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A More Subtle Demonstration that Telomere Length is Not a Good Measure of Aging

Researchers here find a disconnect between DNA methylation patterns shown to correlate well with age and processes associated with longer telomere length. Telomeres are caps of repeated DNA at the ends of chromosomes that shorten with each cell division, a part of the mechanism limiting the life span of somatic cells. Their average length tends to shorten with age when considered across large populations in a statistical analysis, but this is a tenuous relationship that has also failed to appear in some smaller studies. Here, it seems that older ages as assessed by DNA methylation can correlate with differences in telomerase, the enzyme responsible for lengthening telomeres, that are associated with longer telomeres.

In any given individual, average telomere length as currently measured in leukocytes from a blood sample is dynamic in response to circumstances; it reflects pace of cell division and the rate at which new cells with long telomeres are generated by stem cells. Unfortunately the large degree of individual and circumstantial variation means that there is little to be meaningfully said about the present value - the information is not actionable in all but rare cases of exceptionally short average length due to disease. The epigenetic clocks derived from DNA methylation measurements are much more solid, repeatable, useful metrics, judging from the evidence to date.

In that broader context, it is interesting to find signs that these two approaches to measuring an aspect of aging are not on the same page, though I think the researchers here overstate the significance of their work and/or engage with a strawman to some degree in their comments. What they have found does fit in with the evidence to date supporting the idea that telomere length is only very loosely associated with aging, with considerable variation between individuals. That is somewhat distinct from the question of whether or not telomerase gene therapies are a useful approach to the treatment of aging or other conditions.

Researchers analyzed blood samples from nearly 10,000 people to find that genetic markers in the gene responsible for keeping telomeres (tips of chromosomes) youthfully longer, did not translate into a younger biologic age as measured by changes in proteins coating the DNA. DNA methylation age is a biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown.

In this genome-wide association study, researchers found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration. Variants in the gene called Telomerase Reverse Transcriptase (TERT) on chromosome 5 that were associated with older IEAA were also associated with longer telomeres indicating a critical role for TERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

"We calculated the epigenetic aging rate for each person using a previously described epigenetic clock method. Next, we related the epigenetic aging rate to millions of genetic locations (SNPs) across all of the chromosomes. Then we studied the SNPs that had very significant associations with epigenetic aging rates. To our surprise, one of these locations was the TERT locus. The finding is surprising because this was not a study of telomere length. TERT is a subunit of the enzyme telomerase, which is widely known because it has been touted as an anti-aging enzyme. Our study highlights the error in the notion that activation of telomerase (as advocated by some) will cure aging. Instead, our study shows that an anti-aging therapy based on telomerase expression would be accompanied by continued aging."

Link: https://www.eurekalert.org/pub_releases/2018-02/hsif-gwa020218.php

Comments

I have always been skeptical about telomeres value as a biomarker of aging, I think there are far better alternatives including Horvath's methylation test.

Posted by: Steve Hill at February 6th, 2018 6:53 AM

This is not new; Horvath was involved with a paper showing this in June 2017, entitled 'GWAS of epigenetic ageing rates in blood reveals a critical role for TERT'. What it actually shows is this: telomerase has a growth factor function, probably because it permits greater proliferation (and hence positively affects regenerative ability) of tissues.

This can be seen in In Vitro studies were TERT immortalized human cells grow faster and have an accelerated epigenetic age (according to the Horvath test) compared to cells that eventually senesce. They are certainly not less healthy however.

In terms of telomere length being an inaccurate measure of age - clearly leucocyte telomere length is a very inaccurate measure of age due to the rapid turnover of this cell type depending on the day to day variation of burden on the immune system. But this does not somehow mean telomeres are irrelevant to aging, or even as suggested by this post, pointing in the wrong direction! You'd need to get biopsies across various tissues first, and get telomere lengths from these, before you could even begin to advance that conclusion.

Posted by: Mark at February 6th, 2018 7:24 AM

Yes, the type of tissue is very important with telomeres. Leucocyte telomere length is an awful biomarker for various reasons and hence why "data" from self-testers claiming age reversal based on leucocyte telomere length should be viewed with skepticism.

Posted by: Steve Hill at February 6th, 2018 9:02 AM

@Steve Hill, likewise, it is not a real hallmark of ageing! Cells in regularly renewed tissues do not divide themselves -- they are produced from stem cell pool whose cells express telomerase all over the life. Cells in not renewed tissues also do not divide and do not loose the telomeres.

Posted by: Ariel at February 6th, 2018 11:31 AM

@Ariel - Lets not start that slapfight again. Data will ultimately prove what is and is not the fundamental damage that underlies aging. Unless it is a massive waste of resources like calorie restriction mimetics, is it worth arguing about?

Posted by: Jim at February 6th, 2018 1:41 PM

Yeah, I am not interested in this slap fight. The data is very clear that telomeres are part of the aging process and that manipulating them changes the phenotype. You are welcome to your pet theories I will stick to the data.

Posted by: Steve Hill at February 6th, 2018 2:39 PM

@Jim: Anyway, you don't have a proof that telomerase therapy is not "a massive waste of resources like calorie restriction mimetics", don't you?

Posted by: Antonio at February 6th, 2018 2:49 PM

LOL of course not because it has not been tested in humans yet! This is how science works, researchers form a hypothesis then they test it. The preclinical data for telomerase obviously has plenty of merit or Agex, CNIO, Telocyte, and others would not be moving towards human trials of it.

Will it work as it does in human cell lines and mice? Maybe and maybe not. But let us find out either way, rather than playing guessing games and engaging in per theory slap fights.

Posted by: Steve Hill at February 6th, 2018 3:47 PM

@Steve Hill: CNIO stands for?

Posted by: Norse at February 6th, 2018 4:36 PM

Centro Nacional de Investigaciones Oncológicas aka Spanish National Cancer Research Centre

Posted by: Steve Hill at February 6th, 2018 5:38 PM

@Steve Hill, I merely look for truth -- can you explain how can telomere shortening occur in postmitotic (like nerves) or not renewed -- which is majority of -- human tissues? Telomere shortening is observed in rare case, for example, in blood or skin -- and it has an explanation -- loosing activity of blood or skin stem cell pool. Hovewer, it does not imply that telomerase therapy has no benefits at all, because it may play another role.

Posted by: Ariel at February 6th, 2018 6:44 PM

Hi all ! Just a 2 cent.

I think that telomere shortening in non-dividing/post-mitotic cells (is not suppose to happen but does) and is due to p53 and damage accumulation. When the telomeres degrade there is a signal (DDR; DNA Damage Response) and this goes straight to activation of inflammation cascade :
p53, ROS, IL-6, ATP loss/mitodysfunction, TNF-a, caspase/cytoC loss and so forth; this erodes the telomere and thus it shrinks despite these telomeres being in a non-dividing post-mitotic cell and normally remaining the same size.
CNS and Neurons show the same, they are post-mitotic, yet lose telomeres length; with age brain damage and stress accelerates telomere loss in neuron (Even if they are non-dividing).
The main contributor is insulin (Alzheimer's diabetes type III) which activates the inflammation cascade (through mTOR) and creates Beta-amyloid formation and neuron death via protein aggregation and ROS overproduction (Which makes for telomeres' DDR and thus, degradation and shortening of them).

''Telomere shortening in the absence of cell division

Chang investigated telomere length in the cardiomyocytes of mice lacking the dystrophin protein at one, four, eight and 32 weeks after birth. He found that, although the cells stopped dividing within one week, the telomeres continued to shorten, losing nearly 40 percent of their length by 32 weeks.

A closer investigation of the affected mouse cardiomyocytes indicated that telomere shortening correlated with increasing levels of a protein called p53 that is known to be elevated in the presence of DNA damage. P53 in turn inhibits the expression of two proteins necessary for mitochondrial replication and function.

"
A new study shows that *telomeres shorten without cell division* in a mouse model of Duchenne muscular dystrophy. Subsequent DNA damage responses and mitochondrial dysfunction are likely cause of heart failure

This is the first time that telomere shortening has been directly linked to mitochondrial function via a DNA damage response in non-dividing cells," said Helen Blau, PhD, professor of microbiology and immunology.

The decrease in the levels of these mitochondrial master regulators led to a reduction in the number of mitochondria in the cell and mitochondrial dysfunction," said Blau. "They make less of the energy molecule ATP and have higher levels of damaging reactive oxygen species. This is what leads to the cardiomyopathy that eventually kills the mice."

Treating 4-week-old mice with a mitochondrial-specific antioxidant limited subsequent mitochondrial damage, the researchers found.

Chang and Blau are interested in learning exactly how the absence of functional dystrophin contributes to telomere shortening in cardiomyocytes. They are also planning to investigate whether artificially lengthening the telomeres could head off heart damage in the mice.

"More research is clearly needed before we attempt to devise any new therapies for humans," said Blau. "But these findings highlight the important role telomeres play in this and possibly many other human diseases in nondividing tissues like neurons and heart muscle."
''

Just a 2 cent.

DNA damage response links short telomeres, heart disorder in Duchenne muscular dystrophy
1. http://med.stanford.edu/news/all-news/2016/10/dna-damage-response-links-short-telomeres-heart-disorder.html

2. Uncoupling of Longevity and Telomere Length in C. elegans
http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.0010030

PS: clearly we are mixture of both, mitotic and post-mitotic tissue, but in both cases, telomeres are lost and shorten : either due to mitotic 'replicative end-problem' or
due to non-mitotic DDR p53/p21/p16 activation.
It's ironic (yet not so much) because both mitotic or non-mitotic end up activating this same inflammation cascade; and it is Required. As ablation of p53/p16ink4/p21 resolves this and cells can be immortalizaed this way. That's because p53 is master regulator of replicative senescence, spontaneous senescence and oncogenic senescence, in Both mitotic and non-mitotic/quiescent cells.

PPS: In the 1. study they do a 'double mutation' on the mice and show that the double-mutants have nearl same features as Duchenne muscular dystrophy disease in humans because: humans have 5-15 kb telomeres, while mice have 40kb telomeres, they have 'leeway/lax' we don't. Thus it is why it affects humans more, but when they put double-mutation those telomeres drop quick in these mice and Resemble the 'human telomeres'; as such they too die of Duchenne dystrophy in the heart cardiomyocyte, like humans.
This demonstrates that telomeres are Both Independent of aging, and Dependent of aging. In humans, we are more dependent of them because we have many dividing/mitotic cells tissue thus we depend on them. Sure fast cell turnover in fast replicating cell tissues nullifies cell telomere loss, but you can an 'overall' loss of telomeres with age in post-mitotic tissues too but it's true it's not the best marker. While post-mitotic ones are not too either because they maintain telomeres since are non-dividing - except they do lose some since stress/ROS damage/DDR does make the telomeres be shrunk (eroding them) in any cell type, dividing or not.

One study had found a good surrogate marker for length of lifespan in the (Birth) telomeres of arterial aortic tissue (like endothelial telomeres at birth) were a good correlation to total longevity of the individual, better than other 'telomere' measurement in like leukocytes, blood or such. My take is that the vascular system is causal to longevity and collagen/ECM in vasculature too. The vasculature 'age' is greatly underrepresented in longevity and major impacting variable. This was demonstrated in long-lived bowhead whales (200 years old MLSP), they have better vasculature preservation, and thus, heart preservation. This is the same thing in long-lived quahogs whom have Long telomeres (preserved and shortening a very slow speed) and a heart that beats for 500 years; vasculature being very important for that to be possible. Short telomere vasculature is bad sign of either post-mitotic DDR/damage or of mitotic replicative senescence.

Posted by: CANanonymity at February 7th, 2018 3:08 AM

@ Ariel - we know that when undergoing damage, tissues can trans-differentiate, i.e. go from a fibroblast into a tissue specific stem cell, and this is triggered by inflammatory signaling. So trying to argue that somatic cells, even in dividing tissues, do not divide, is obviously wrong, and in fact the division between stem and somatic cells is actually a very hazy line. In any case stem cells also lose telomere length with age, because they do not express enough telomerase to cancel out the shortening effect of their division, and also the added shortening caused by inflammation (which damages cells in addition to spurring regeneration). As CANanoymity rightly points out, cells in non (or very slowly) dividing tissues can lose telomere length too, and this is mainly due to inflammation - but what causes this inflammation in a human being? I expect the answer will be that inflammation is rising with age because the body is trying to spur regeneration in old (telomere depleted) stem and somatic cells. If this is correct, we will find that telomeres are absolutely central to aging, and cause a cascade of problems, including in slow or non-dividing tissues. Time and data, as Steve is fond of saying, will prove me wrong or right.

Posted by: Mark at February 7th, 2018 3:32 AM

Like Michael Fossel says "Data is king", we will find out either way soon enough.

Posted by: Steve Hill at February 7th, 2018 4:54 AM

@CANanonymity, @Mark, thank you for your explanation. Hovewer, even from your info it is clear that the telomere shortening is not a cause but a consequence of primary ageing processes. Either loosing stem cell activity or DDR. They both can be consequences of inflammation which has various sources -- mainly senescent cells, glucosepane crosslinks and lipofuscine. These 3 causes are much more 'primary' because they can only accumulate and cannot be cleared out by our organism, and thus should be used as direct biomarkers of ageing.

@Steve Hill, pure data cannot prove anything, it is just a source. Only argument can do. See epistemology of Karl Popper and David Deutsch.

Posted by: Ariel at February 7th, 2018 6:00 PM

Nonsense ariel.we will see what the study data shows everything else is a pointless slap fight and waste of time.

Posted by: Steve Hill at February 8th, 2018 2:11 AM

Very good comments by all above on a difficult longevity subjects. I would add one other longevity factor and that is the FOXO gene. FOXO3A protects stem cell pools, and if you inherited good FOXO3A SNP alleles, you will have increased potential for longevity, its as simple as that in my opinion. And organisms like HYDRA that are immortal because of their FOXO gene.

Posted by: Biotechy at February 8th, 2018 3:47 AM

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