Arguing for Work on Telomerase Therapies in Humans
Permalink | View Comments (4) | Post Comment | | Posted by Reason

The best understood activity of the enzyme telomerase is that it lengthens telomeres, the repeating DNA sequences at the end of chromosomes that form a part of the mechanism to limit the number of times a cell can divide. Average telomere length in tissues is very dynamic, a reflection of the interplay of numerous processes that lengthen and shorten telomeres or change the number of cells with long versus short telomeres. The average tends to fall with ill health and age, which is how work on telomerase-enhancing treatments started, with the aim of reversing this signature in the hope that it will improve matters.

My take on reduced telomere length is that it is a consequence of damage and dysfunction, not a primary cause of aging - though it might have further detrimental effects once it exists. The principle counterpoint to that position is that telomerase enhancement in mice lengthens life. So either I'm wrong or one of the other activities of telomerase is significant, such as interactions between telomerase and mitochondria.

This open access review is a fair summary of the arguments to try increasing the activity of telomerase in humans. Note that many of the groups most vocal on this topic at the moment are selling supplements or herbal extracts backed by sketchy or irrelevant data, the usual modus operandi in the "anti-aging" industry, and an annoyance for anyone looking for serious scientific work on targeting telomerase - so take everything that contingent has to say with a grain of salt:

The elderly population is increasing progressively. Along with this increase the number of age related diseases, such as cardiovascular, neurodegenerative diseases, metabolic impairment and cancer, is also on the rise thereby negatively impacting the burden on health care systems. Telomere shortening and dysfunction results in cellular senescence, an irreversible proliferative arrest that has been suggested to promote organismal aging and disabling age-related diseases.

Given that telomerase, the enzyme responsible for maintaining telomere lengths, is not expressed at levels sufficient to prevent telomere shortening in most of our cells, telomeres progressively erode with advancing age. Telomerase activation, therefore, might serve as a viable therapeutic strategy to delay the onset of cellular senescence, tissue dysfunction and organismal decline. Here we analyze the more recent findings in telomerase activation as a potential key modulator for human healthspan and longevity.

Link: http://dx.doi.org/10.1016/j.arr.2013.12.006

Comments

I suspect telomerase is causal. 5 years of adequate lifestyle change were said to increase telomeres by about 10%, while those without the positive lifestyle changes lost 3% of telomeres over five years.

https://www.ucsf.edu/news/2013/09/108886/lifestyle-changes-may-lengthen-telomeres-measure-cell-aging

We know that improved lifestyle reduces mortality and increases lifespan, now it seems it might also increase telomeres moderately(study needs to be verified by other sources, as increasing telomeres is quite a feat with just lifestyle.).

That said, it's said that increased telomeres from short state can in animals remove balding, gray hair, revert age related brain atrophy. In human skin it is said to restore youthful gene expression and appearance. It should also keep cells from becoming senescent cells, and I would hypothesize(though haven't seen data yet) that it might rescue many cells which've entered senescence and revert them back to functional status.

Regards cancer I've heard that very short telomeres might increase genomic instability and moderate length would prevent that. Which if true suggest that rather than abolishing telomerase expression in most cells in the body, regulating telomerase expression to maintain moderate length would've have been optimal and been sufficient to prevent cancer probably superior to the current implementation in humans. In any case, If I recall correctly, it is said that there exist a telomerase independent method of lengthening telomeres, so not expressing telomerase does not mean a cancer cell can't find a way to lengthen telomeres.

Regards restoration of gene expression to a youthful state, restoring gene expression to a youthful state should revert age related increased membrane peroxidation index as the membrane composition is highly regulated which most likely involves gene expression. It would be interesting to see if the worsened mitochondrial population with age is a result of worsening gene expression patterns reducing quality control or if it's not, if it is restoring gene expression could over time restore mitochondrial population quality.

Posted by: Darian S at February 26, 2014 8:56 AM

@Darian - This is speculation, but if all that was required for longer lifespans was a bump in telomerase activity, wouldn't natural selection have carried that out already?

Contrast that with the SENS hypothesis that aging is molecular and cellular damage that the body cannot repair at any reasonable cost.

Posted by: Jim at February 26, 2014 11:56 PM

Indeed; it's not like there aren't plenty of species whose telomeres don't shorten with age, in fact there's a species of bird whose telomeres get -longer- with increasing age, and it ages quite normally.

Telomere length seems to most likely be a measure of stem cell activity. Stem cells typically have high levels of telomerase activity, so any cells they give rise to will also have long telomeres. The environment that a stem cell is in determines its activity, and aging damage suppresses stem cell activity, to the extent that stem cells in a centenarian will for the most part basically just sit around doing nothing. As such, it's unsurprising that you're going to find shorter telomeres in older people, because their stem cells aren't producing new cells with long telomeres; instead pretty much all tissue maintenance is attained through the division of somatic cells, which leads to telomere shortening. However, if you transplant stem cells from an old animal into a young one, the stem cells will begin to act normally once more, and once again start giving rise to cells with longer telomeres. The same thing should happen if you were to repair all the cellular and molecular damage of aging that suppresses stem cell activity.

Posted by: Arcanyn at February 27, 2014 2:45 AM

"Contrast that with the SENS hypothesis that aging is molecular and cellular damage that the body cannot repair at any reasonable cost."

If that were the case, we should see SENS like approaches being implemented by nature in negligible Senescence species. If all they've is mostly the same genes and differing expression patterns, then existing mechanisms are sufficient if ramped up. We have over 98% genetic similarity with our closest relative yet over twice the lifespan.

What approach doubled species lifespan?
If we were bonobos with 40year lifespans and we asked SENS proponents. They'd say most of the longevity changes were already implemented by nature in achieving this lifespan and they'd propose the SENS solutions as a way to lengthen lifespan.

If like me you believed existing mechanisms are mostly sufficient for vast lifespan increase, then you'd suggest mostly gene expression changes with high conservation of the genome. What did nature do? AFAIK, it simply mostly tweaked gene expression and presto triple lifespan.

If you ask me, it is likely that similar tweaks could very likely carry us all the way up to negligible senescence.

Let's see what we find from the genetic sequences of negligible senescence organisms.

"Indeed; it's not like there aren't plenty of species whose telomeres don't shorten with age, in fact there's a species of bird whose telomeres get -longer- with increasing age, and it ages quite normally."
I've not looked into it deeply, but according to Dr. Bill Andrews, it is only a few species who have significant aging contribution from short telomeres.

"The same thing should happen if you were to repair all the cellular and molecular damage of aging that suppresses stem cell activity."
And it also as mentioned seems to slightly begin to occur with lifestyle changes that increase telomeres.

Posted by: Darian S at February 27, 2014 5:15 PM
Post a comment; thoughtful, considered opinions are valued. Please note that comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.









Remember personal info?