomb of immunity problems;; so they upshoot of dying is immunity protection while that life window; while Eternal life makes possible 'unadaptation' happen because cells don't acquire any 'new memories/adaptations' to 'new viruses...like covid or the new supermutant form of covid;; you need memory for that in immune cells; Erase the Memory...and you are now vulnerable) It's why reprogramming does not want to Erase Completely the Identity of the Cell...only reverse its Epigenetic Age on the DNAm epiclock.
And also that thing with over 7 days reprogramming and terratoma formation/cancer formation..

So, I believe, in humans in vivo; epigenetic aging is causal to aging and is also a tabs-counter and is important about which genes are activated/deactivated with age....but telomere-cell proliferation continues its course Separate from epiclock...as like a 2nd layer if you will of aging..but independent mostly. For humans, epigenetic aging is consequential because it affects chromosomes...and chromsomes are Definitely aging pure. In humans, we have a WINDOW of 122 years or so....in that window it is the FUNCTION....if you go above that time...you lose function and there is incompatibility for Continued function; replicative senescence will happen and will Contribute to SAFH/chromosome problems..which are Not Viable..for continued life. Telomeres are behind that (Replicative Senescence -> SAFH/progerin/LAMIN a/histone loss).
So it ties neatly together.

What does this mean? IT means in humans, we have to 'make it work' in that window...*mmortalized cells/cancer cells hijack telomerase and keep telomeres frozen/they can replicate forever/are *mmortal...YET THEY AGE...on the epiclock...tehy age constantly...but never die/end. In humans that is Incompatible...can't work...it will 100% mean chromosome dysfunction/dysassembly and Overtaking of rogue cells/cancer....transformation/ALT/telomere fusion/SCE (Sister chromatids exchange...chromatid chromosome). It will, simply put, cause chromosomal HAVOC. and that is what happens with age - in ALL - animals. Including greenland sharks living 5 centuries or even Hexactinellida jellyfish that are supposedly *mmortal (due to them having permanence telomerase in their stem cells line whenever they revert to immature stage/prepubert... do the 'loop di loop' neoteny on and on).

So, for human, we must Absolutely, be able to cure the telomere problem AND the epigenetic problem; without both it is impossible to get around it; there must be chromosomal (and byso DNA) changes Visible to Reverse aging. We have 120 years window to make it happen; above that, impossible. I have difficulty believe that making a 120 person reverse to 20 possible because it would mean complete reversion of telomeres and epigenetic clock;; you cannot LET there epigenetic clock continue (JUST LIKE cells 'in culture in vitro' that were *mmortalized with TERT transfection, and become 'older'/age by epiclock by NEVER stop dividing/are *mmortall whic means epiclock is only a tab-counter in vitro at least). Not in vivo; in vivo there are dynamics/morpho dynamic forces at play (the cells do not act exactl the same 'in vivo vs in vitro'; on chromosome and is incompatible with continnued life. It is why we must make it happen in the human life window; and we MUST reverse the epigenetic clock age (unlike *mmortalized cells taht can be eternally old...doesn't matter) but for 'normal function'/chromosomal arrangement (correct); it is important; so that we can remain Young body 'Physically manifesation' (just like the FS-X people)., but we would remain 'as adults' 'yougn adults'....forever. And we must Absolutely solve the telomer shortening riddle problem; it is Impossible to make Eternal life with micro-telomeres or ultra-fast rate shortening ones...cells will arrest.

Just a 2 cent.

PS: Epigenetic aging is That ambiguous and contradictory, imagine.

PPS: I am mixing FSX and SX...it's not the same Fragile Syndrome X is different than 'Sydrome X, 'Syndrome X is called 'Neotenic Complex Syndrome' (that's the one I meant ..sorry mixing them)
That is what the 'non-aging adult' children suffer of...and that Is slowed/no aging on chromosome (but complication with function of them/not compatible over long run as they say 'developmental delays').

1. https://abcnews.go.com/Health/girl-ages-unravel-secret-eternal-youth/story?id=19974247
2. https://abcnews.go.com/Health/maryland-20-year-dies-aged/story?id=20712718
3. https://en.wikipedia.org/wiki/Brooke_Greenberg
4. https://en.wikipedia.org/wiki/Neotenic_complex_syndrome

PPPS:

After more research it seems that, some at least, of their tissues still age normally and so they are not Really epigenetically speaking reversed/neotenous; just theiy remain young

I mean they remain 'small size/undevelopped' but their tissues age by epigeneti clock even so.
Here is S. Horvath's results:

5. Epigenetic age analysis of children who seem to evade aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468314/