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Anti-Aging Breakthrough With Telomerase Knockout Mice by Jeffrey Dach MD

Posted Dec 03 2010 4:16pm

Anti-Aging Breakthrough in Mice

by Jeffrey Dach MD

A new study by Harvard professor Ronald A. DePinho, published in Nature showed dramatic reversal of aging in mice. The mice had been genetically modified to age rapidly by "knocking out" the gene that makes telomerase, the enzyme responsible for maintaining the telomeres.  The genetically manipulated mice had short telomeres which caused premature aging with atrophy (shrinkage) of the brain and spleen, loss of sense of smell, and loss of fertility with testicular atrophy. 

Reversing Aging

The next step of the experiment was to give back the missing gene for telemerase and see if that would reverse all these signs of aging in the mice.  For this next step, the aged mice were treated with a drug (4-OHT) which served to "turn on" production of telomerase and lengthen the telomeres.  This dramatically reversed the signs of aging with the aged mice surprisingly rejuvenated.  Their shrunken brains, spleens and testes resumed normal size, and they regained their sense of smell.  The aged infertile males once again became fertile, and fathered large litters.

Left image: Telomere  on the end of the chromosome. image courtesy of wikimedia commons

What is a Telomere?  Telomeres Control Aging

Telomeres are small strands of DNA code in our genes that control aging and cell replication.  The telomeres are located at the end each chromosome (see diagram), and each time the cell replicates itself, the telomere shortens a little bit and eventually, after about 50 replications, cell replication stops in a process known as "cell senescence", or the Hayflick limit.  The telomeres control this process.

Nobel Prize for Telomere Research

Carol Greider and colleagues were awarded the 2009 Nobel Prize in Medicine for their discovery and work on telomerase, the enzyme that lengthens telomeres.  In 1984,  Greider  discovered the enzyme telomerase and later she found that telomerase can prevent shortening of the telomeres, preventing the aging process.  Her findiongs were published in 1985 in the journal, Cell.  Later in 1997, in collaboration with Ronald A. DePinho, Greider produced a telomerase "Knockout Mouse", a mouse genetically modified to have the telomerase enzyme removed, causing short telomeres and premature aging.  This was the rapid aging mouse model used by DePinho in his new study mentioned above.

How to Turn on Telomerase Activity and Find the Fountain of Youth.

By now, it is should be obvious to you that activating telomerase, protects the telomeres from shortening and serves as an anti-aging treatment, slowing or reversing aging.  On the contrary, knocking out or inhibiting telomerase activity results in shortened telomeres with acceleration of the aging process.

What Activates Telomerase ?

The answer to this question can be found in an excellent 2002 review article by Cong entitled Human Telomerase and Its Regulation .   Among other things, the bioidentical hormones, 17 beta estadiol (estrogen) and testosterone activate telomerase. 

Estrogen Activates Telomerase

The major mechanism for control and activation of telomorase  is the hTERT promoter gene which stands for the human Telomerase Reverse Transcriptase (hTERT) gene.  When the hTERT gene is sequenced, and the code examined, one finds two estrogen receptor elements in this gene.  This explains why 17-beta estradiol activates telomerase.  Simply put, the fact that there are estrogen receptors in the TERT gene means that estrogen activates telomerase. 

Estrogen Blockers

Estrogen blockers such as tomoxifen block these receptors and trun off telomerase.  Androgens were also foudn to turn on the hTERT gene and activate telomerase, and as expected, androgen blocker drugs inhibit telomerase.

Doing Genetic Gymnastics To Use Tamoxifen

Although much of the scientific work and reserch on telomerase activity has focused on estrogen (a bioidentical hormone) as the regulator and activator of telomerase activity, the DePinho Harvard group did something different.  They genetically modified the mouse TERT gene so they could use a synthetic hormone called 4-OHT, which is actually Tamoxifen.  Normally, Tamoxifen is an estrogen receptor blocker and  known inhibitor of telomerase activity.   The Depinho group did some genetic gymnastics and modified the genes of the mice so the Tamoxifen would activate the TERT gene, rather than inhibit it.

More on Tamoxifen

Tamoxifen, originally made by Astra-Zeneca, had global sales in 2001 of a billion dollars.  This was a big selller, a blockbuster.  As you might guess, Astra-Zeneca is a large pharmaceutical company with deep pockets for funding academic research.

So, why did  the Harvard group use a synthetic hormone called 4-OHT, to increase telomere length when research over the past decade shows that 17 Beta -Estradiol is tthe natural agent for this?   Why not use 17-Beta Estradiol to produce the same anti-aging effects as the DePinho mouse telomere study.

This is yet another example of the rules of success in academic research,  The first rule for success  is do not compete with your Big Pharma by showing a bioidentical hormone as essential for health. Do not compete with the pharmaceutical industry by showing a natural substance such as 17 - Beta Estradiol outperforms a synthetic chemically altered drug sold by the pharmaceutical industry.

Instead of the using the more logical choice, a bioidentical hormone, you must use one of the Pharmaceutical Industry's synthetic chemicals as the effective agent in your study.  This makes the Drug Industry happy with your research findings, with more funding and consulting fees in the pipeline.  That's why tamoxifen was used as the promoter agent in DePinho's mouse study.

Bioidentical Hormones are the Most Logical Choice

If you are a human being and not a mouse, then the most logical and effective way to increase telomerase activity, lengthen the telomers and reverse aging is with the human bioidentical hormone, 17 Beta estradiol, also known as estrogen.  In 1999, more than a decade ago,Kyo demontrated that 17 Beta Estradiol activates telomerase via direct and indirect effects on the hTERT promoter region.  In 2000 Silvia Misiti showed that telomerase activity and TERT gene expression is regulated by and dependent on 17 Beta Estradiol, which by the way, is a BIoidentical Hormone.   In 2008, Bayne showed that estrogen deficiency  in mice leads to telomere shortening and rapid aging.  A 2009 study by Rodrigo showed that both 17 Beta Estradiol was effective in increasing TERT gene expression and telomerase enzymatic activity.  Quite contrary to DePinho's study, the effect of estradiol on telomerase function was abolished by Tamoxifen, an estrogen blocker drug.  A recent December 2010 study from Imanishi  in Japan showed that 17 Beta Estradiol (estrogen) augments telomerase activity, thereby accelerating recovery after injury and reducing the effects of aging (reducing senescence).  If this isn't a description of anti-aging effects, I don't know what is.

Published in the journal Gut in 2004, Sato found that estradiol prevents telomere shortening in human liver cells as well as chemically induced mouse liver cirrhosis model.  Sato states that estradiol is the preferred treatment and superior to  Dr Depiho;s genetic engineering proposals.

Bioidentical Hormones Levels Decline After Age 50

Bioidentical hormones are the hormones normally found in the human body.  After age 50, hormone levels decline in men and wormen, heralding the onset of degenerative changes also known as aging.  It makes sense to replenish these hormones to normal levels which we now know activates telomere lengthening, and reverses senescence.

Why the Genetic Engineering Gymnastics ?

In real life, Tamoxifen is anti-estrogen and acts to inhibit telomerase activity.  So, you might be wondering why DePinho's group did some genetic engineering gymnastics to get the right receptors loaded onto the TERT gene, so that Tamoxifen could be used as the promoter drug, a drug that actually blocks the effect of 17-Beta Estradiol and is a TERT inhibitor in actual real life.  It's all about Big Business and Big Pharma.

Pharmaceutical Industry and a Conflict of Interest

If you are wondering if telomere research at Harvard is tainted by Big Business and Big Pharma money, the answer is yes, of course.  It's all disclosed in the public record .The mouse telomere study lead author, Dr DePinho received more than $83,000 dollars as a consultant to the Glaxo-Smith Klein drug company in 2009-2010 .  Dr DePinho also  co-founded Karyopharm, a privately held Oncology company which recenty raised $20 Million in financing for its line of  Novel Nuclear Transport Modulators.  Dr DePinho is also one of the Directors at the Dana-Farber Cancer Institute which recently raised 1 Billion Dollars to fund its research activities (how much of this from Big Pharma?).  So yes, of course, there is big money and big pharma involved in the halls of academic medicine, and this explains why a synthetic drug like 4-OHT (4 hydroxy tamoxifen) was used in the mouse telomere study instead of the more logical choice of 17 beta estradiol (estrogen)

NIH  Funding to Repeat the Study with 17 Beta Estradiol.

Here is my reseach proposal for the NIH.  Allocate the funding to repeat the mouse telomere study with 17 Beta Estdadiol, which I predict, will provide the same or better benefits in reversing telomere associated aging.  It's that simple.  Call or write your Congressman to get this simple study funded.

Links and References

Jeffrey Dach MD
7450 Griffin Road
Davie, Fl 33314

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The reader is advised to discuss the comments on these pages with his/her personal physicians and to only act upon the advice of his/her personal physician. Also note that concerning an answer which appears as an electronically posted question, I am NOT creating a physician -- patient relationship. Although identities will remain confidential as much as possible, as I can not control the media, I can not take responsibility for any breaches of confidentiality that may occur.

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