Telomere Erosion is Complex, But Looks More Like a Measure of Damage than a Source of Damage

Telomeres are repeating DNA sequences of that cap the ends of chromosomes. A little of that length is lost when DNA is copied during cell division, and telomere length is thus a part of the system of linked mechanisms that limits the replicative life span of ordinary somatic cells. The vast majority of cells in the body are somatic cells, and they are subject to this Hayflick limit: they can only divide a few dozen times before self-destructing or lapsing into a senescent state. Tissues consisting of somatic cells are maintained by stem cell populations that deliver a supply of fresh somatic cells with long telomeres: when a stem cell divides one of the daughter cells remains a stem cell while the other differentiates to become a somatic cell of a specific type.

How do stem cells continue to deliver long-telomere descendants if they are consistently dividing? They lengthen their telomeres through the activity of telomerase, an enzyme whose chief identified function is to add more repeating DNA sequences to the ends of telomeres. In our species telomerase is only active in some circumstances, such as in stem cells and cancers, but many other species, including other mammals, have somewhat different telomere dynamics. That is a basic sketch of a very complex system: cells have a countdown mechanism, tissues are largely made of cells that cannot adjust that mechanism, and a small, select group of cells that continually reset their own countdown are responsible for building new cells as the old ones run down and die.

Average telomere length, proportion of very short telomeres, and other similar statistics are usually measured in immune cells present in a blood sample. Average telomere length decreases with advancing age, but also with illness. On a fairly short time frame this measure can move up and down: the erosion over a lifetime is a long slope made up of a lot of oscillation about a mean. A range of research and development over the past decade has focused on restoring telomere length as a potential life-extending treatment, based on the idea that loss of telomere length is a contributing cause of aging. A number of early attempts failed to get anywhere, but a few years ago researchers demonstrated improved health and life extension in mice via artifically increased telomerase activity. The root causes are not yet firmly pinned down, but probably have a lot to do with increased stem cell activity and consequently better tissue and organ maintenance over the course of degenerative aging. That, of course, is not the same thing as merely having longer telomeres on average in somatic cells.

The bulk of the rest of the evidence regarding telomere biology looks very much to me as though average telomere length is a very indirect reflection of the state of our biology as a whole. How damaged are we? How active are our stem cells? What is being measured by average telomere length in white blood cells is some amalgam of the pace of cell replacement by stem cells, state of immune system health, and the level of underlying damage that drives changes in those biological systems. There are counter-arguments to that view, such as the recent discovery that telomeres seem to influence gene expression profiles across the genome differently depending on their length.

Here is an open access paper that looks at some of the recent research into telomere length and its role in our biology, concluding that "recently obtained knowledge shifts the telomere paradigm from a simple clock counting cell divisions to a more complex process recording the history of stress exposure within a cell lineage."

Telomeric aging: mitotic clock or stress indicator?

Telomeres are located at chromosomal ends and allow cells to distinguish chromosome ends from double-strand breaks and protect chromosomes from end-to-end fusion, recombination, and degradation. Telomeres are not linear structures, telomeric DNA is maintained in a loop structure due to many key proteins. This structure serves to protect the ends of chromosomes. Telomeres are subjected to shortening at each cycle of cell division due to incomplete synthesis of the lagging strand during DNA replication owing to the inability of DNA polymerase to completely replicate the ends of chromosome DNA ("end-replication problem"). Therefore, they assume to limit the number of cell cycles and act as a "mitotic clock". Shortened telomeres cause decreased proliferative potential, thus triggering senescence.

Telomere length is highly heterogeneous in somatic cells, but generally decreases with age in proliferating tissues thereby constituting a barrier to tumorigenesis but also contributing to age-related loss of stem cells. Telomerase maintains telomere length by adding telomeric DNA repeats to chromosome ends in prenatal tissues, gametes, stem cells, and cancerous cells. In proliferative somatic cells, it is usually inactive or expressed at levels that are not high enough to maintain the stable telomere length. Repair of critically short ("uncapped") telomeres by telomerase enzyme is limited in somatic cells, and cellular senescence, apoptosis and/or a permanent cell cycle arrest are triggered by a critical accumulation of uncapped telomeres. Shortened telomeres have also been observed in a variety of chronic degenerative diseases, including type 2 diabetes, cardiovascular disease, osteoporosis, and cancer. The specific molecular mechanism by which short telomeres trigger the development of diseases is, however, not yet determined. It has been proposed that telomere shortening per-se might not be a direct signal for cell cycle arrest, but rather the consequence of telomere loss. It can promote a pro-inflammatory secretory phenotype, in turn contributing to a variety of age-related diseases.

Replicative attrition, however, is not the only explanation for age-dependent telomere shortening. Some studies demonstrate that this process can be non-replicative and significantly stress-dependent because of the deficiency of a telomere-specific damage repair. Oxidative stress is one of the most important stress factors causing telomere shortening. Telomeric DNA is known to be more susceptible to oxidative damage than non-telomeric DNA. In human cell lines, telomeres generally shorten by 30-200 base pairs at each round of DNA replication, but only approximately 10 base pairs of this reduction are a consequence of the end-replication problem; the remaining loss is likely owing to oxidative damage.

The complexity of processes underlying age-related telomere erosion came from several longitudinal studies of telomere dynamics in vivo. Traditionally, it was assumed that telomeres are stable structures, which may be changed only in unidirectional way - shortening over the lifetime. Today, however, it has become increasingly clear that telomeres shortening over time in an oscillatory rather than linear fashion and they may be either shortened or lengthened under certain conditions. Several pilot studies indicate that treatment procedures targeting to reduce stress, e.g. meditation, along with the enhanced physical activity and changes in dietary patterns, can slow or even reverse telomere shortening owing to the elevated telomerase activity. The elongation of telomeres may be caused by the telomerase-mediated extension or appear due to the "pseudo-telomeric lengthening." The latest is due to the fact that, since telomere lengths are commonly measured in a mixed leukocyte population, mean telomere length can increase because of a redistribution of cell subpopulations, i.e., change in the percentage of various cell types in the blood samples.

Given data from recent studies, a concept that replicative senescence is a "clocked" and stepwise process seems doubtful, and repeatedly reported reproducibility of both replicative lifespans and rates of telomere shortening could be the result of stochastic rather than programmed events. In other words, it seems that telomeres can be an indicator of stress-induced damage level rather than a mitosis "counter." Moreover, considering the fact that oxidative stress represents a common causative mechanism for both age-related telomere shortening and age-associated disease, there are reasons to believe that relationships between telomere length and morbidity or mortality are non-causal, and telomere length can be an indicator of previous exposure to oxidative stress that may, in turn, cause both greater telomere shortening and higher risk of chronic disease. Thereby, perceived stressful events, though correlated with telomere length, may likely have independent effects on health and longevity. By summarizing recent research findings, it is concluded that recently obtained knowledge "shifts the telomere paradigm from a simple clock counting cell divisions to a more complex process recording the history of stress exposure within a cell lineage." This point of view, based on the accumulated evidence, appears plausible, and requires further investigation.


Telomere length does influence gene expression via TPE and TPE old so as they shorten different genes are silenced or expressed. This combines with histone coding and Methylation patterns which then contributes to the aged phenotype.

Damage starts the cascade off and the rest is a downward spiral that follows a programmed set of increasingly desregulated function IMO.

One thing which does not appear to have been answered, in parabiosis and blood exchange where rejuvenation is seen, are factors in the blood causing changes to telomere lengths too? If so it would explain why some of the rejuvenation occurs as the blood has changed gene expression via TPE changes and Methylation/histones. I have trawled all the papers and not one of them appears to have checked changes to Telomeres.

Posted by: Steve H at April 11th, 2015 8:49 AM

There seems to be a lot of wishful thinking around Telomeres, with people hoping that by simply increasing their length a fountain of youth will follow. What confuses me is that the SENS foundation's proposal for reversing aging isn't that much more complex (requiring technological demonstrations in 7 rather than 1 area). Yet people don't seem to get so fired up about it?

Maybe this is just because I am still in my 30s and feel (rightly or wrongly) that I have a bit more time to wait for things to pain out. If I was north of 50 maybe I'd be more eager to believe that a single treatment will be a panacea.

Posted by: Jim at April 11th, 2015 5:42 PM

Well, I am 50 and have never bought into the idea that telomere shortening is a cause of aging. The reason is two-fold. One, aging affects the tissues that is comprised of cells that replicate slowly (brains, hearts, muscle, etc.) as much as those that replicate rapidly. Second, as this paper suggests, telomere shortening is a regulated process that can be up and down regulated as conditions require.

This is all good work because it rules out an additional potential cause of aging, thus narrowing the potential causes of aging to those as specified by the SENS concept (mitochondrial DNA dysfunction, lysosomal accumulation, etc.).

Posted by: Abelard Lindsey at April 12th, 2015 10:32 AM

No one said it was a magic bullet but gene expression is definitely influenced by telomere length. This is the telomere positioning effect and it very likely influences the local phenotype in combination with genes expressed via methylation and histone coding. Length can and does fluctuate and likely is influenced by youthful systemic milieu too as seen in parabiosis where actual rejuvenation is seen.

Changing gene expression brought on by shortening telomeres may well contribute to the downward spiral but it's not the only cause. A way to deal with telomeres would be reset the local phenotype which would restore efficient function. The work of irina conboy partly funded by sensrf is investigating how phenotype can be chranged via factors so epigenetic control is a viable Pathway to reverse some of the damage and or dysfunction. Telomeres are part of that epigenetic system and their length is relevant. Longer telomeres = favourable gene expression, protection from cancer and increased genomic stability, short telomeres = replicative senescence and worst case negative factors and gene expression via the sasp effect.

I don't believe telomeres need targeting specifically however I believe they will change according to the local environment. Ergo change the local phenotype and the telomeres should in theory adapt with it.

Posted by: steve h at April 12th, 2015 1:32 PM

I don't believe telomeres need targeting specifically however I believe they will change according to the local environment. Ergo change the local phenotype and the telomeres should in theory adapt with it.

This is what I've thought over the past few years. Even aerobic exercise is known to extent telomere length. Some of the SENS therapies will extend telomeres as side effect.

Posted by: Abelard Lindsey at April 12th, 2015 1:38 PM

Aberlard exactly! Exercise and I believe even meditation has shown to fluctuate telomere length. I recently wondered if exercising actually changes gene expression for a while hence the effect on telomere length for a short period.

The strange thing is of all the Parabiosis/HPE experiments to date no one has measured changes in telomere length. Old cells moved into young environments rejuvenate so that surely must mean telomeres increase too. Of course some cells can replicate indefinatly given the correct phenotype which is why parabiosis and HPE and even GDF-11 can rejuvenate as they change the local phenotype. I think there is a great deal of mileage in that pathway of research and it would work well with SENS to address some of the 7 damage types.

As I have said before I believe aging is a damage/program hybrid and Epigentics could be used to great effect in turning around many aging issues. Not everything of course but the stuff that cannot be fixed SENS is working on.

Posted by: Steve H at April 12th, 2015 1:49 PM

Ok so the Cancer protection is debateable but TPE and TPE-OLD still influence the local environment. I suspect that Telomeres are not the central factor at work though and fluctuate acording to their local phenotype. Circulating factors are likely a far bigger influence on the systemic environment as they program cell age via histones and Methylation etc... This is why we are seeing quite promising results from parabiosis, GDF-11, Oxytocin etc...

If you can restore the Stem Cell Niche to a younger phenotype anyway its irrelevant as the body will just produce more daughter cells to replace those lost. As I understand it the tricky part is making the Stem Cell Niche youthful so Stem Cells resume efficient repair and function (Conboy beyond parabiosis).

Posted by: Steve H at April 13th, 2015 3:30 AM

And no restoring Stem cells and systemic milleu to a younger phenotype is not going to stop aging completely but it is going to help.

Posted by: Steve H at April 13th, 2015 5:18 AM

An interesting paper that shows just how Telomere length does effect gene expression and as they shorten genes expressed increase considerably, this presumably then guides the cell to senescence and potentially SASP.

Interesting how TERT reverses at least 84%-86% of up and down regulated genes showed reversion.

Posted by: Steve H at April 17th, 2015 5:56 AM
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