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

Anti-Aging Breakthrough in Mice

by Jeffrey Dach MD

A new study by Harvard professor Ronald A. DePinho, just published in Nature shows dramatic reversal of aging in mice.(1)(2) The "biological clock" of these mice had been modified to make them age rapidly.  This was done with genetically engineering which  "knocked out" the gene that makes telomerase, the enzyme responsible for maintaining the telomeres.  These genetically manipulated mice had short telomeres,  and premature aging with atrophy (shrinkage) of the brain, spleen, loss of sense of smell, and loss of fertility with testicular atrophy. 

Reversing Aging with the "The Ponce De Leon Effect"

The next step of the experiment was to give back the missing gene for telomerase 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.  Is this the next anti-aging breakthrough? Can treatment to restore telomerase and telomere length potentially restore organ function and reverse degenerative disease in the elderly?


Left image: Telomere  cap at the end of the chromosome. After each cell replication, a small piece of telomere DNA is lost, until cell replication stops. This is the "biological clock". image courtesy of wikimedia commons

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

Telomeres are the biological clock that control aging and cell replication.  They are small strands of DNA code at the end of each chromosome (see diagram above).  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.(3) 

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.(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)  Later, in 1997, Greider collaborated with Ronald A. DePinho to produce a telomerase "Knockout Mouse", a mouse genetically modified to have the telomerase enzyme removed, causing short telomeres and premature aging.(6)  This was the rapid aging mouse model used by DePinho in his new study published in Nature.

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 ".(7)   Among other things, the bioidentical hormones, 17 beta estadiol (estrogen) activates 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.(7) 

Estrogen Blockers

Estrogen blockers such as tomoxifen 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 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 Progentior 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 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 .(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 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).

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)(20)(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)

Jeffrey Dach MD
www.jeffreydach.com

Financial Disclosure: I have no financial interest in any of the companies or products mentioned in this article.

Links and References

(1) http://www.nature.com/news/2010/101128/full/news.2010.635.html
Published online 28 November 2010 Nature - Telomerase reverses ageing process- Dramatic rejuvenation of prematurely aged mice hints at potential therapy.

(2) http://www.nature.com/nature/journal/vaop/ncurrent/full/nature09603.html
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

(3)http://www4.utsouthwestern.edu/cellbio/shay-wright/publications/hayflick.nature.pdf
Hayflick, his limit, and cellular ageing Jerry W. Shay and Woodring E.Wright
Nature Reviews Mol Cell Bio 72 | OCTOBER 2000 | VOLUME 1

(4) http://www.nytimes.com/2009/10/06/science/06nobel.html
New York Times- 3 Americans Share Nobel for Medicine By NICHOLAS WADE October 5, 2009

(5) http://www.ncbi.nlm.nih.gov/pubmed/3907856
Cell. 1985 Dec;43(2 Pt 1):405-13. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Greider CW, Blackburn EH.

(6) http://www.ncbi.nlm.nih.gov/pubmed/9335332
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.

(7) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC120798/
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

(8) http://www.news-medical.net/health/What-is-Tamoxifen.aspx
Tamoxifen is an antagonist of the estrogen receptor in breast tissue.
Global sales of tamoxifen in 2001 were $1,024 million.

(9) http://www.womenshealthtrack.vcu.edu/pdf/Osborne.pdf
A LASTAIR 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


(10) http://cancerres.aacrjournals.org/content/59/23/5917.full
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

(11) http://mcb.asm.org/cgi/content/full/20/11/3764
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.

(12) http://www.ncbi.nlm.nih.gov/pubmed/18936784
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.

(13) http://bloodjournal.hematologylibrary.org/cgi/content/full/114/11/2236
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

(14) http://www.ncbi.nlm.nih.gov/pubmed/19965898
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. Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan.

(15) http://journals.lww.com/jhypertension/Abstract/2005/09000/Estrogen_reduces_endothelial_progenitor_cell.14.aspx
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

(16) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774098/?tool=pubmed
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

(17) http://circ.ahajournals.org/cgi/content/abstract/113/12/1605
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.


(18) http://projects.propublica.org/docdollars/states/massachusetts
Dollars for Docs, What Drug Companies are Paying Your Doctor

(19) http://onlinelibrary.wiley.com/doi/10.1038/bjp.2008.272/abstract
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.

(20) http://www.ncbi.nlm.nih.gov/pubmed/20838231
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.

(21) http://www.ncbi.nlm.nih.gov/pubmed/17312453
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.


(22) http://www.tasciences.com/pdf/Harley_CMM_final.pdf
Current Molecular Medicine 2005, 5, 29-38 205 Telomerase Therapeutics for Degenerative Diseases. Calvin B. Harley* Geron Corporation, Menlo Park, CA, 94025, USA


(23) http://pharmalive.com/News/index.cfm?articleid=747325&categoryid=40
Sierra Sciences' Plan to Cure Aging is Validated by Newly Published Proof of Concept Experiment . Sierra Sciences has also developed mechanisms for screening thousands of natural products a week for telomerase induction, and expects to be able to launch a nutraceutical that turns on telomerase in humans by early 2011.  Dr. Andrews and Sierra Sciences have entered into a partnership with John Anderson, founder of Isagenix, International and CEO of Dream Master Laboratories, a manufacturer and formulator of natural products, to quickly bring this nutraceutical to market. "Telomere shortening has a role in a vast number of diseases," said Dr. Andrews.  "We see telomere shortening as a primary culprit in everything from atherosclerosis to osteoporosis to macular degeneration; really, any disease you're more likely to suffer from at age 70 than age 30 probably has something to do with telomere shortening.  Just as telomerase activation reversed degeneration in the organs of these mice, we expect that it can do the same for humans.  Telomerase activation technology promises to be the most significant advance in human health since germ theory."



Jeffrey Dach MD
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