A new study by Harvard professor Ronald A. DePinho, published in Nature showed dramatic reversal of aging in a genetically engineered mouse model. The mice had been genetically modified to age rapidly. They were given shortened dysfunctional telomeres which, in turn caused age-related shrinkage of the brain and spleen. The aged mice also had loss of sense of smell, and loss of fertility with testicular atrophy. To reverse the effects of aging, the mice treated with a promoter drug (4-OHT) to increase telomerase activity and lengthen the telomeres. This increase in telomerase activity dramatically reversed the signs of aging in the mice. Four weeks after treatment with the drug (4-OHT), the mice were surprisingly rejuvenated, with their shrunken brains, spleens and testes resuming normal size. The rejuventated mice also regained their sense of smell, and the males became fertile, fathering large litters.
Telomeres and Aging
Telomeres are small strands of DNA code in our genes that control aging and cell replcication. Located at the end each chromosome, the telomere shortens each time the cell divides. After about 50 cell replications, the shortened telomere stops cell replication, a process known as “cell senescence”, or the Hayflick limit.
Carol Greider and others were awarded the 2009 Nobel Prize in Medicine for their work on telomerase, the enzyme that lengthens telomeres. Greider discovered the enzyme telomerase in 1984, while working as a graduate student at the University of California in Berkeley. Her work showed that telomerase can prevent shortening of the telomeres. This was published in Cell in 1985. Working with Ronald A. DePinho in 1997, Greider created a telomerase “Knockout Mouse” which is 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.
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 will slow or reverse the process of 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. 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 reviewed, it turns out there are two estrogen receptor elements in this gene. This explains why 17-beta estradiol activates telomerase. Simply out, there are estrogen receptors in the gene that makes telomerase. 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 previous work on telomerase activity has focused on bioidentical hormones as regulators and activators 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 Depiho group did some genetic gymnastics and modified the genes of the mice so the Tamoxifen would activate the TERT gene, rather than inhibit it. Tamoxifen’s global sales in 2001 was close to a Billion dollars, and was originally made by Astra-Zeneca, 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 Telomere research over the past decade showed that this is accomplished by 17 Beta -Estradiol which has been shown to increase TERT gene expression and telomerase enzymatic activity. 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.
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 Estradiol, 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.
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To read more on Dr Dach’s work please visit his website at www.jeffreydach.com and if you have any questions or comments on his articles you can contact him via the website.