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
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
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
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
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
Pharmaceutical Industry and a Conflict
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
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
Cell. 1985 Dec;43(2 Pt 1):405-13. Identification of a specific telomere
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Jerry W. Shay
Tamoxifen is an antagonist of the estrogen receptor in breast tissue.
Global sales of tamoxifen in 2001 were $1,024 million.
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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
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Wang, X S Hu, X G Guo, Y P Shang, H J Chen, C L Zeng, F R Zhang, J Z
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the Antiproliferative Activity of Rapamycin. Preliminary Study. Parzonko A,
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most significant advance in human health since germ theory."
Author: Jeffrey Dach MD