Telomere length variation suggest bad players in the mix

Ed Park, MD age-related-diseases, aging, dr ed park, TA-65, Telomere erosion, telomere measurement 0 Comments

Here is the problem with trying to measure aging merely as consistent loss of telomeres.

Yes, telomere erosion causes stem cells to mutate and cause dysfunction we recognize as aging.

Yes, this attrition of stem cells causes a depletion of stem cell reserves.

However, certain cells obtain mutations in their ability both recognize DNA damage and kill themselves off when they lose p53 (the watchman of the genome) gene integrity.

Merkle et al. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature: 545. 229–233. 11 May 2017

This study suggests quite logically that cells losing the ability to kill themselves tend to survive. Over time, the dutiful and dysfunctional stem cells die off but others, like the Mafia capos or career politicians, become unable to kill themselves so they persist and cause problems while still lengthening their telomres.

This study challenges the oversimplification that telomeres only shorten with age.  I completely agree with their conclusion that seeking to explain telomere length distributions as merely shorter misses the point. They tend to get shorter in normal cells because of replicative senescence of the reserve pool and the representation of p53-competent stem cells. But there are also stem cells which are telomerase positive and apoptosis-incompetent which over the course of a lifetime become increasingly represented.

In some older people, their remaining stem cells continue to lengthen their telomeres and resist suicide. The normally-regulating and shortening stem cells are still represented in the measurements but so are the tough-as-nails ones that have lost the ability to die. As we age and fail to purge those damaged cells, their relative representation increases as the “weaker” more dutiful ones die off. But variation in lengths increase as we entopically evolve into genetic mosaics of ourselves (the zombification of aging).

It turns out that that this study of healthy seniors (over 85 without any serious illness) revealed that they have boring and homogenous telomere length variation compared to younger people although their average lengths were predictably shorter. The ability to rebalence, lengthen, maintain, and trim telomeres may be at work, and it could also be sheer luck (like winning musical chairs). But this could also represented impressive efficiency at apoptosis preventing the rise of capos in a mixed population.

We age because we can still function with damaged cells. Our old and damaged cells survive partly because of an inhibitor of p53-mediated apoptosis called FOXO4. Interestingly, when a competitive inhibitor of this FOXO4 inhibitor action is used, old cells die and the aged cells die off as shown in this study. But if p53 is broken as in the capo/career politician cells, then removing the inhibition of p53 does no good.

In the final analysis, aging involves depletion of the reserve pool of stem cells, preferential survival of stem cells which have lost the ability to kill themselves, and a universal drift away from genomic integrity produced by slightly “lossy” information reproduction (DNA errors occurring around one in three cell divisions) and catastrophic chromosome breakage and aneuploidy. This process is mainly caused by telomere erosion, end-to-end-fusion, and post-mitotic aneuploidy which is universally lethal unless telomerase is adequate and the p53 cell suicide program is no longer functioning properly.

By the time we are old and ill, our bodies are being run by a bunch of selfish, dysfunctional bosses, unless we have the set of circumstances that led those super seniors to maintain healthy, well-balanced distributions of stem cells and their telomeres that were mentioned above.

Just in case you didn’t follow the reasoning, here is the take home lesson:

short average telomere length with high variation= bad;

the same average telomere length with low variability =good.

In my clinical experience, the Life Length reporting of histograms was useful for this purpose and showed the main demonstrable change when taking telomerase activators. Although not routinely reported due to complaints from doctors who didn’t want the additional data, it can still be obtained upon request.

 

Ed Park, MD
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Ed Park, MD

I graduated from Harvard with honors in Biological Anthropology prior to earning my Medical Degree and Masters in Public Health from Columbia University.

In 2007, I became the nineteenth patient to sign up for the use of a herbally-extracted telomerase activator.

The results were so positive that I founded Recharge Biomedical Clinic in 2008 and have since become the leading medical expert in this exciting new field of regenerative medicine treating over 1,300 patients with this exciting new telomerase activation medicine.

I won two Houston Film Festival Awards for my screenplays about Hypatia of Alexandria and Ed Brown of Kentucky.

In 2010 I wrote and self-published a Sci-Fi Graphic Novel called MAXIMUM LIFESPAN

In 2013, I wrote and published "Telomere Timebombs; Defusing the Terror of Aging"

My websites are:
http://www.lokahi.guru (where you can learn about my RECHARGE adaptogenic supplement)
http://www.rechargebiomedical.com and
http://www.telomeretimebombs.com

You can sign up for my weekly blogs on this page and subscribe to my YouTube videos at https://www.youtube.com/drpark65
Ed Park, MD
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