Reproductive Longevity and Aging: Geroscience Approaches to Maintain Long-Term Ovarian Fitness

Abstract

Increases in delayed childbearing worldwide have elicited the need for a better understanding of the biological underpinnings and implications of age-related infertility. In women 35 years and older the incidences of infertility, aneuploidy, and birth defects dramatically increase. These outcomes are a result of age-related declines in both ovarian reserve and oocyte quality. In addition to waning reproductive function, the decline in estrogen secretion at menopause contributes to multisystem aging and the initiation of frailty. Both reproductive and hormonal ovarian function are limited by the primordial follicle pool, which is established in utero and declines irreversibly until menopause. Because ovarian function is dependent on the primordial follicle pool, an understanding of the mechanisms that regulate follicular growth and maintenance of the primordial follicle pool is critical for the development of interventions to prolong the reproductive life span. Multiple pathways related to aging and nutrient-sensing converge in the mammalian ovary to regulate quiescence or activation of primordial follicles. The PI3K/PTEN/AKT/FOXO3 and associated TSC/mTOR pathways are central to the regulation of the primordial follicle pool; however, aging-associated systems such as the insulin-like growth factor-1/growth hormone pathway, and transsulfuration/hydrogen sulfide pathways may also play a role. Additionally, sirtuins aid in maintaining developmental metabolic competence and chromosomal integrity of the oocyte. Here we review the pathways that regulate ovarian reserve and oocyte quality, and discuss geroscience interventions that leverage our understanding of these pathways to promote reproductive longevity.

Keywords: Delayed childbearing; Ovarian aging; Ovarian reserve; Primordial follicles; mTOR.

Figure 1.

Aging-related pathways and their role in ovarian aging and regulation of the primordial follicle pool. Multiple pathways, including PI3K/PTEN/AKT/FOXO3, TSC/mTOR, growth hormone (GH)/IGF-1, H₂S, and sirtuins, converge in the mammalian ovary to regulate the quiescence and activation of primordial follicles. Behavioral and pharmacologic interventions (orange italic font) to prevent depletion of the ovarian reserve target distinct points along these pathways. Dotted lines represent areas of emerging research, whereas as solid lines represent established pathways within the mammalian ovary. Abbreviations used are as follows: insulin-like growth factor-1 (IGF-1); phosphatidylinositol bisphosphate (PIP2); phosphatidylinositol triphosphate (PIP3); phosphoinositide-dependent kinase-1 (PDK1); protein kinase B (AKT); forkhead box O3 (FOXO3); phosphatidylinositol 3 kinase (PI3K); anti-Müllerian hormone (AMH); sirtuin 1 (SIRT1); tuberous sclerosis complex 1 (TSC1); tuberin (TSC2); mammalian target of rapamycin (mTOR) complex 1 (mTORC1); dietary restriction (DR); 2-deoxyglucose (2-DG); cystathionine γ-lyase (CGL); ribosomal protein S6 (S6); eukaryotic initiation factor 4E-binding protein 1 (4E-BP1); H₂S (hydrogen sulfide); primordial follicle pool (PFP).