Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice

Abstract

The menopausal transition in human females, which is driven by a loss of cyclic ovarian function, occurs around age 50 and is thought to underlie the emergence of an array of health problems in aging women. Although mice do not undergo a true menopause, female mice exhibit ovarian failure long before death because of chronological age and subsequently develop many of the same age-associated health complications observed in postmenopausal women. Here we show in mice that inactivation of the proapoptotic Bax gene, which sustains ovarian lifespan into advanced age, extends fertile potential and minimizes many age-related health problems, including bone and muscle loss, excess fat deposition, alopecia, cataracts, deafness, increased anxiety, and selective attention deficit. Further, ovariectomy studies show that the health benefits gained by aged females from Bax deficiency reflect a complex interplay between ovary-dependent and -independent pathways. Importantly, and contrary to popular belief, prolongation of ovarian function into advanced age by Bax deficiency did not lead to an increase in tumor incidence. Thus, the development of methods for postponing ovarian failure at menopause may represent an attractive option for improving the quality of life in aging females.aging ͉ apoptosis ͉ menopause ͉ ovary A lthough the process of aging has been attributed in part to increased apoptosis in various tissues (1), animal models lacking cell death-regulatory genes are rarely subjected to longitudinal aging studies. In females, one of the first organ systems to fail with age is the reproductive axis, which in humans is a principal contributing factor to the onset of menopause (2). Ovarian failure, whether natural (age-related) or induced as a consequence of pathological insults, is driven by depletion of ovarian follicles, the hormonally active support structures that house oocytes, through apoptosis (3). As a consequence, dramatic changes in the endocrine activity of the female gonads ensue, which are thought to underlie the emergence of a spectrum of physiological and psychological health complications in aging females (2). Although it has been shown that aged female mice transplanted with ovaries of young donors live longer than nontransplanted control or ovariectomized females (4), it remains unclear whether postmenopausal health complications arise as a direct result of ovarian failure or simply reflect the aging process.Despite the fact that mice do not undergo a true menopause, female mice exhaust their follicle pool long before death because of chronological age (5), similar to that seen in humans (6). Further, aging female mice exhibit many of the same health complications associated with postmenopausal life in women (see below). In a previous study, we reported that oocyte and follicle loss in female mice lacking the proapoptotic Bax protein is attenuated, leading to a dramatic prolongation of ovarian function into very advanced age (7). To better understand the consequences of Bax deficiency and sustained ovar...

PUMA regulates germ cell loss and primordial follicle endowment in mice

“…PUMA mediates germ cell loss fertility was not prolonged, but age-related health problems, including bone and muscle loss, were reduced as a consequence of prolonged ovarian function (Perez et al 1999(Perez et al , 2007. These studies support the notion that ovarian function, and possibly fertility, may be prolonged by even a modest increase in the number of initial primordial follicles, conferring significant benefits to health and fertility.…”

T3 preserves ovarian granulosa cells from chemotherapy-induced apoptosis

“…Very few models of protection of the ovary from chemotherapy toxicity have been reported in the literature (Morita et al 2000, Perez et al 2007a,b, Yeh et al 2008, Gonfloni et al 2009, Salih 2011. In this context, one of the major compartments deserving such protection is represented by granulosa cells, which are mainly responsible for hormone production and thus follicular progression.…”

“…Apoptosis has been identified as a key event in the depletion of oocytes and follicles in both aged and chemotherapy-treated women (Fujino et al 1996, Perez et al 2007a. The main compromised compartment is the granulosa cell layer.…”

Genetics of mitochondrial dysfunction and infertility

“…Mitochondria may play an important role in the depletion of oocytes by apoptosis (8). Data from the BAX null mouse indicates that the mitochondrial apoptotic pathway is involved in the atresia of the oocytes (12).…”