Theorizing on Interactions Between Telomeres and the DNA Damage Response in Cellular Senescence

Cells can enter a senescent state in response to damage, ceasing to divide. This reduces the risk of cancer under most circumstances, but is also a part of the wound healing process. This isn't all good, however. Senescent cells secrete factors that harm surrounding tissue function over the long term, and the growing numbers of these cells with age is one of the causes of age-related disease and dysfunction. Researchers here look more deeply into how various mechanisms in a cell conspire to cause senescence. They are aiming to produce a more unified view of the varied entry points to this cell state. You should scroll down in the open access paper to the diagram near the end - this is a collection of mechanisms that really benefits from a visual explanation:

Genome integrity is preserved by the DNA damage response (DDR) that, in the presence of DNA damage, arrests the cell cycle progression while coordinating DNA repair events. If damage is not resolved, cells can enter into an irreversible state of proliferative arrest called cellular senescence. In the past years, a strong link between telomere-initiated cellular senescence and organismal ageing has emerged, [where aging is] associated with accumulation of markers of cellular senescence and DDR persistence at telomeres.

Since the vast majority of the cells in mammals are non-proliferating, how do they age?Telomere-initiated cellular senescence seems to be a plausible mechanism to explain the ageing-associated functional decline of proliferating tissues in vivo. However, it is reasonable to assume that some other mechanisms may be in place in non-proliferating cells in which no telomeric attrition due to the end replication problem is expected to occur, either because these cells are quiescent or differentiated. Surprisingly however, we and others have shown that telomeres might have a central role in senescence establishment independently from their shortening.

In these reports, random DNA damage [leads] to DDR activation that preferentially persists at telomeres over time. Cells with persistent DDR activation show a senescent phenotype that cannot be prevented by exogenous expression of telomerase, further excluding a contribution of telomere shortening. The mechanism proposed to explain this phenomenon is the suppression of effective DNA repair at telomeres by TRF2, a telomeric DNA binding protein. Consistent with this model, DDR activation at telomeres is more frequent in mouse and baboon tissues from aged animals, when compared with their young counterparts. This observation also suggests that having long telomeres may have an important drawback, since more telomeric DNA can offer a wider target for random DNA damage that cannot be repaired. Indeed, in different mammalian species, telomere length and lifespan are inversely correlated.



Would this suggest then that we cannot repair the damage by intervention. How would we go about bypassing this problem and ensuring cells remain healthy and able to replicate?

Posted by: Steve H at December 18th, 2014 9:59 AM

You periodically kill the senescent cells that have gone into cell cycle arrest and you maintain the telomeres of healthy cells by outside intervention. There are paths to doing both that need development.

Posted by: Gary at December 18th, 2014 10:32 AM


So basically Senescent cell targeting ala ApoptoSENS?

When you say outside intervention do you mean something like adding Stem Cells with fresh Telomeres to the body or do you mean increasing the Telomere length of existing cells at the site?

I am aware of a number of researchers involved in Telomere renewal so that's potentially good news. I know that some are hoping to activate Telomerase to that end but there is the ongoing debate about that causing Cancer or restored Telomeres in fact protecting against it.

Plus Sens is involved in developing something to target the Senescent cells so lets hope they make good progress with that.

Posted by: Steve H at December 18th, 2014 11:37 AM

I believe that transient induction of hTERT to lengthen the shortest of the short telomeres (Ch 17 in humans) should be attempted as a SENS-type therapy to repair the damage associated with short telomeres. There are several approaches that might be considered; a literature search will highlight options.

I don't believe that transient induction of hTERT will in any way contribute to cancer so long as the induction is temporary and not constitutive. "Goldilocks Zone" telomere lengthening is what should be our goal – see Wright and Shay's most recent Nature paper on the telomere position effect ("TPE-OLD").

A number of groups and companies are also studying how to delete senescent cells using biological or small-molecule therapies. The next year should see some progress.

Posted by: Gary at December 19th, 2014 1:20 AM

That sounds promising, I know at least one company that is planning introducing hTERT to the human body to that end and it sounds like there are a number of others by what you are saying.

I think the Telomere issue should be a huge priority as it really kicks off so many aging problems so to me tackkling it first is a no brainer. I also share your view that Telomerase induction does not cause Cancer though Cancer uses Telomerase that's not really the same thing.

If we can fix this problem it could potentially add decades to lifespan giving us time to fix the other problems like accumulated cell junk etc...

Posted by: Steve H at December 19th, 2014 2:00 AM

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