Longevity and Sex Hormones

There are hundreds of journal articles demonstrating the health-longevity benefits of estradiol. The main mechanism by which women extend life with HRT, and conversely die sooner with less estradiol is through estradiol promoting anti-oxidant production, which thus lowers the risk of numerous chronic age related conditions. Others positive effects from HRT include bone remodeling which prevents osteoporosis, mild androgen affect through conversion of about 10% to testosterone, which prevents sarcopenia prevent loss of muscle, anti-inflammatory effect for reduction of risk of rheumatoid arthritis. The greatest life extension comes through the prevention of cardiovascular disease, which comes mainly through the anti-oxidation and down regulating the immune response and thereby reducing atherogenesis and thus cardiovascular disease. For a complete list of benefits, why pharma’s HRT are significantly inferior to natural HRT, the junk science used staring in the late 90s by pharma to limit HRT usage, and recommendation for natural HRT go to http://healthfully.org/rc/id2.html .

There are hundreds of journal articles demonstrating the longevity for testosterone supplement, though a number for its health benefits. The association is weak because the research has been done. HRT for women has been widely marketed for decades because the progestin added entail that the product was patentable. With Testosterone that approach to market never met success. In the 1980 Goodman and Gilman pharmacology textbook, page 1456-8 are listed 18 analogues of testosterone, none of them have every been widely used. However, for testosterone, given that it has just one functional group difference for that of estrogen, and given that many of the health benefits, a reasonable conclusion is that there are significant health benefits that promote longevity. Moreover, given that those in the lowest 20% (quintile) have a mortality rate twice that of the highest quintile, this confirms the hypothesis (note: those in the lowest quintile have a much higher percentage of people with major health issues including diabetes, cancer, cancer, etc. for which some cause low testosterone.) For benefits of testosterone supplement, response to pharma’s junk science, and recommendations go to http://healthfully.org/rc/id7.html.

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http://sageke.sciencemag.org/cgi/content/abstract/2005/23/pe17 , Science of Aging, June 8, 2005

Why Females Live Longer Than Males: Control of Longevity by Sex Hormones

Abstract: Females live longer than males in many species, including humans. We have traced a possible explanation for this phenomenon to the beneficial action of estrogens, which bind to estrogen receptors and increase the expression of longevity-associated genes, including those encoding the antioxidant enzymes superoxide dismutase and glutathione peroxidase. As a result, mitochondria from females produce fewer reactive oxygen species than those from males. Administering estrogens has serious drawbacks, however--they are feminizing (and thus cannot be administered to males) and may increase the incidence of serious diseases such as uterine cancer in postmenopausal women. Phytoestrogens, which are present in soy or wine, may have some of the favorable effects of estrogens without their undesirable effects. Study of gender differences in longevity may help us to understand the basic processes of aging and to devise practical strategies to increase the longevity of both females and males.

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Shows that estrogen down regulates insulin and reduces oxidative stress in female mice.

http://www.jbc.org/content/280/16/16417.short

Estrogen, Insulin, and Dietary Signals Cooperatively Regulate Longevity Signals to Enhance Resistance to Oxidative Stress in Mice--2005

[Partial abstract] Suggesting that the suppressed insulin signaling leads to an enhanced antioxidant defense. It was found that the survival of mice under 80% oxygen [oxidative stress via high air oxygen] was extended when they were administered estradiol. In contrast, mutant and wild-type female mice showed shortened survivals when their ovaries were removed. The influence of estrogen is remarkable in mutant mice compared with wild-type mice, suggesting that estrogen modulates insulin signaling in mutant mice. Furthermore, we showed additional extension of survival under oxidative conditions when their diet was restricted. Collectively, we show that three distinct signals; insulin, estrogen, and dietary signals work in independent and cooperative ways to enhance the resistance to oxidative stress in mice.

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There are major issue with a population study. These include too low a dose, estrogen mimic instead of estrogen, using a different estrogen estriol which is an antagonist (blocks) of estradiol, and using it with a progestin such as medroxyprogesterone which also blocks some of the beneficial effects of estradiol. Finally many of the women used equine (horse estrogen) which is of unknown value (the 625 mg. is the commonly used horse estrogen dose). Nevertheless there was modest benefit. In a similar Danish study using Nordisc survival was with long-term usage (over 10 years) extended life 4 years.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373269/

Menopause. 2006 Jan-Feb; 13(1): 12–18. doi: 10.1097/01.gme.0000172880.40831.3b

Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study--2006

Objective

To examine the effect of postmenopausal estrogen therapy (ET), including duration and recency of use, on all-cause mortality in older women.

Design

As part of a prospective cohort study of residents of a California retirement community begun in the early 1980s, Leisure World Cohort women (median age, 73 y) completed a postal health survey including details on ETuse and were followed up for 22 years (1981–2003). Age- and multivariate-adjusted risk ratios (RR) and 95% CIs were calculated using proportional hazard regression.

Results

Of the 8,801 women, 6,626 died during follow-up (median age, 88 y). ET users had an age-adjusted mortality rate of 52.9 per 1,000 person-years compared with 56.5 among lifetime nonusers (RR = 0.91; 95% CI, 0.87–0.96). Risk of death decreased with both increasing duration of ET and decreasing years since last use (P for trend <0.001). The risk was lowest among long-term (≥15 y) users (RR = 0.83; 95% CI, 0.74–0.93 for 15–19 y and RR = 0.87; 95% CI, 0.80–0.94 for 20+ y). For long-term users, the age-adjusted mortality rate was 50.4 per 1,000 person-years. Lower-dose users (≤0.625 mg) had a slightly better survival rate than higher-dose users (RR = 0.84; 95% CI, 0.78–0.91 vs RR = 0.91; 95% CI, 0.83–0.97). [This is because Prempro, horse estrogen with MPA, is in the high dose group]. Risk did not differ by route of administration (P = 0.56). Further adjustment for potential confounders had little effect on the observed RRs for ET.

Conclusion

Long-term ET is associated with lower all-cause mortality in older women.

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Full http://www.sciencedirect.com/science/article/pii/S0014579305004540 doi:10.1016/j.febslet.2005.03.090

Why females live longer than males? Importance of the upregulation of longevity-associated genes by oestrogenic compounds--2005

Abstract

Females live longer than males in many mammalian species, including humans. Mitochondria from females produce approximately half the amount of H₂O₂ than males. We have found that females behave as double transgenics overexpressing both superoxide dismutase and glutathione peroxidase. This is due to oestrogens that act by binding to the estrogen receptors and subsequently activating the mitogen activated protein (MAP) kinase and nuclear factor kappa B (NF-κB) signalling pathways. [Some] Phytoestrogens mimic the protective effect of oestradiol using the same signalling pathway. The critical importance of upregulating antioxidant genes, by hormonal and dietary manipulations, in order to increase longevity is discussed.

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http://biomedgerontology.oxfordjournals.org/content/early/2012/03/25/gerona.gls068.short

J Gerontol A Biol Sci Med Sci(2012)doi: 10.1093/gerona/gls068

The Role of Androgens and Estrogens on Healthy Aging and Longevity—2012

Abstract

Aging is associated with a loss of sex hormone in both men (andropause) and women (menopause). In men, reductions in testosterone can trigger declines in muscle mass, bone mass, and in physical function. In women, the impact of the loss of sex hormones, such as estradiol, on bone is well elucidated, but evidence is limited on whether the loss of estradiol negatively affects muscle mass and physical function. However, deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons. Thus, consideration should be given as to whether targeted hormone replacement therapies may prove effective at treating clinical conditions, such as age-related sarcopenia, cancer cachexia, and/or acute or chronic illnesses. If initiated carefully in the appropriate clinical population, hormone replacement therapies in men and women may prevent and reverse muscle and bone loss and functional declines and perhaps promote healthy aging and longevity.

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An excellent review of the literature

Estradiol and testosterone differ from each other by one functional group, thus their bio-activities often overlap. (Dihydrotestosterone form is responsible for most of the sex related changes.) Very possible following menopause the 2 other estrogens (since estradiol is declines with menopause) maintain the vascular benefits into old age, while with men there is no similar process following andropause. There are no longer-term studies of testosterone replacement in men to confirm or contradict this theory. A search of scholar.google entering “testosterone replacement + rats” is tentatively confirmative.

For the full article go to http://journal.frontiersin.org/article/10.3389/fphys.2012.00089/full

REVIEW ARTICLE Front. Physiol., 10 April 2012 | http://dx.doi.org/10.3389/fphys.2012.00089

Testosterone and vascular function in aging

Sex hormones, including testosterone, have important extragonadal effects and experimental and clinical data point to important effects of sex hormones on the cardiovascular system (Reckelhoff, 2005)…. low levels are associated with the progression of atherosclerosis, production of pro-inflammatory cytokines, increased arterial thickness, increased levels of glucose, total cholesterol, and low-density lipoprotein, all important in cardiovascular disease.

Commonly, testosterone replacement improves cardiovascular and metabolic functions (Ruige et al., 2011; Hyde et al., 2012). In addition, a prospective observational study with men aged 70–96 years demonstrated that low testosterone in men, independent of pre-existing health conditions, and other risk factors, is associated with increased mortality risk (Fukai et al., 2011).

Experimental data demonstrate that testosterone induces relaxation of many vascular beds, including coronary, mesenteric, iliac, renal, and femoral arteries in several animal species such as rabbit, dog, rat, pig, both in vivo and in vitro conditions [lowers blood pressure]. In general, most studies indicate that the relaxation induced by testosterone involves endothelium-independent mechanisms, potassium channel-opening actions and calcium antagonistic effects (Yue et al., 1995; Chou et al., 1996; Crews and Khalil, 1999; Murphy and Khalil, 1999; English et al., 2000, 2002; Deenadayalu et al., 2001)…. Using endothelial cell cultures these authors demonstrated that testosterone enhances NO production by directly acting in the endothelial cells via PKC- and MAPK-dependent pathways. Testosterone also significantly increased DNA synthesis indicating that androgens may also modulate vascular endothelial cell growth (Campelo et al., 2012). In addition, testosterone, at physiological concentrations and via androgen receptor activation, induces proliferation, migration, and colony formation activity of EPCs (Foresta et al., 2008), indicating that the release of EPCs by bone marrow may be an additional mechanism by which testosterone modulates endothelial function (Foresta et al., 2006)…. Testosterone also stimulates thromboxane synthase as well as COX-1 and COX-2, which are key enzymes in the synthesis of prostaglandins (Cheuk et al., 2000; Song et al., 2004). Accordingly, the aging-associated decrease in testosterone levels may interfere with vascular function via changes in the thromboxane/COX pathway (Figure 1).

Hypogonadism is a condition associated with endothelial dysfunction (Akishita et al., 2007; Foresta et al., 2008). A study where male patients were submitted to examination of vasomotor function of the brachial artery and intima-media thickness (IMT) of the carotid artery, showed that low levels of testosterone are associated with endothelial dysfunction, independent of age, body mass index, hypertension, hyperlipidemia, diabetes mellitus, or current smoking, suggesting a protective effect of testosterone on endothelial function (Akishita et al., 2007). Likewise, testosterone has been shown to improve hemodynamic parameters in patients and animal models of heart failure, especially via a reduction in peripheral vascular resistance and increased coronary blood flow through vasodilation and via direct effects in the cardiac tissue (e.g., by inhibition of cardiac cAMP-phosphodiesterases; Bordallo et al., 2011; Nguyen et al., 2011)…. Transdermal testosterone replacement therapy increased androgen bioavailability and decreased pulse wave velocity, indicating that testosterone replacement can diminish arterial stiffness associated with male hypogonadism (Yaron et al., 2009). [The use of transdermal or other prepackaged testosterone products are designed to only increase the level from low to normal for the elderly Far greater benefits are obtained by increasing the dose by two to 3 fold so as to obtain a high youthful level. Two positives examples are Jk and Dr. Paul Thompson of Cenegenics who is seen on television and in magazines. They are two examples. The higher level is necessary to counter the reduce bioactivity that occurs with aging. Remember that pharma is in the business of treating illness, thus they oppose the use of effective dose of testosterone—their normal business practice.]

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Of course similar, though greater benefits are true for natural hormone replacement therapy for women, see HRT. And of course pharma has used the worse formulation Prempro and the NIH’s WHI study (2002) to limit HRT usage. Note A century ago men lived longer than women, mainly because of the risks of delivering children and the drain of going through over a half-dozen pregnancies. Men are still subjected to greater environmental hazards in the work place, a factor contributing to the difference in death rate. I would also include the earlier decline in testosterone which is about 50 percent when compared to a study dine in 1914. I suspect that estrogen mimic, possible from the increase in soya bean products whose usage by food manufacturers has steadily increased.

http://sageke.sciencemag.org/cgi/content/abstract/2005/23/pe17 Sci. Aging Knowl. Environ., 8 June 2005
Vol. 2005, Issue 23, p. pe17

Why Females Live Longer Than Males: Control of Longevity by Sex Hormones

Abstract: Females live longer than males in many species, including humans. We have traced a possible explanation for this phenomenon to the beneficial action of estrogens, which bind to estrogen receptors and increase the expression of longevity-associated genes, including those encoding the antioxidant enzymes superoxide dismutase and glutathione peroxidase. As a result, mitochondria from females produce fewer reactive oxygen species than those from males.