Telomere Length and the Epigenetic Clock Do Not Correlate with One Another

Average telomere length, as presently assessed in immune cells taken from a blood sample, is a truly terrible basis for measuring the pace of aging. Only in large studies is a statistical decline with aging seen, and even then not in all studies. For any given individual this measure is very dynamic, reflecting short term immune system changes that have little to do with aging - and thus a specific measure or set of measures isn't all that actionable.

The study here, in which no correlation was found between telomere length and an epigenetic clock, should be taken as a reinforcement of this point. Despite the challenges remaining in the development of epigenetic clocks, such as the question of what exactly it is that they do measure about aging, they do reliably correlate with risk of age-related disease in individuals and small study groups, which is more than can be said for telomere length. The epigenetic clock is a far, far better foundation for a useful biomarker of aging, one that can be used to quickly assess the results of alleged rejuvenation therapies, than is the case for telomere length.

Aging is accompanied by a range of DNA modifications. Telomere length, which shortens as a consequence of DNA replication, has been widely accepted as a biomarker of aging. While being inversely correlated with chronological age, telomere length is also associated with a range of age-associated phenotypes and clinical diseases. Recently, a novel candidate epigenetic biomarker of aging has been shown to predict an individual's chronological age with high accuracy: the epigenetic clock is based on the weighted DNA methylation fraction of a number of DNA methylation (DNAm) age correlates with cell passage number in vitro and can be predicted across different tissues, including non-proliferating ones in vivo, suggesting that DNA methylation is not exclusively reflecting mitotic age.

This is in line with the finding that DNAm age and relative leukocyte telomere length (rLTL) were independently associated with chronological age and mortality. The few existing studies found no supporting evidence of a significant association between rLTL and DNAm age or reported a weak association. Moreover, rLTL was reported to have a lower predictive power in estimating chronological age in comparison to the epigenetic clock.

While the number of studies reporting a positive correlation between DNAm and chronological age in a range of different study populations rises, there is accumulating evidence suggesting that DNAm age somewhat reflects biological age. Under the assumption that DNA methylation age reflects biological age, calculating the deviation of the epigenetic age estimate and the chronological age gives rise to a second potentially clinically relevant measure: DNAm age acceleration. Here we aim to explore the association of rLTL and the epigenetic clock variables, DNAm age and DNAm age acceleration, in the context of cardiovascular disease in the LipidCardio cohort.

Both rLTL (0.79 ± 0.14) and DNAm age (69.67 ± 7.27 years) were available for 773 subjects (31.6% female; mean chronological age 69.68 ± 11.01 years). While we detected a significant correlation between chronological age and DNAm age, we found neither evidence of an association between rLTL and the DNAm age nor rLTL and the DNAm age acceleration in the studied cohort, suggesting that DNAm age and rLTL measure different aspects of biological age.



the only reliable method of telomere length for biological age measurement? Count the percentage of senescent cells.

Posted by: SilverSeeker at July 4th, 2019 10:22 AM

But not all senescent cells express the same markers; also not all senescent cells have short telomeres.

Probably the best we can do at present is the percentage of short telomeres as measured by Lifelength. It's still leukocytes, so you'd need a fair few measurements to filter out the noise. Ideally we need to sample a tissue type that isn't SO dynamic.

Posted by: Mark at July 4th, 2019 10:48 AM

Having said all that, short telomeres are both statistically and mechanistically linked to poor health outcomes, even only looking at leukocytes. Whereas methylation changes could easily turn out to be a consequence rather than a cause of aging, even though their correlation with biological age is stronger than LTL.

Posted by: Mark at July 4th, 2019 10:53 AM

I found Jerry Shay's video from "Undoing Aging 2019" interesting where he stated that it was the critically short telomeres that were the problem. Another problem was that the current way telomeres were measured couldn't capture that there were some that were shorter. He has apparently developed an assay to discover if the short ones are there.

Posted by: Lee at July 4th, 2019 1:41 PM

Could you elaborate about leukocytes, please? As it is something that is getting tested so often, a low number of leukocytes is bad while a high number might be good? Also...mine are always low, so that's why I am interested...

Posted by: Chris at July 4th, 2019 1:58 PM

Hi there! Just a 2 cents.

Mark hit the nail on it, total number of telomeres (short) in the grand total determines lifespan just as well as Horvath clock but not to same precision. This was demonstrated in long-lived birds telomeres - faster aging one accumulate far more short telomeres. And the longest lived bird kept More Tall telomeres (both quantitative (number of tall ones) + qualitative (size of telomeres/keep them tall) than short ones. The only exception is albatros birds that have taller telomeres as they age, yet they die at 35 or so; this means predation removing the 'individuals too quickly' and thus 'obscuring results'. Most likely, these birds are simply killed/eaten or something - but if in lab, protected they might live 100 years easy...just like a blue ara parrot (the record is a 111 years old amazone ara parrot - and they keep their telomeres tall). I will take long lived parrots over short-lived mice with long telomeres, faster aging mice - still, have faster telomere loss. Likewise for people with JGPS progeria (losing 10x times more telomeres than regular humans (50bp vs 500bp = 15y vs 122y). And same thing with dogs, they lose HGPS human values = 500bp = 15y lifespan for dog.
In fact, mice that obtain telomerase/hTERT (hTERT Tg Mice) have an 'averaging 'up'' of all the shortest ones...this means telomerase immediately acts on the shortest ones to prevent dangerous telomere uncapping. It does not touch the tallest ones because there anti-elongation mechanism at the telomeres once it reaches a certain length (TRF1, TRF2 are the main inhibitors of 'more elongation', thus they act as a 'break' to stop telomerase in its 'elongation process' once the telomere is sufficiently tall). These mice see improvement in health, that's because accumulation of short unstable telomeres causing telomere uncapping/DDR/telomere demethylation and thus, oxidative stress, this will shows as nuclearDNA DSBs/SSBs or mitochondrialDNA 8-oxo-dG lesions or deletions even (and thus improvement of mitochondrial ETC/OXPHOS Complexes IMM function = health improvement). Once there is a sufficient amount of short telomeres, the organ can dysfunction and cause sudden death (or disease).

Telomere methylation is directly correlated to DNA methylation and both go hand in hand. Attack one or the other and you cause aging, currently, both are attacked. Telomeres become short and demethylated, while centromeres or sub-telomeres can also demethylate; decompacted loose chromosomes (uncoiling) will cause aging advancement as the 'genes' are 'released/unsilenced'...-> inflammation -> chronic oxidative stress (not hormesis) -> unrepaired DNA damage/DNA loss -> health loss/disease/age acceleration.

Just a 2 cents.

PS: Yes, your leukocytes telomeres length matters Greatly...much more than this article is saying; leukocytes telomeres - at all time points in life - dictate your life. So better keep them high; people will weaek immune systems have short telomeres leukocytes and mortality can be predicted 'ahead'...because they will have immune senescence and die of that or of cancer (immune senescence causing cancer because no more immunity; many short telomere leukocytes = high mortality/ immunosenescnce/cancer (your chances of becoming centenarians are much smaller; centenarians have Taller telomeres in white blood cells/(better immunity activity - you need it to live long, your wbc leukocytes are crucial for that) not shorter). There was a recent study that verified telomere length Over Whole thousands of people..and clearly you can see a very linear 'dropping' with All organs. Going from 10-8kb down to 3-5kb telomere length at death.

We cannot lose telomeres to reach LEV, impossible; telomeres must come back up or eliminate shortens one

Posted by: CANanonymity at July 4th, 2019 3:11 PM

Hi Chris! Just a 2 cents. I don't want to be a bringer of bad news, it is important to improve your immune system, low leukocytes is bad in long term; and will compromise health/immunity/immune system, which exposes to cancer/pathogens/viral invasion. Studies showed that people, with age, have a loss of total numbers of blood leukocytes...thus, it is important to, immediately, work on it to improve it - work your immune system; it's crucial to your life/span.

Just a 2 cents.

Posted by: CANanonymity at July 4th, 2019 4:24 PM

"telomere length is greater in the high-performing centenarians; and (c) telomerase activity following stimulation is greater in the high-performing centenarians"

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

Posted by: Lee at July 4th, 2019 4:59 PM

@Chris - don't worry about leukocyte number too much; that is something separate to leukocyte telomere length, and a low count, in old age at least, is correlated with longevity (probably because hyper active immune response in the old is bad, just as under response is also bad).

At the moment telomere blood tests are the only ones that are easy to do (I don't fancy giving bone marrow, do you?), but red blood cells don't have DNA, so you have to use the small amount of blood cells that do (i.e. white blood cells). There is a correlation between LTL and telomere length in other tissues, but it's weak, probably because of the noise in LTL, which go up and down all the time depending on stress, infection, etc.

@CANanonymity - it is interesting what you say about Albatrosses, they don't appear to age, just get stronger and fly further with age. Which makes sense when you say they maintain their telomeres. It is not clear what kills them. Maybe there is a limit on food supply.

Mice do accumulate short telomeres, even with their active telomerase. And this is correlated with their health outcomes. See this Blasco paper:

So obviously mice lose telomeres at a prodigious rate, too fast for them to replace. Whereas humans lose telomeres much more slowly, but have no replacement mechanism.

Posted by: Mark at July 5th, 2019 5:21 AM

@Mark / CANanonymity

Thanks for the info!

Posted by: Cris at July 5th, 2019 2:48 PM

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