Bioidentical Hormones 101 
The Book, by Jeffrey Dach MD

Chapter 54. Anti-Aging Breakthrough with Bioidentical Hormones

Juan Carlos Ponce De Leon, Telomerase, Telomeres, Jeffrey Dach MD

Chapter 54. Anti-Aging Breakthrough with Bioidentical Hormones

Ponce de Leon was the famous explorer who searched for the fountain of youth, the magic waters that restored youth and vigor and reversed aging.  Although Ponce de Leon failed to find the “fountain of youth”, Ronald A. DePinho, a Harvard professor may have succeeded with his genetically modified mouse experiment which reversed aging in mice.  This study was published in Nature.(1-2)   The doctor used special mice that had been genetic engineered to age rapidly.   The gene that controls aging had been "knocked out”, so these mice had accelerated aging with shrinkage (atrophy) of the brain, spleen, loss of sense of smell, and loss of fertility with testicular atrophy. 

Left Image:  Juan Ponce De Leon, famous explorer searched for the fountain of youth. Wood engraving 1858, courtesy of Library of Congress  Courtesy of wikimedia commons.

Reversing Aging with the "The Ponce De Leon Effect"

The next step of the aging mouse experiment was to reverse aging and make the mice younger. This was done by giving back the missing gene that had been “knocked out” 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 dramatically reversed the signs of aging.  The aged mice were surprisingly rejuvenated.  Their shrunken brains, spleens and testes resumed normal size, and they regained their sense of smell.  The infertile males once again became fertile, and fathered large litters.  Is this the next anti-aging breakthrough? Can this type of treatment potentially restore organ function and reverse degenerative disease in the elderly?

What is a Telomere?  Telomeres are the Biological Clock that Control Aging

De Pinho’s mouse aging experiment was based on our knowledge of the telomere which serves as a biological clock for aging and cell replication.  The telomere is a strand of DNA information which shortens with each cell replication.  After about 50 cell replications or so, telomere shortening instructs the cell to stop replication in a process known as "cell senescence", or the Hayflick limit.(3)   Cessation of cell replication directly causes aging, senescence and death.   Shortening of the telomeres hastens aging, and lengthening the telomeres halts or reverses aging, producing the Ponce De Leon, “fountain of youth” effect.

Nobel Prize for Telomere Research

Much of our knowledge of telomeres and aging is credited to the work of Carol Grieder and her colleagues, awarded the 2009 Nobel Prize in Medicine for discovery and work on telomerase, the enzyme that lengthens telomeres.(4)  In 1984,  Greider  discovered the enzyme telomerase and later she found that telomerase can prevent shortening of the telomeres, which prevents and reverse the aging process.  Her findings were published in 1985 in the journal, Cell.(5)  Activating the enzyme, 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 allows telomeres to shorten and accelerate aging.

The Race to Activate Telomerase

How can we activate telomerase?  The answer to this question can be found in an excellent 2002 review article by Cong entitled, “Human Telomerase and Its Regulation".(7)   Among other things, the bioidentical hormones, 17 beta estradiol (estrogen) activates telomerase. 

hTERT Gene and Estrogen Activation of Telomerase

The major mechanism for control and activation of telomerase 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.  The fact that there are estrogen receptors in the hTERT gene means that estrogen activates telomerase.(7)   Estrogen blockers such as Tamoxifen™ block these receptors and turn off telomerase.  Androgens were also found to turn on the hTERT gene and activate telomerase, and as expected, androgen blocker drugs inhibit telomerase.(7)

Doing Genetic Gymnastics To Use Tamoxifen

Although much of the scientific research 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 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 seller, a blockbuster.  As you might guess, Astra-Zeneca is a large pharmaceutical company with deep pockets for funding academic research.(8)(9)  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 the natural agent for this?   Why not use 17-Beta Estradiol to produce the same anti-aging effects as the DePinho mouse telomere study? 

Bioidentical Hormones are the Most Logical Choice

Whether you happen to be a human being or a mouse, then the most logical and effective way to increase telomerase activity, lengthen the telomeres and reverse aging is with the human bioidentical hormone, 17-Beta-Estradiol, also known as estrogen.   In 1999, more than a decade ago, Kyo demonstrated that 17-Beta-Estradiol activates telomerase via direct and indirect effects on the hTERT promoter region.(10)   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.(11)  In 2008, Bayne  showed that estrogen deficiency in mice leads to telomere shortening and rapid aging. (12)  Another study in 2009 by Rodrigo T. Calado from the NIH (National Institute of Health) showed that 17-Beta-Estradiol was effective in increasing TERT gene expression and telomerase enzymatic activity.  Quite contrary to DePinho's mouse aging model, the beneficial effect of 17-Beta Estradiol on telomerase function was abolished by Tamoxifen™, an estrogen blocker drug.(13) 

A recent December 2010 study from Imanishi from 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.(14)(15)

Published in the journal Gut in 2004, Sato  found that Estradiol prevents telomere shortening in normal human liver cells, as well as in a mouse model of chemically induced  liver cirrhosis.  Sato states that estradiol is the preferred treatment and superior to  Dr. Depinho's genetic engineering proposals.(16)

An important study in Circulation 2006  found that 17-Beta Estradiol enhances recovery after heart attacks by augmenting incorporation of endothelial stem cells and inducing new collateral vessels in the ischemic myocardium.  This beneficial effect is related to telomerase activation of the Endothelial Progenitor cells. (17)

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 women, 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.(18)  The anti-aging mouse study author, Dr. DePinho received more than $83,000 dollars as a consultant to the Glaxo-Smith Klein drug company in 2009-2010.(18)  Dr DePinho also  co-founded Karyopharm, a privately held Oncology company which 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).

The Race for Natural Substances That Activate Telomerase and Reverse Aging

Resveratrol, Silymarin and Gingko Biloba are natural substances found to activate telomerase with potential for anti-aging. (19-21)  Calvin Harley of Geron Corporation, and John Anderson and William H Andrews of Sierra Sciences are leading the race to develop safe products as nutritional supplements to activate telomerase and reverse aging.  Dr. Andrews says "Telomerase activation technology promises to be the most significant advance in human health since germ theory."(22-23)

References  For Chapter 54. Anti-Aging Breakthrough

Published online 28 November 2010 Nature - Telomerase reverses ageing process- Dramatic rejuvenation of prematurely aged mice hints at potential therapy.

Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice Mariela Jaskelioff,Florian L. Muller,Ji-Hye Paik,Emily Thomas,Shan Jiang,Andrew C. Adams,Ergun Sahin,Maria Kost-Alimova,Alexei Protopopov,Juan Cadiñanos,James W. Horner,Eleftheria Maratos-Flier& Ronald A. DePinho Nature (2010)Published online 28 November 2010

Hayflick, his limit, and cellular ageing Jerry W. Shay and Woodring E.Wright
Nature Reviews Mol Cell Bio 72 | OCTOBER 2000 | VOLUME 1

New York Times- 3 Americans Share Nobel for Medicine By NICHOLAS WADE October 5, 2009

Cell. 1985 Dec;43(2 Pt 1):405-13. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Greider CW, Blackburn EH.

Cell. 1997 Oct 3;91(1):25-34. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW. Cold Spring Harbor Laboratory, New York 11724, USA.

Microbiol Mol Biol Rev. 2002 September; 66(3): 407–425.
Human Telomerase and Its Regulation. Yu-Sheng Cong,* Woodring E. Wright, and Jerry W. Shay

Tamoxifen is an antagonist of the estrogen receptor in breast tissue.
Global sales of tamoxifen in 2001 were $1,024 million.

ALASTAIR J.J. WOOD , M.D., Editor Drug Therapy, Tamoxifen in the Treatment of Breast Cancer C. Kent Osborne, M.D., NEJM 1998 Volume 339 Number 22 , 1609

Estrogen Activates Telomerase. Satoru Kyo1, Masahiro Takakura, Taro Kanaya, Wang Zhuo, Kohtaro Fujimoto, Yukihito Nishio, Akira Orimo, and Masaki Inoue. Cancer Res December 1, 1999 59; 5917

Molecular and Cellular Biology, June 2000, p. 3764-3771, Vol. 20, No. 11
Induction of hTERT Expression and Telomerase Activity by Estrogens in Human Ovary Epithelium Cells. Silvia Misiti, et al., Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome, Italy.

Cell Res. 2008 Nov;18(11):1141-50. Estrogen deficiency leads to telomerase inhibition, telomere shortening and reduced cell proliferation in the adrenal gland of mice. Bayne S, Jones ME, Li H, Pinto AR, Simpson ER, Liu JP. Department of Immunology, Central Eastern Clinical School, Monash University, Melbourne, Australia.

Blood, 10 September 2009, Vol. 114, No. 11, pp. 2236-2243.
Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Rodrigo T. Calado et al. National Institutes of Health, Bethesda, MD

Ther Adv Cardiovasc Dis. 2010 Feb;4(1):55-69. Epub 2009 Dec 4. Endothelial progenitor cell senescence--is there a role for estrogen? Imanishi T, Tsujioka H, Akasaka T.

Journal of Hypertension:September 2005 - Volume 23 - Issue 9 - p 1699-1706
Estrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activity Imanishi, Toshio; Hano, Takuzo; Nishio, Ichiro

Gut. 2004 July; 53(7): 1001–1009. Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis. R Sato et al. Department of Pathology, Iwate Medical University School of Medicine, Morioka, Japan

Circulation. 2006;113:1605-1614.)
Molecular Cardiology - Estradiol Enhances Recovery After Myocardial Infarction by Augmenting Incorporation of Bone Marrow–Derived Endothelial Progenitor Cells Into Sites of Ischemia-Induced Neovascularization via Endothelial Nitric Oxide Synthase–Mediated Activation of Matrix Metalloproteinase-9  Atsushi Iwakura, MD, PhD et al.

Dollars for Docs, What Drug Companies are Paying Your Doctor

Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms L Xia, X X Wang, X S Hu, X G Guo, Y P Shang, H J Chen, C L Zeng, F R Zhang, J  Z ChenArticle first published online: 29 JAN 2009 British Journal of Pharmacology Volume 155, Issue 3, pages 387–394, October 2008.

J Cardiovasc Pharmacol. 2010 Aug 31. [Epub ahead of print]
Silymarin Inhibits Endothelial Progenitor Cells Senescence and Protects Against the Antiproliferative Activity of Rapamycin. Preliminary Study. Parzonko A, Naruszewicz M.Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, Poland.

J Cardiovasc Pharmacol. 2007 Feb;49(2):111-5. Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity. Dong XX, Hui ZJ, Xiang WX, Rong ZF, Jian S, Zhu CJ. Department of Cardiology, the First Affiliated Hospital, Medical School of Zhejiang University, Hangzhou, China.

Current Molecular Medicine 2005, 5, 29-38 205 Telomerase Therapeutics for Degenerative Diseases. Calvin B. Harley* Geron Corporation, Menlo Park, CA, 94025, USA

Sierra Sciences' Plan to Cure Aging is Validated by Newly Published Proof of Concept Experiment . “Telomerase activation technology promises to be the most significant advance in human health since germ theory."

Author: Jeffrey Dach MD

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