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High Functioning Centenarians Have Longer Telomeres, More Telomerase Activity, and Better Measures of Immune Function

Today I'll point out an open access paper in which the authors divide centenarians into two groups based on the degree of age-related dysfunction. They find that centenarians with comparatively lower levels of dysfunction also have longer telomere length and more telomerase activity in white blood cells taken from a blood sample. Further, aspects of their immune response that are not directly related to telomeres and telomerase also appear more capable.

In one sense this telomere length data is the expected result: telomere length is a measure of biological aging. When considered generally it is a measure of the burden of age-related molecular damage and consequent dysfunction, but when measured in white blood cells it is also to some degree a measure of the decline of the immune system. Less functional centenarians are clearly more physiologically aged than more functional centenarians, and therefore should exhibit shorter average telomere length.

On the other hand, telomere length in white blood cells is such a terrible measure of aging that finding no difference between the two groups would also be unsurprising. Over the years, a fair number of comparison studies have failed to find the expected differences in telomere length between study populations of differing health status. Telomere length as it is presently measured only reliably shows correlations with aging over very large study populations, averaging out the large short-term fluctuations resulting from health and environmental changes, and is certainly not much use as a marker for individual decision making in health matters.

Thus I would say that the more important data here is that directly relating to the immune response, rather than the telomere length results. The immune system is critical not just in defense against pathogens, but also in destroying errant and potentially harmful cells, as well as playing an important role in regeneration and tissue maintenance. When the immune system falters with age, declining into chronic inflammation and incapacity, a great many other functions decline with it.

Telomere length and telomerase activity in T cells are biomarkers of high-performing centenarians

It is generally recognized that the function of the immune system declines with increased age and one of the major immune changes is impaired T-cell responses upon antigen presentation/stimulation. Some "high-performing" centenarians (100+ years old) are remarkably successful in escaping, or largely postponing, major age-related diseases. However, the majority of centenarians ("low-performing") have experienced these pathologies and are forced to reside in long-term nursing facilities.

Previous studies have pooled all centenarians examining heterogeneous populations of resting/unstimulated peripheral blood mononuclear cells (PBMCs). T cells represent around 60% of PBMC and are in a quiescent state when unstimulated. However, upon stimulation, T cells rapidly divide and exhibit dramatic changes in gene expression. We have compared stimulated T-cell responses and identified a set of transcripts expressed in vitro that are dramatically different in high- vs. low-performing centenarians.

We have also identified several other measurements that are different between high- and low-performing centenarians: (a) The amount of proliferation following in vitro stimulation is dramatically greater in high-performing centenarians compared to 67- to 83-year-old controls and low-performing centenarians; (b) telomere length is greater in the high-performing centenarians; and (c) telomerase activity following stimulation is greater in the high-performing centenarians. In addition, we have validated a number of genes whose expression is directly related to telomere length and these are potential fundamental biomarkers of aging that may influence the risk and progression of multiple aging conditions.

Comments

Hi there ! Just a 2 cents.

''(a) The amount of proliferation following in vitro stimulation is dramatically greater in high-performing centenarians compared to 67- to 83-year-old controls and low-performing centenarians;''
This is a clear demonstration that cell proliferation drives mechanistic aging in the epigenome, and that telomere length is a mostly measure of fitness (secondary) and thus health, not aging (primary). Intrinsic aging is controlled at the epigenetic level which alters the metabolism speed; which itself alters aging speed too.

This was demonstrated with IEAA and EEAA (Internal/External Epigenetic Accelerated Aging), both IEAA and EEAA show accelerated proliferation, loss of quiescence and accelerated 'growth' (IGF/mTOR (For fitness)) and also stem cell use. But, above all, both IEAA and EEAA show elongated telomeres and upon hTERT activation/telomerase entry, there is distinct 'advancement' of DNA methlyation clock. Showing that telomerase/telomeres are a double-edged sword, only made to act as fitness sinks and
as cancer inhibitors (senescence when telomeres are small and cancer is about to overtake), thus an antagonist pleiotropic enzyme. Now, I am 100% sure that telomeres and epigenome are 2 of the same thing, but different even so, they are not the same (at the same time! that's confusing), yet linked. What happens in the telomere realm is not the same as what happens at the methylation level realm. One is your health/fitness 'clock' if you will, while the other is your 'Real' clock, the clock that matters
and decides why you die at 120; the one that is your 'signature/identity/phenotype' of your body (the epigenetic clock). A 60-year old does not have the epigenetic clock of a 100-year old, they both have different identities; and both their clocks keep tabs on time. The 100-year old one is about to expire. No matter, how 'fit' or how tall the telomeres are in those centenarians.

If you were to ask me, does this mean telomeres are just conditional thing, I would think sort of yes, but they are important and needed; but, clearly, there are centenarians 'low performers' with health problems..they are a 100 years old TOO. So, no, telomeres are a seperate thing from aging, just like health barometer, but not a age barometer. The fact that telomerase Increases epigenetic aging is a serious demonstration of 'negative feedback aging' - countering cancer - and aging you in the process. Telomerase is just a 'safe' mechanism to protect you from 'more damage', but when it is called, it kills you at the same time it's helping you; how so ? By aging you in 'tabs' on the epigenetic counter (IEAA/EEAA). Telomerase is direct concert with epigenome and talks to it, by sending 'Aging' signals to it; you would think that CEO Mrs.Parrish Telomerase hTERT therapy was the thing, but it'S all an error after all; but the upshoot is improved health and possibly living to a 120. Don't expect telomerase to make you live 500 or any thing anytime soon. The epigenetic clock won't let that happen and in fact, it's telomerase, itself, that won't let that happen because it continuously ages you (your 'age identity/signature' in the methylome) as it fixes stuff by increasing telomere length. (Damocles Double edged sword).

This was also demonstrated with people with tall telomeres, they noticed that, in general, these people were more 'cancer prone' because of the higher 'proliferation' in their cells (as demonstrated in these fit centenarians), it was shown by the number of skin nevis/moles/benign tumors forming; showing that high telomerase enables tumors and 'growth'. Taller telomeres, yes, more fitness, healthier, but more chances of mutation from excessive proliferation (by telomerase). It's funny because the people
with shorter telomeres were experiencing slowed IEAA and EEAA, they were aging slower yet had smaller telomeres; again, this is at the junction of growth/proliferation/metabolistic speed/stem cells/pluripotency/cancers and the epigenetic clock orchestrating much of it by gene silencing or activation/expression in various (non)CpG islands/locusts. As many pointed before, the epigenetic program keeps changing with age, for the worse; and at over a 100, it's bad, real bad, that 'signature program' is not helping you anymore (I.e. tons of pro-inflammatory genes are continuously active, slowly killing you, lil by lil, until it's over. But, I think it's even more complex than that, the epigenome can order mass mitochondrial ending, just like mPTP opening, en masse; you would lose all your cytochrome C in an instant and life ends there, from one day to the next when the epiclock says 'game over - try again (if only we could have a reset button like in video games or 50 lives like Mario)').

So is aging, programmed, yes. Is aging damage, yes. Is it the end, yes; unless we do something about it.

Just a 2 cents.

PS: No, Mrs. Parrish will not be able to live to 1000 years like AdG said, but could live 120-150 healthy by doing her hTERT (other herbs already activate telomerase (ginseng/gingko/astragalus/Cycloastragenol..do you see anyone imm*rtal from that or in the past); and relatively cancer free (as was shown in epiprogramming where partial reversal of epigenetic age using Oct/Sox/Nanog/C-myc/etc genes can revert cell age identity to 0, but there is a possibility of cancer formation during that process depending on how long the exposure (C-myc is a highly cancer forming/proliferation increasing gene), so during the experience if kept below 2 weeks the cancer formation was less; but above 15 days, tumors spontaneously form. So as long you do telomere elongation in 'short burst' you improve health, thus reduce the chance of having a weak immune system by low telomeres in immune cells (leukocytes for example), taller telomeres in immune cells mean more active 'cancer-killing' power immunity (T-cell/NK-cells). But the inverse effect is IEAA/EEAA, as you age in methylome. God really had us figured out, one way or another, and no way to outwit him/it; evolution is million of years of perfectioning, osmosis/balancing and symbiosis. Everything happens in balance, like it should, like it was planned billions of years ago and happened, and here we are, now.

Posted by: CANanonymity at December 6th, 2018 4:35 PM

@CANanonymity so far there is no evidence of a biological limit to lifespan, thus LEV is a realistic goal but I agree we need a robust comphrahensive approach in orde to get their and stay ahead of the game. Telomere elongation is only one part of the puzzle as there are 8 other hallmarks of aging to address

Posted by: Scott e at December 6th, 2018 8:14 PM

@CANanonymity Aging is a quasi-program it is not programmed per se. You should take a look at the work of David Gems to understand what I mean specifically by that. I have said for years now that aging is a mix of damage and program, in the sense that it is a quasi-program.

Telomeres are linked directly to the epigenetic state, Blasco demonstrated this earlier this year by partial reprogramming which resets telomeres. Telomeres are important in terms of their effect on gene expression, their contribution to genomic stability, and their link to Mitochondrial function via the PCG-1a axis. However, I do not think we need to target them directly. I am optimistic about partial reprogramming via OSKM or other methods to fix this issue and a number of other problems.

Posted by: Steve Hill at December 10th, 2018 6:11 AM

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