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Sex Differences in Healthy Longevity

That men and women are different in significant ways has been realized for a long time. But researchers are just now beginning to explore in-depth a broad range of sex-differences in health and longevity. The topic goes far beyond trivial differences in map-reading skills or the willingness to ask for directions. Important health outcomes — cognitive function, cardiovascular disease risk, cancer incidence, even longevity — display sex differences.

Scientists at the Murphy Foundation have a serious interest in sex-differences in healthy longevity. The following annotated list of scientific papers benchmarks some of the evidence that is accumulating in the underexplored field of sex-differences in healthspan.

Parker, W.H., Broder, M.S., Chang, E., Feskanich, D., Farquhar, C., Liu, Z., et al. (2009). Ovarian conservation at the time of hysterectomy and long-term health outcomes in the Nurses’ Health Study. Obstetrics & Gynecology, 113(5), 1027-1037.

In this study of more than 29,000 women who underwent hysterectomy for benign uterine disease, women who kept their ovaries for at least 50 years had a survival advantage over women who underwent ovarian removal before 50 years of age. The authors believe these results signal that it is time for women and their physicians to rethink automatic ovary removal at the time of hysterectomy.

Nakamura, E. & Miyao, K. (2008). Sex differences in human biological aging. Journal of Gerontology A Biol Sci Med Sci, 63(9), 936-944.

This study of 86 men and 93 women in Japan evaluated the use of 5 parameters to explore sex-specific differences in rate of functional decline. The results suggested that women have a slower rate of aging than men.

Kulminski, A., Ukraintseva, S.V., Akushevich, I., Arbeev, K.G., Land, K., & Yashin, A.I. (2007). Accelerated accumulation of health deficits as a characteristic of aging. Experimental Gerontology, 42(10), 963-970.

This study provided cross-sectional and longitudinal comparisons of frailty index among elderly U.S. men and women.

Milne, E.M. (2007). Postponement of postmenopausal mortality acceleration in low-mortality populations. New York Academy of Sciences, 1100, 46-59.

This study analyzed post-menopausal mortality acceleration in women and equivalent- aged men using World Health Organization (WHO) data on mortality. The investigator concluded that mortality acceleration in women during post-menopausal years is internationally consistent across 34 countries.

Shardell, M., Hicks, G.E., Miller, R.R., Kritchevsky, S., Andersen, D., Bandinelli, S., et al. (2009). Association of low vitamin D levels with the frailty syndrome in men and women. Journal of Gerontology A Biol Sci Med Sci, 64(1), 69-75.

This study of more than 1,000 men and women of age 65 years and older showed vitamin D insufficiency (serum 25-hydroxyvitamin D3 < 30 ng/mL) was associated with frailty in men, but not in women.

Merz, C.N., Johnson, B.D., Berga, S.L., Braunstein, G.D., Azziz, R., Yang, Y., et al. (2009). Total estrogen time and obstructive coronary disease in women: insights from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE). Journal of Women’s Health, 18(9),1315-22.

This study of women with cardiac disease showed a complex relationship between duration of lifetime estrogen exposure and adverse cardiovascular events.

Waters, D.J., Chiang, E.C., Cooley, D.M., & Morris, J.S. (2004). Making sense of sex and supplements: differences in the anticarcinogenic effects of selenium in men and women. Mutation Research, 551(1-2), 91-107.

In this review of prospective cohort studies from 7 countries, we concluded that the available information supports the notion that cancer risk in men is more profoundly influenced by low selenium status than cancer risk in women. These results emphasize that the ambitious goal of cancer prevention will likely require personalized, and perhaps sex-specific, strategies.

Wallace, K., Kelsey, K., Schned, A., Morris, J.S., Andrew, A., & Karagas, M.R. (2009). Selenium and risk of bladder cancer: a population-based case-control study. Cancer Prevention Research, 2(1), 70-73.

This case-control study of bladder cancer (857 incident cases, 1191 cancer-free controls) showed low selenium status may be a more important risk factor for bladder cancer in women than in men. Also, the dose-response between selenium and bladder cancer risk might not be linear, but instead U-shaped.

Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Evens, P.C., et al. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature, 421(6919), 182-187.

In this study, female mice with heterozygous knockout of the insulin-like growth factor receptor lived 33% longer than wild-type mice and displayed an increased resistance to oxidative stress. In contrast, the longevity of male mice with the same genetic alteration was not significantly affected.

Turturro, A., Duffy, P., Hass, B., Kodell, R., & Hart, R. (2002). Survival characteristics and age-adjusted disease incidences in C57BL/6 mice fed a commonly used cereal-based diet modulated by dietary restriction. Journal of Gerontology A Biol Sci Med Sci, 57(11), B379-89.

In this study, female mice gained more longevity benefit from caloric restriction than male mice. The results suggest males and females may respond differently to longevity-promoting interventions.

Ali, S.S., Xiong, C., Lucero, J., Behrens, M.M., Dugan, L.L. & Quick, K.L. (2006). Gender differences in free radical homeostasis during aging: shorter-lived female C57BL6 mice have increased oxidative stress. Aging Cell, 5(6), 565-574.

Investigators studied C57BL6 mice, a strain in which females have a survival disadvantage compared to males. They found that females, the disadvantaged sex, gained a greater longevity benefit than males when treated with a drug that reduces oxidative stress.

Borras, C., Sastre, J., Garcia-Sala, D., Lloret, A., Pallardo, F.V., & Vina, J. (2003). Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radical Biology & Medicine, 34(5), 546-552.

This study demonstrated that the mitochondria of female rats generate less reactive oxygen species than mitochondria of male rats. Interestingly, ovary removal increased oxidative stress in female rats; this detrimental effect of ovariectomy was reversed by estrogen replacement.

Almeida, M., Han, L., Martin-Millan, M., Plotkin, L.I., Stewart, S.A., Roberson, P.K., et al. (2007). Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. Journal of Biological Chemistry, 282(37), 27285-27297.

This study in mice showed taking way gonads from females and males increases oxidative stress in bone. Oxidative stress may mediate aging-related loss of bone mass and strength.

Kousteni, S., Chen, J.R., Bellido, T., Han, L., Ali, A.A., O’Brien, C.A., et al. (2002). Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science, 298(5594), 843-846.

This study explored the ability of sex steroids to reverse the adverse effects of gonadectomy on bone mass and strength in female and male mice.