On the Benefits of Estrogens in the Context of Longevity Differences by Gender

Why do women tend to live longer than men? There are a good many possible explanations for this well characterized observation. Gender differences in the pace of aging appears to be a robust outcome of the intersection of natural selection with a given mating strategy, but that doesn't say much about the specific mechanisms involved. Sex hormones are the obvious starting point for any investigation of the relevant molecular biology. In humans, estrogen provides numerous physiological benefits in addition to being a sex hormone, and so a higher estrogen level in women is a possible candidate mechanism.

The tudy reported in today's open access paper is an interesting examination of some of the outcomes on metabolism in women who undergo induced menopause followed by estrogen replacement therapy. The effects of these changes are so sweeping that it is hard to separate those relevant to aging: evidence tends to be more suggestive than conclusive in this sort of investigation. No one study will be compelling on its own. The weight of literature does lean in the direction of a sizable role for estrogen in determining a slower pace of aging in women versus men, however.

Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause

The great increase in average life expectancy during the 20th century emerges as one of society's greatest achievements. As a matter of fact, in the last two decades, life expectancy at birth has increased by 5-10 years. Regardless of the cultural or socioeconomic context, women have lived longer than men in different countries and in every era. Nowadays, 75% and 90% of people older than 100 years and 110 years (respectively) are women, and the longest living centenarian person (122 years old) was a woman. This phenomenon occurs not only in humans, but in many species, like all Old-World monkeys, apes, short-finned pilot whales, African lions, red deer, and Wistar rats, in which female life expectancy exceeds male life expectancy by 16%.

One plausible explanation for this protection against aging is that females are endowed with higher levels of estrogens than males. Estrogens are known to have many beneficial effects: cardioprotection, skeletal homeostasis maintenance, brain function, and hematopoietic stem cell division enhancement, among others. Moreover, intramuscular estrogen levels have been recently associated with skeletal muscle strength and power. Furthermore, they act as antioxidants in vitro and also have beneficial effects against oxidative stress in vivo. Indeed, a few years ago, we reported that estrogens were able to induce antioxidant and longevity-related genes, such as glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD) in rats, through a mechanism involving the ERK1-2/NFκB pathway. We thus suggested that this finding could explain why females suffer less oxidative stress than males in many species, including humans.

However, all these estrogen beneficial effects may be lost in menopause. Indeed, we observed that when mimicking postmenopausal loss of estrogens by ovariectomizing Wistar rats, their peroxide production rose, and their glutathione levels decreased. They were restored after estrogen replacement therapy. This confirmed the impact of estrogen as a causative agent for this effect and made us hypothesize that this finding could be extrapolated to humans, that is, that estrogen replacement therapy (ERT) may be useful to restore estrogen levels and thus the estrogen-related beneficial effects.

Thus, the aim of this study was to confirm the ability of estrogens to upregulate antioxidant and longevity-related genes in humans, particularly in women, after a medically induced menopause. As expected, we found that medically induced menopause significantly decreased sexual hormone (estrogens and progesterone) levels. It also lowered glutathione peroxidase (GPx), 16S rRNA, P21, and TERF2 mRNA expression and blood glutathione levels. Estrogen replacement therapy significantly restored estrogen levels and induced mRNA expression of Mn-SOD, GPx, 16S rRNA, P53, P21, and TERF2 and restored blood gluthatione levels. Progesterone replacement therapy induced a significant increase in MnSOD, P53, sestrin 2, and TERF2 mRNA expression when compared to basal conditions. These findings provide evidence for estrogen beneficial effects in upregulating antioxidant and longevity-related genes in women.

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