Mechanisms of ovarian aging.

Ovarian aging in women correlates with the progressive loss of both the number and quality of oocytes. When these processes occur early or are accelerated, their clinical correlates are diminished ovarian reserve and/or premature ovarian insufficiency. Both these conditions have important consequences for the reproductive and general health of women, including infertility. Although there are many contributing factors, the molecular mechanisms underlying many of the processes associated with ovarian aging have not been fully elucidated. In this review, we highlight some of the most critical factors that impact oocyte quantity and quality with advancing age. We discuss chromosomal factors including cohesion deterioration and mis-segregation, errors in meiotic recombination, and decreased stringency of the spindle assembly checkpoint. DNA damage, telomere changes, reactive oxygen species and mitochondrial dysfunction as they relate to ovarian aging, and well-known gene mutations associated with primary ovarian insufficiency and diminished ovarian reserve are also discussed. Additionally, studies investigating recently acknowledged cytoplasmic factors associated with ovarian aging including protein metabolic dysregulation and microenvironmental alterations in the ovary are presented. We use both mouse and human studies to support the roles these factors play in physiologic and expedited ovarian aging, and we propose directions for future studies. A better understanding of the molecular basis of ovarian aging will ultimately lead to diagnostic and therapeutic advancements that would provide women with information to make earlier choices about their reproductive health.