Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency

Female mammals are endowed with a finite number of oocytes at birth, each e nclosed by a single layer of somatic (granulosa) cells in a primordial foll icle(1,2). The fate of most follicles is atretic degeneration(1,3), a proce ss that culminates in near exhaustion of the oocyte reserve at approximatel y the fifth decade of life in women, leading to menopause(4,5). Apoptosis h as a fundamental role in follicular atresia(6,7), and recent studies have s hown that Bar, which is expressed in both granulosa cells(8,9) and oocytes( 10), may be central to ovarian cell death(6-12). Here we show that young ad ult female Bax(-/-) mice possess threefold more primordial follicles in the ir ovarian reserve than their wild-type sisters, and this surfeit of follic les is maintained in advanced chronological age, such that 20-22-month-old female Bax(-/-) mice possess hundreds of follicles at ail developmental sta ges and exhibit ovarian steroid-driven uterine hypertrophy. These observati ons contrast with the ovarian and uterine atrophy seen in aged wild-type fe male mice. Aged female Bax(-/-) mice fail to become pregnant when housed wi th young adult males; however, metaphase II oocytes can be retrieved from, and corpora lutea form in, ovaries of aged Bax(-/-) females following super ovulation with exogenous gonadotropins, and some oocytes are competent for in vitro fertilization and early embryogenesis. Therefore, ovarian lifespan can be extended by selectively disrupting Bar function, but other aspects of normal reproductive performance remain defective in aged Bax(-/-) female mice.