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We compared a group of 78 female centenarians living in the suburban Boston area (Massachusetts, USA) with a similar birth cohort of 54 women born in 1896, but who died at 73 years of age in 1969 (Fig. 1). We located the next-of-kin of these subjects using data provided by the Massachusetts Registry of Vital Records. By comparing women with the same year of birth, we minimized concerns about temporally related influences upon fertility such as health and contraception-related trends, war, fluctuations in the economy (the boom of the 1920s, the Great Depression) and so on. Subjects from both the centenarian and septuagenarian groups were excluded if they did not have the opportunity to have children (never married or hysterectomy before age 35 years). There were no significant differences between the two cohorts in terms of rate of hysterectomy, loss of spouse before age 45, marriage without children, years of education, religion or race.

Figure 1: Percentage of women having children at or beyond ages 35 and 40.
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The difference in the number giving birth at or after age 35 in the two groups was not statistically significant (odds ratio=1.5, 95% confidence interval (CI): 0.7-3.1, P=0.3), but was significant in those giving birth at or after age 40 (odds ratio=4.0, 95% CI: 1.02-18.7, P=0.02).

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Our findings may allow the prediction of individuals predisposed to extreme longevity and may also have implications regarding the theoretical basis of menopause and human lifespan. During the first quarter of this century, fertility-enhancing interventions for older women were not available. Under these circumstances, later menopause, as well as pregnancy after age 40, may be associated with extreme longevity.

Menopause could act evolutionarily to protect the ageing woman from the hazards of childbirth. We therefore support the theorythat as humans evolved and became able to reach greater ages, there came a point when survival during childbirth began to decline as a function of further ageing and increased frailty1. ‘Premature’ death of the mother would also put at risk any existing children and their potential for reproduction2. At the age when the risk of child-bearing outweighs the benefit of producing progeny, natural selection would favour women who became infertile; thus, the evolutionary pressure for menopause.

Although menopause still occurs, the genes that allowed a woman to age more slowly continue to exert their influence. A continued slow rate of ageing and perhaps also a decreased susceptibility to diseases associated with ageing that can cause premature mortality would therefore allow a woman to achieve extreme longevity. These observations in humans concur with selection experiments in fruitflies in which the ability to produce eggs later in life is correlated with greater life expectancy3.

It was recently noted that women who took oestrogen were less likely to develop Alzheimer's disease or were likely to show a delay in onset if the disease did develop4. The same may be true for women who go through menopause later, who have a prolonged exposure to endogenously produced oestrogen (or other concomitantly produced substances). By avoiding, or at least delaying, diseases associated with ageing that can cause premature mortality, such as Alzheimer's disease, heart disease or stroke, these women can therefore achieve greater longevity.

It has been suggested that the selective forces determining longevity in females were the driving force behind the lifespan of humans5. Extending this theory, we argue that the driving selective force of human lifespan is maximizing the period of time during which women can bear children. The age at which female survival is diminished by further reproduction may therefore be the determinant of subsequent lifespan. One might ask why menopause does not occur in most other mammalian species6,7, and the answer may be that in those species the mortality risk of giving birth is relatively low even at advanced age and does not outweigh the benefit. We should now search for associations between genes that regulate reproductive fitness and ovarian ageing and genes that regulate rates of ageing and susceptibility to diseases associated with ageing.