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Telomere Length as Presently Measured is Not a Useful Biomarker of Aging

Average telomere length is currently usually measured in leukocytes obtained from a blood sample. When considering the statistics of a sizable population, average telomere length tends to trend downwards over a lifetime. Telomeres form a part of the complex mechanism that limits somatic cell replication: they shorten with each cell division, and cells with very short telomeres self-destruct or become senescent, ceasing to replicate in either case. Stem cells deliver a supply of new somatic cells with long telomeres to make up the numbers. So average telomere length is a blurred measure of stem cell activity and pace of cellular replication - and in the immune system the latter is highly variable, depending on the current state of health and presence of threats. Telomere length thus varies considerably between individuals of a similar age and health status, and also over quite short periods of time for any given individual. Even in smaller groups, the statistical association with aging can be weak to non-existent. All of this means that telomere length isn't all that helpful as a guide for medical decisions or as a way to evaluate the state of aging.

The associations between mortality and traditional biomarkers such as blood pressure, cholesterol, and body mass index (BMI) weaken with age. The search for a definitive aging biomarker is encumbered by the heterogeneity of cellular aging. Post-mitotic cells are not subjected to the replicative stresses experienced by mitotic cells; therefore, some tissues exhibit greater biological aging than others. The highly variable human lifespan highlights that the mere passage of chronological time is not an effective, isolated measure of aging. Biological aging refers to processes that proceed independently of chronological aging that reduce organismal viability and increase vulnerability. Telomeres are regarded by many as the heir apparent of aging biomarkers, recording both chronological and biological age.

A growing body of evidence also indicates that telomeres are responsive to habitual physical activity (PA). Despite the telomere's popular designation as a mitotic clock, the relationship between telomere length and aging is inconsistent and does not meet the requisite biomarker criteria. Closer examination of the association with PA also reveals inconsistencies and methodological confounders. The clinical and public interest in the PA-telomere association is predicated upon several tacit assumptions: (i) mean telomere length is causally associated with biological aging and age-related pathologies and (ii) PA can lengthen mean telomere length and that in doing so; (iii) PA will reduce biological aging and disease burden.

The proposed associations with aging and exercise are biologically plausible. Telomere length holds tantalizing promise as a biomarker; however, a host of evidential inconsistencies and paradoxes must be addressed. Leukocyte telomere length (LTL) is highly variable at birth, a metric influenced by genetic inheritance and paternal age at conception. It reflects lifelong exposure to oxidative and inflammatory burden yet childhood LTL has more predictive fidelity than LTL in adulthood or old age. Oscillating throughout the lifespan, even inexplicably lengthening despite advancing age, mean LTL differs between genders. Attrition rates also differ between genders and appear dependent upon initial telomere length. Shortening trajectories can be further influenced by variable exposure to a wide range of environmental stimuli. The association between PA is more questionable with 50% of studies failing to find a significant association.

Investigations into plausible mechanisms have returned promising yet inconsistent findings. The prevailing consensus is that exercise-induced reductions in oxidative stress and inflammation likely mediate the effect. The possibility that LTL is a physiological epiphenomenon cannot be excluded. Changes in LTL may simply be coincidental processes that reflect, without directly influencing, the primary mechanism. It is likely that telomere length per se is significant only in so much as it reflects the resultant phenotype via pathways such as senescence-associated inflammation. It has been proposed that evolutionary pressures have fine-tuned telomere length to reduce the risk of short and long telomere pathologies, namely atherosclerosis and cancer. The long-term consequences of manipulating telomere length are not well understood and should therefore be approached with equal measures of enthusiasm and evidence.

Link: http://dx.doi.org/10.3390/ijms18122573

Comments

So glad I have not yet invested any time, money or energy into telomere lengthening drugs. I do exercise 4 times a week. Inflammation is probably key here, from SASP perhaps. I wonder if we can just find a way to get our bodies to produce more stem cells or reset cells to an earlier state somehow.

Posted by: Nathan at December 29th, 2017 7:47 AM

Yet, telomere length and telomerase activity are associated with cell immortality in cancer in most cases. Thus, in many instances, cell immortality requires an adequate telomere length through sufficient telomerase activity. This implies, that, indeed, that cell senescense,death, and individual mortality and morbidity are inversely related to telomere length and telomerase acivity.

Posted by: C.V. Compton Shaw at December 29th, 2017 10:06 PM

Hi all, just a 2 cent,

I think telomere research is flawed when it looks at snippets of time and tries to make any conclusion, like saying 'your telomeres did not change in a month, thus telomeres are useless markers'. It's lacking the big picture, whole life LTL shows a different story : telomere shrinking as a natural process by end-replication problem and a lack of (enough) telomerase to counter somatic telomeric DNA loss. While stem cells might differentiate into tall-telomere cells - but (most) the stem cells themselves are bound by telomere loss/shriking mechanism and don't evade that either for they do not use telomerase (sufficiently) for themselves to counter their Own telomeres' loss, only during the differentiation process do they use telomerase to lengthen telomeres when in these new differentiated cells - not Themselves(except special primordial germ cells in sexual organs whom rely on telomerase for infinite replicative potential).

Studies have shown that telomeres Can shrink or Not during bouts of diseases/when health compromised - Both. THis means, there are Dependent and Independent pathways from telomere control (and certain pathways affect teh outcome, Spontaneous Senescence (stress-induced senescence) being the major one (DNA oxidation, (DNA Damage Response/DDR), overt ROS increase etc...); this pathway can create senescence with little telomere involvment or shrinking; studies have shown that Senescence can happen with No oxidative processes happening; thus 'signals' can 'activate' senescence.

Such as is the case for Oncogenic senescence, where TNF-a, IL-6 activate p53 to try to destroy tumors but in doign so accelerate senescence of other healthy cells (through SASP and through cancer cells highjacking p53 and telomerase)). These are much more 'Signals' that alter the epigenome and why we see acceleraeted epigenetic aging in cancer patients while the telomeres might not be showing that much difference.

While replicative senescence is the one involved with telomere control and, especially, in Total Maximal Lifespan of the human; because in humans it is the 'limiting/limit' mechanism that catches you over 120 years old. Your cells enter replicative senescence after replicating for your entire life; and there is an end to it - because telomeres are counters of replicative 'rounds' - they shrink (by end-repication problem) and thus, Less replicative 'life' left, until division ceases (when the telomeres are sufficiently low enough and 'signal' the cell to be mTOR-geronconverted to replicative senescence))).

Plus, if a 115 year old woman has 2-3kb LTL it is all I need to know about telomeres,
while a Progeria HGPS has 5-6kb LTL in less than 15 years by losing TTAGGG in order of 500 bp/y(accelerated aging syndrome))). This demonstrates that telomeres are a major limiting factor/causal in your maximal lifespan - not in what happens in between; this is the 'health/disease' department and 'other' types of senescences (not the telomere-replicative one that is).

Also, studies showed that people whom had small LTL where much more likely to be diseased and dying within 10-15 years later - this could be verified and showed taht morbidity/mortality rose strongly as your LTL shrank. LTL is part of your immune system, and immune cells depend on telomerase (and why WILT is a double edged sword, though if done once per 10 years it'S not so bad though as long as you don't diminish your immune system, for you will get cancer - Despit trying to Stop Telomerase acces in tumors. Without your functioning leukocyte/NK/T-cell/macrophages...no more cancer Killing power; cancer patients oftenly show weaken immune system. I know, my mother died of cancer very young (56 years old) and her immune system vanished during her battle. The immune system is Critical to protecting against cancer because it works in tandem with TNF-a/IL6/IL10/INF-g/p53/p16/cytokines/working with immune system...all of this is part of the immune system and is needed to stop cancer formation (ROS are increasingly produced through TNF-a/IL6/p53 and are intended to destroy tumors; at the same time they destroy healthy cells (by ROS) which is why TNF-a activation, macrophage/monocyte/immune system inflammatory activations are a compensatory response against cancer (kind of like fighting fire with fire))).

Thus, telomeres are very important (not the be all end all of course), telomeres shrinking is a problem. And this study shows that, sometimes, there is Lenghtening of LTL in certain cases instead of just always shortening; demonstrating that telomerase can have access somehow, if sufficient.

One more point polar clams vs temperate clams telomeres; the longest lived-ones keep tall telomeres (And is the reason why they can live so long) while the short lived-ones don't and display a rapid telomere loss (just like in mice; while mice have very long telomeres but defective genome/are made for sexual reproduction not DNA stability/lack of DNA repair and lose redox; thus they don,T even 'reach' their replicative potential - while Naked Mole Rats (NMRs) other rodents, do. Because they keep the same elements that allow humans to reach 122 and thus why a mice lives 2 years and naked mole rat lives 35 years; and progeria HGPS human lives 15 years while a centenarians lives 122 years old; and a clam can live 5 years in temperate region or live 500 years in polar regions).

Posted by: CANanonymity at December 29th, 2017 11:52 PM

Yes agreed, telomeres are very important, it's just a pity there is no easy way to get a good measurement of their length across the proliferative cells of our body (not just in blood). If you're just using LTL you literally need to get measurements every month minimum to see real trends and not just fluctuations.

Posted by: Mark at December 30th, 2017 6:38 AM

Researchers concluded this about telomeres: "we were surprised to find evidence for inflammation as driver of ageing up to (semi-)supercentenarians, while telomere length/cell senescence was no longer predictive for successful ageing once longevity had been achieved. In a previous study comprising only 38 participants, longer telomeres were associated with better health and independence in centenarians. However, other studies had shown before that telomere length loses its predictive power as a biomarker of mortality and morbidity risk at ages above 75 years
Our study showed that over a very wide age range from 45 to 115 years, including unprecedentedly large numbers of the extremely old, inflammation is an important driver of ageing that might be amenable to future pharmacological intervention. Accordingly, designing novel, safe anti-inflammatory or immune-modulating medication has major potential to improve healthy lifespan.
EBioMedicine
Volume 2, Issue 10, October 2015, Pages 1549-1558
https://www.sciencedirect.com/science/article/pii/S2352396415300815

Posted by: Bill Sardi at December 31st, 2017 8:12 AM

Yes, telomere length is a biomarker of your biological age, and should be measured periodically, say every 10 years to see if you are ahead of the aging curve or behind it. I have the longevity producing PAI1 mutation that results in 10% longer telomeres than the normal population. Now people without this gene mutation have shorter telomeres, and if we could knockout the bad allele for the SERPINE1 gene that produces the PAI1 SNP, those people could get longer telomeres and longer lifespan. Perhaps CRISPR technology could be used to accomplish this beneficial genetic manipulation. There are many diseases that tax the immune system and permanently shorten telomeres. If the medical profession would employ the leucocyte telomere biomarker, the Doctor's could see if you have short telomeres, and find out why, and correct it if at all possible.

Posted by: Biotechy at December 31st, 2017 10:05 AM

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