Abstract
Age-related ovarian failure in women heralds the transition into postmenopausal life, which is characterized by a loss of fertility and increased risk for cardiovascular disease, osteoporosis and cognitive dysfunction. Unfortunately, there are no options available for delaying loss of ovarian function with age in humans. Rodent studies have shown that caloric restriction (CR) can extend female fertile lifespan; however, much of this work initiated CR at weaning, which causes stunted adolescent growth and a delayed onset of sexual maturation. Herein we tested in mice if CR initiated in adulthood could delay reproductive aging. After 4 months of CR, the ovarian follicle reserve was doubled compared to ad libitum (AL)-fed age-matched controls, which in mating trials exhibited a loss of fertility by 15.5 months of age. In CR females returned to AL feeding at 15.5 months of age, approximately one-half remained fertile for 6 additional months and one-third continued to deliver offspring through 23 months of age. Notably, fecundity of CR-then-AL-fed females and postnatal offspring survival rates were dramatically improved compared with aging AL-fed controls. For example, between 10 and 23 months of age, only 22% of the 54 offspring delivered by AL-fed females survived. In contrast, over 73% of the 94 pups delivered by 15.5- to 23-month-old CR-then-AL-fed mice survived without any overt complications. These data indicate that in mice adult-onset CR maintains function of the female reproductive axis into advanced age and dramatically improves postnatal survival of offspring delivered by aged females.
Highlights
Compared to other organ systems, the female reproductive axis ages exceptionally early in life, culminating in a cessation of normal ovarian function that in humans heralds the onset of menopause at around 50 years of age (Richardson et al, 1987; Faddy et al, 1992)
A progressive decline and exhaustion of the ovarian oocyte-containing follicle reserve is the prime determinant of the age of onset of menopause (Richardson et al, 1987; Faddy et al, 1992; Tilly, 2001; Charleston et al, 2007; Hansen et al, 2008), a period in life associated with a loss of fertility and the emergence of a diverse spectrum of health issues resulting from an absence of cyclic ovarian function (Buckler, 2005)
While the mechanisms by which caloric restriction (CR) sustains fertility with age remain to be fully characterized, studies with rats and mice have shown that oocyte numbers are higher in CR females when compared to age-matched ad libitum (AL)-fed controls (Lintern-Moore & Everitt, 1978; Nelson et al, 1985). These findings suggest that the beneficial effects of CR on female reproductive function are at least partly mediated via maintenance of the ovarian follicle reserve in aging animals
Summary
Compared to other organ systems, the female reproductive axis ages exceptionally early in life, culminating in a cessation of normal ovarian function that in humans heralds the onset of menopause at around 50 years of age (Richardson et al, 1987; Faddy et al, 1992). Concomitant with reduced follicle numbers, the quality of the remaining oocytes in females generally declines with advancing age, leading to extremely poor success rates of natural and assisted fertility attempts (Navot et al, 1991; van Kooij et al, 1996). This latter outcome is an increasingly problematic issue as more and more women, especially in Western societies, are postponing childbearing to older ages (Ventura, 1989; Ventura et al, 2004; Hamilton et al, 2007). Despite the promising nature of these findings in mice, strategies for delaying ovarian aging or the timing of menopause in women do not currently exist
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