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Bioidentical Hormones Reverse Aging New Harvard Study by Jeffrey Dach MD

Posted Dec 03 2010 8:56am
 






Anti- Aging Breakthrough 
by Jeffrey Dach MD

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.

Telomere Ron Depinho Aging Mouse Study Left image:  Telomere   on the end of the chromosome. image courtesy of wikimedia commons

What is a Telomere?  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.

Nobel Prize for Telomere Research

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.

More on Tamoxifen

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.

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.

Jeffrey Dach MD
7450 Griffin Road
Davie, Fl 33314
954-983-1443
http://www.jeffreydach.com  
http://www.drdach.com  
http://www.naturalmedicine101.com  
http://www.truemedmd.com   

Links and references

http://www.nature.com/news/2010/101128/full/news.2010.635.html
Published online 28 November 2010 | Nature | doi:10.1038/news.2010.635
Telomerase reverses ageing process. Dramatic rejuvenation of prematurely aged mice hints at potential therapy. Ewen Callaway


http://online.wsj.com/article/SB10001424052748703785704575642964209242180.html?mod=googlenews_wsj

Aging Ills Reversed in Mice Scientists Tweak a Gene and Rejuvenate Cells, Raising Hopes for Uses in Humans.

By tweaking a gene, the researchers reversed brain disease and restored the sense of smell and fertility in prematurely aged mice.

The team made genetically engineered mice that aged prematurely. The animals had short, dysfunctional telomeres and suffered a range of age-related problems. Their spleens were atrophied, their intestines were damaged, and the sense of smell was impaired. The brains were also shrunken, and the animals were incapable of growing new brain cells. Male mice had smaller-than-normal testes and produced depleted amounts of sperm.

The researchers had devised an estrogen-based drug that would switch on the animals' dormant telomerase gene, known as TERT. The drug, in the form of a time-release pellet, was inserted under the skin of some mice. A similar pellet without the active drug was given to a separate group of control mice.

A month later, the treated mice showed surprising signs of rejuvenation. Overall, their telomeres had lengthened and the levels of telomerase had increased. This woke up the dormant brain stem cells, producing new neurons. The spleen, testes and brain grew in size.

In addition, key organs started to function better. The treated mice regained their sense of smell. The male animals' once-depleted testes produced new sperm cells, and their mates gave birth to larger litters. The treated animals went on to have a typical lifespan, though they didn't live longer than normal mice.

Partial reversal of aging achieved in mice. Control of telomerase gene appears to control process

Harvard scientists at Dana-Farber Cancer Institute say they have for the first time partially reversed age-related degeneration in mice, resulting in new growth of the brain and testes, improved fertility, and the return of a lost cognitive function.

In a report posted online by the journal Nature in advance of print publication, researchers led by Ronald A. DePinho, a Harvard Medical School (HMS) professor of genetics, said they achieved the milestone in aging science by engineering mice with a controllable telomerase gene. The telomerase enzyme maintains the protective caps called telomeres that shield the ends of chromosomes.

As humans age, low levels of telomerase are associated with progressive erosion of telomeres, which may then contribute to tissue degeneration and functional decline in the elderly. By creating mice with a telomerase switch, the researchers were able to generate prematurely aged mice. The switch allowed the scientists to find out whether reactivating telomerase in the animals would restore telomeres and mitigate the signs and symptoms of aging. The work showed a dramatic reversal of many aspects of aging, including reversal of brain disease and infertility.

While human applications remain in the future, the strategy might one day be used to treat conditions such as rare genetic premature aging syndromes in which shortened telomeres play an important role, said DePinho, senior author of the report and the director of Dana-Farber’s Belfer Institute for Applied Cancer Science. “Whether this would impact on normal aging is a more difficult question,” he added. “But it is notable that telomere loss is associated with age-associated disorders and thus restoration of telomeres could alleviate such decline.” The first author is Mariela Jaskelioff, a research fellow in medicine in DePinho’s laboratory.

Importantly, the animals showed no signs of developing cancer. This remains a concern because cancer cells turn on telomerase to make themselves virtually immortal. DePinho said the risk can be minimized by switching on telomerase only for a matter of days or weeks — which may be brief enough to avoid fueling hidden cancers or cause new ones to develop. Still, he observed, it is an important issue for further study.

In addition, DePinho said these results may provide new avenues for regenerative medicine, because they suggest that quiescent adult stem cells in severely aged tissues remain viable and can be reactivated to repair tissue damage.

“If you can remove the underlying damage and stresses that drive the aging process and cause stem cells to go into growth arrest, you may be able to recruit them back into a regenerative response to rejuvenate tissues and maintain health in the aged,” he said. Those stresses include the shortening of telomeres over time that causes cells and tissues to fail.

Loss of telomeres sends a cascade of signals that cause cells to stop dividing or self-destruct, stem cells to go into retirement, organs to atrophy, and brain cells to die. Generally, the shortening of telomeres in normal tissues shows a steady decline, except in the case of cancer, where they are maintained.

The experiments used mice that had been engineered to develop severe DNA and tissue damage as a result of abnormal, premature aging. These animals had short, dysfunctional telomeres and suffered a variety of age-related afflictions that progressed in successive generations of mice. Among the conditions were testes reduced in size and depleted of sperm, atrophied spleens, damage to the intestines, and shrinkage of the brain along with an inability to grow new brain cells.

Rather than supply the rodents with supplemental telomerase, the scientists devised a way to switch on the animals’ own dormant telomerase gene, known as TERT. They engineered the endogenous TERT gene to encode a fusion protein of TERT and the estrogen receptor. This fusion protein would only become activated with a special form of estrogen. With this setup, scientists could give the mice an estrogen-like drug at any time to stimulate the TERT-estrogen receptor fusion protein and make it active to maintain telomeres.

Against this backdrop, the researchers administered the estrogen drug to some of the mice via a time-release pellet inserted under the skin. Other animals, the controls, were given a pellet containing no active drug.

After four weeks, the scientists observed remarkable signs of rejuvenation in the treated mice. Overall, the mice exhibited increased levels of telomerase and lengthened telomeres, biological changes indicative of cells returning to a growth state with reversal of tissue degeneration, and increase in size of the spleen, testes, and brain. “It was akin to a Ponce de León effect,” noted DePinho, referring to the Spanish explorer who sought the mythical Fountain of Youth.

“When we flipped the telomerase switch on and looked a month later, the brains had largely returned to normal,” said DePinho. More newborn nerve cells were observed, and the fatty myelin sheaths around nerve cells — which had become thinned in the aged animals — increased in diameter. In addition, the increase in telomerase revitalized slumbering brain stem cells so they could produce new neurons.

“One of the most amazing changes was in the animals’ testes, which were essentially barren as aging caused the death and elimination of sperm cells,” recounted DePinho. “When we restored telomerase, the testes produced new sperm cells, and the animals’ fecundity was improved — their mates gave birth to larger litters.”

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.

Abstract
Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition of telomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.

http://bloodjournal.hematologylibrary.org/cgi/content/full/114/11/2236
http://bloodjournal.hematologylibrary.org/cgi/reprint/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. Calado1, William T. Yewdell1, Keisha L. Wilkerson1, Joshua A. Regal1, Sachiko Kajigaya1, Constantine A. Stratakis2, and Neal S. Young1
1 Hematology Branch, National Heart, Lung, and Blood Institute, and 2 Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD


Androgens have been used in the treatment of bone marrow failure syndromes without a clear understanding of their mechanism of action. Blood counts of patients with dyskeratosis congenita or aplastic anemia with mutations in telomerase genes can improve with androgen therapy. Here we observed that exposure in vitro of normal peripheral blood lymphocytes and human bone marrow–derived CD34+ cells to androgens increased telomerase activity, coincident with higher TERT mRNA levels. Cells from patients who were heterozygous for telomerase mutations had low baseline telomerase activity, which was restored to normal levels by exposure to androgens. Estradiol had an effect similar to androgens on TERT gene expression and telomerase enzymatic activity. Tamoxifen abolished the effects of both estradiol and androgens on telomerase function, and letrozole, an aromatase inhibitor, blocked androgen effects on telomerase activity. Conversely, flutamide, an androgen receptor antagonist, did not affect androgen stimulation of telomerase. Down-regulation by siRNA of estrogen receptor- (ER), but not ERβ, inhibited estrogen-stimulated telomerase function. Our results provide a mechanism for androgen therapy in bone marrow failure: androgens appear to regulate telomerase expression and activity mainly by aromatization and through ER. These findings have potential implications for the choice of current androgenic compounds and the development of future agents for clinical use.

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,1 Simona Nanni,1 Giulia Fontemaggi,1 Yu-Sheng Cong,2 Jianping Wen,2 Hal W. Hirte,3 Giulia Piaggio,1 Ada Sacchi,1 Alfredo Pontecorvi,1,4 Silvia Bacchetti,2,* and Antonella Farsetti1,5,*  Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute,1 and Institute of Experimental Medicine, National Research Council,5 Rome, and Institute of Medical Pathology, Catholic University, Milan,4 Italy, and Department of Pathology and Molecular Medicine2 and Department of Medicine,3 McMaster University, Hamilton, Ontario, Canada

In mammals, molecular mechanisms and factors involved in the tight regulation of telomerase expression and activity are still largely undefined. In this study, we provide evidence for a role of estrogens and their receptors in the transcriptional regulation of hTERT, the catalytic subunit of human telomerase and, consequently, in the activation of the enzyme. Through a computer analysis of the hTERT 5'-flanking sequences, we identified a putative estrogen response element (ERE) which was capable of binding in vitro human estrogen receptor  (ER). In vivo DNA footprinting revealed specific modifications of the ERE region in ER-positive but not ER-negative cells upon treatment with 17-estradiol (E2), indicative of estrogen-dependent chromatin remodelling.

In the presence of E2, transient expression of ER but not ER remarkably increased hTERT promoter activity, and mutation of the ERE significantly reduced this effect. No telomerase activity was detected in human ovary epithelial cells grown in the absence of E2, but the addition of the hormone induced the enzyme within 3 h of treatment. The expression of hTERT mRNA and protein was induced in parallel with enzymatic activity. This prompt estrogen modulation of telomerase activity substantiates estrogen-dependent transcriptional regulation of the hTERT gene. The identification of hTERT as a target of estrogens represents a novel finding which advances the understanding of telomerase regulation in hormone-dependent cells and has implications for a potential role of hormones in their senescence and malignant conversion.

http://cancerres.aacrjournals.org/content/59/23/5917.full
Cancer Res. 1999 Dec 1;59(23):5917-21. Estrogen Activates Telomerase
Satoru Kyo1, Masahiro Takakura, Taro Kanaya, Wang Zhuo, Kohtaro Fujimoto, Yukihito Nishio, Akira Orimo, and Masaki Inoue

We demonstrated that estrogen activates telomerase via direct and indirect effects on hTERT promoter.

http://www.ncbi.nlm.nih.gov/pubmed/16093915
J Hypertens. 2005 Sep;23(9):1699-706.

Estrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activity. Imanishi T, Hano T, Nishio I. Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimidera, Wakayama City, Wakayama 641-8510, Japan. t-imani@wakayama-med.ac.jp

Abstract
BACKGROUND: Recent studies have demonstrated that aging or senescence constitutes a potential limitation to the ability of endothelial progenitor cells (EPCs) to sustain ischemic tissue and repair. Conversely, estrogens have been shown to accelerate recovery of the endothelium after vascular injury.

OBJECTIVE: To investigate whether estrogens are able to prevent senescence of EPCs.

METHODS AND RESULTS: Human EPCs were isolated from peripheral blood and characterized. After ex-vivo cultivation, the cells became senescent as determined by acidic beta-galactosidase staining. 17beta-estradiol dose-dependently inhibited the onset of EPC senescence in culture. Because cellular senescence is critically influenced by telomerase, which elongates telomeres, we measured telomerase activity using a polymerase chain reaction (PCR)-enzyme-linked immunosorbent assay (ELISA) technique. 17beta-estradiol significantly increased telomerase activity. Interestingly, reverse transcriptase-PCR analysis demonstrated that 17beta-estradiol dose-dependently increased the catalytic subunit, telomerase reverse transcriptase (TERT) - an effect that was significantly inhibited by pharmacological phosphatidylinositol 3-kinase (PI3-K) blockers (either wortmannin or LY294002). Because the expression of TERT is regulated by the PI3-K/Akt pathway, we examined the effect of 17beta-estradiol on Akt activity in EPCs. Immunoblotting analysis revealed that 17beta-estradiol dose-dependently led to phosphorylation and, thus, to activation of Akt in EPCs. We also examined whether the protective effect of 17beta-estradiol on EPC senescence translates into the augmentation of mitogenic activity in EPCs. A [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenol)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay demonstrated that the mitogenic potential in EPCs treated with 17beta-estradiol exceeded that in untreated (control) EPCs (P < 0.01). In addition, EPCs released vascular endothelial growth factor (VEGF) protein--an effect that was significantly augmented by 17beta-estradiol. Finally, in a Matrigel assay, EPCs treated with both 17beta-estradiol and VEGF were shown to be more likely to integrate into the network formation than those treated with VEGF alone.

CONCLUSION: The inhibition of EPC senescence by estrogen in vitro may improve the functional activity of EPCs in a way that is important for potential cell therapy.

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.
Recent studies have demonstrated that aging or senescence constitutes a potential limitation to the ability of endothelial progenitor cells (EPCs) to sustain ischemic tissue repair. Excess amount of reactive oxygen species (ROS) is involved in senescence, causing defective neovascularization. Conversely, estrogens have been shown to accelerate recovery of the endothelium after vascular injury. Estrogen reduces EPC senescence through augmentation of telomerase activity. In addition, the inhibition of EPC senescence by estrogen in vitro may improve the functional activity of EPCs in a way that is important for potential cell therapy. This review describes current understanding of EPC senescence and the role of estrogen in preventing EPC senescence.

--

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. ShayDepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039

(iv) Steroid hormones.
Human telomerase activity is detected in normal human endometrium during the menstrual cycle and is tightly correlated with the proliferative activity of endometrial cells (134, 227). These observations suggested that steroid sex hormones might regulate telomerase activity.

Sequence analyses of the hTERT promoter revealed two potential estrogen response elements. One is located at −950 bp upstream of the ATG and contains an Sp1 site adjacent to an estrogen response half-site known to function as an estrogen response element. The second element is located at −2754 bp upstream of the ATG (37, 133). Recent studies have now demonstrated that estrogen activates telomerase through direct transcriptional regulation of hTERT expression in hormone-sensitive tissues (133, 166).Studies in estrogen receptor-positive human ovary epithelial cells showed that telomerase activity is readily detectable, in parallel with induction of hTERT mRNA and protein expression, within 3 h of treatment with 17β-estradiol. Estrogen activation of hTERT transcription seems to depend on estrogen receptor α but not estrogen receptor β in these cells. In vivo DNA footprinting revealed specific modifications of the −950 estrogen response element in estrogen receptor α-positive but not -negative cells upon treatment of with 17β-estradiol. In addition, luciferase reporter assays showed that the −950 estrogen response element is directly responsible for the observed induction of hTERT transcription by estrogen and that this estrogen response element is functional when placed into the heterologous thymidine kinase promoter (166).The activation of the hTERT promoter by estrogen was also observed in a breast cancer cell line MCF-7, in which an estrogen response element located at −2754 upstream of the ATG plays a major role in mediating hTERT activation as well as having an indirect effect on hTERT activation through induction of c-myc by estrogen (133).

In breast cancer and colon cancer cell lines, tamoxifen, a nonsteroid antiestrogen drug widely used as adjuvant therapy to treat breast cancer, reduces telomerase activity (2, 179). The antagonistic effect of tamoxifen on estrogen-induced telomerase activity is consistent with its inhibitory effect on activation of the hTERT promoter by estrogen (166).

A second sex steroid hormone, progesterone, is known to antagonize estrogen's actions and inhibit estrogen-induced cell proliferation and has been used therapeutically to treat estrogen-dependent cancers (101). Evidence indicates that the hTERT promoter is a target of progesterone (242). Progesterone exerts a biphasic effect on hTERT expression, depending on the duration of exposure: hTERT mRNA is induced within 3 h but decreases after 12 h. Exposure to progesterone inhibits estrogen-induced activation of hTERT expression (242). The mechanism by which progesterone regulates hTERT expression seems complex. Although it may involve the mitogen-activated protein kinase-signaling pathway, the downstream effectors interacting directly with the hTERT promoter are unknown. On the other hand, progesterone induces expression of p21, a cyclin-dependent protein kinase inhibitor that negatively regulates the cell cycle. It is known that cell cycle exit results in downregulation of telomerase (19, 109). Therefore, progesterone's negative effects on the hTERT activation by estrogen may be indirect.

The effects of androgens on telomerase activity have also been studied in human prostate cancer cells. Telomerase activity is reduced by androgen deprivation in the androgen-sensitive cell line LNCaP but is reactivated upon treatment with testosterone. However, androgens have no effect on telomerase activity in the androgen-independent cell line DU145 (218). The mechanism underlying activation of telomerase by androgens is unknown; the conversion from androgen to estrogen could contribute to telomerase activation, or androgens could activate hTERT transcription directly. These possible mechanisms remain to be investigatedThe finding that steroid hormones directly target human telomerase may provide important insights into the molecular mechanisms of tumorigenesis in hormone-dependent tissues and perhaps, in the future, clinical management of hormone-dependent cancers.


http://physrev.physiology.org/cgi/content/full/88/2/557
Physiol. Rev. 88: 557-579, 2008; doi:10.1152/physrev.00026.2007
Telomeres and Aging  Geraldine Aubert and Peter M. Lansdorp
Terry Fox Laboratory, British Columbia Cancer Agency, and Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

http://www.physorg.com/news/2010-11-partial-reversal-aging-mice.html
Partial reversal of aging achieved in mice November 29, 2010 By Richard Saltus Enlarge
Researchers led by Ronald A. DePinho (above), a Harvard Medical School professor of genetics, say their work shows for the first time a dramatic reversal of many aspects of age-related degeneration in mice, a milestone in aging science achieved by engineering mice with a controllable telomerase gene. The projection of chromosomes seen here shows telomeres (highlighted in red) on their ends. Photo by Kris Snibbe.


Estradiol better than genetic engineering for lengthening telomeres in liver model

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774098/?tool=pubmed
Gut. 2004 Jul;53(7):1001-9.
Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis.

Sato R, Maesawa C, Fujisawa K, Wada K, Oikawa K, Takikawa Y, Suzuki K, Oikawa H, Ishikawa K, Masuda T. Department of Pathology, Iwate Medical University School of Medicine, 020-8505 Morioka, Japan.

The present study suggested that administration of exogenous oestradiol could rescue hepatocytes from extensive telomere shortening by upregulation of TA, resulting in prolongation of their life span, in vitro and in vivo. 

The telomerase gene therapy proposed by Depinho and colleagues2,18 is a fascinating option for restoring telomere length in patients with end stage liver failure. However, gene therapy using human telomerase RNA (human telomerase RNA component: hTERC) has a few limitations that need to be overcome before actual clinical application. As the hTERC gene is not deficient in human hepatocytes, it remains obscure whether hTERC gene delivery by adenovirus vectors would be able to increase telomerase activity and prevent critical telomere shortening in human hepatocytes as well as in hTERC deficient mice. In addition, considering the safety of vectors and the risk of cancer development by uncontrolled upregulation of TA, gene therapy would only be justified in patients with end stage liver failure (senescence or pre-crisis).48–50

However, the ideal telomerase therapy would be one that achieves early telomerase reactivation long before cirrhosis, thus preventing telomere dysfunction and genetic instability and reducing the rate of hepatocellular carcinoma development.

For early start and long term telomerase therapy in patients with chronic liver disease, exogenous oestradiol administration is a more suitable therapeutic option than gene therapy. 

Results: Expression of hTERT mRNA and its protein was upregulated by oestradiol treatment. Telomere length decreased in Hc-cells and h-Nheps with accumulated passages whereas with long term oestradiol exposure it was greater than without oestradiol. The incidence of β-galactosidase positive cells, indicating a state of senescence, decreased significantly in oestradiol treated cells in comparison with non-treated cells (p<0.05). TA in both male and female rats with CCl4 induced liver fibrosis was significantly higher with oestradiol administration than without (p<0.05). Long term oestradiol administration markedly rescued the hepatic telomere from extensive shortening in both male and female rats.

Conclusion: These results suggest that oestradiol acts as a positive modulator of the hTERT gene in the liver. Oestrogen dependent transactivation of the hTERT gene is a new strategy for slowing the progression of chronic liver disease

http://circres.ahajournals.org/cgi/content/full/103/1/34#R35-169037
Estrogen Receptor- and Endothelial Nitric Oxide Synthase Nuclear Complex Regulates Transcription of Human Telomerase by Annalisa Grasselli, Simona Nanni, Claudia Colussi, Aurora Aiello, Valentina Benvenuti, Gianluca Ragone, Fabiola Moretti, Ada Sacchi, Silvia Bacchetti, Carlo Gaetano, Maurizio C. Capogrossi, Alfredo Pontecorvi, Antonella Farsetti From Rome

http://www.ncbi.nlm.nih.gov/pubmed/14673504
Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003 Dec;35(12):1117-22.

[Effects of sodium selenite on telomerase activity and telomere length]
[Article in Chinese] Liu Q, Wang H, Hu DC, Ding CJ, Xiao H, Xu HB, Shu BH, Xu SQ.

Abstract
To study the biological basis of selenium in resisting senescence through its effects on cellular telomerase activity and telomere length. In the experiments, the cell line of hepatocytes L-02 was divided into three groups supplemented with sodium selenite at final concentrations of 0, 0.5 and 2.5 micromol/L, respectively. Cellular telomerase activity was measured by telomeric repeat amplification protocol and enzymatic luminometric inorganic pyrophosphate detection assay. RT-PCR was used to semi-quantitatively detect human telomerase reverse transcriptase (hTERT) gene expression. The change of telomere length was assayed through flow cytometry and fluorescence in situ hybridization. Results showed that L-02 cells had low telomerase activity and hTERT gene expression level when cultured in the normal way. The cells grew well after 3-week-cultivation in the media supplemented with 0.5 or 2.5 micromol/L sodium selenite. Besides, sodium selenite significantly increased cellular telomerase activity and hTERT gene expression level. The telomere length of L-02 cells was also extended after 4-week-cultivation with sodium selenite. Thus, sodium selenite at nutritional doses could prolong the life span of hepatocytes L-02 through increasing telomerase activity and telomere length. This result provides a possible mechanism for explaining the anti-senescence function of selenium.



Financial Disclosures

http://projects.propublica.org/docdollars/states/massachusetts

De Pinho, Ronald Boston GSK 2009 Q2-Q4 Consulting: $5500.00 

Ronald A Depinho GSK  2010 Q1-Q2 Consulting: $78000.00

Karyopharm is a privately held oncology company headquartered in Newton, Massachusetts. The Company was founded in 2009 by Drs. Sharon Shacham, Michael Kauffman, Ronald DePinho, and Giulio Draetta.

Karyopharm Therapeutics Inc. Closes $20 Million Series A Financing to Advance Pipeline of Novel Nuclear Transport Modulators for - FierceBiotech

http://www.fiercebiotech.com/press-releases/karyopharm-therapeutics-inc-closes-20-million-series-financing-advance-pipeline-novel#ixzz16iZze5Pd

Dr. DePinho is the Director of the Belfer Institute for Applied Cancer Science and Professor of Medicine and Genetics at the Dana-Farber Cancer Institute and Harvard Medical School.

Read more: Karyopharm Therapeutics Inc. Closes $20 Million Series A Financing to Advance Pipeline of Novel Nuclear Transport Modulators for - FierceBiotech

http://www.businesswire.com/news/home/20101001005137/en/Dana-Farber-Cancer-Institute-completes-historic-1-billion  
Dana-Farber Cancer Institute completes historic $1 billion capital campaign
Largest hospital-based campaign in New England helps advance cancer research and care

Comment to WS Journal

The finding of Dr, Ronald A. DePinho, that 12 Beta estradiol reverses senescence through its action on TERT in the telomeres has been discovered previously by others and is in fact old news.  What is new about  his research is the use of a genetically engineered mouse model with abnormal telomers and accelerated aging.  The ability of 17 Beta estradiol to reverse and restore these aged mice is indeed remarkable.

references

J Hypertens. 2005 Sep;23(9):1699-706. Estrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activity.Imanishi T

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,

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