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 multi-system aging and the initiation of frailty. Both reproductive and hormonal ovarian function are limited by the primordial follicle pool (PFP), which is established in utero and declines irreversibly until menopause. Because ovarian function is dependent on the PFP, an understanding of the mechanisms that regulate follicular growth and maintenance of the PFP is critical for the development of interventions to prolong the reproductive lifespan. 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 PFP; however, aging-associated systems such as the insulin-like growth factor-1 (IGF-1)/growth hormone (GH) pathway, and transsulfuration/hydrogen sulfide (H2S) 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.

Antioxidant Intervention Attenuates Aging-Related Changes in the Murine Ovary and Oocyte

“…Advanced maternal age (AMA) represents a significant decrease in fertility associated with reduced ovarian follicle quantity and oocyte quality, increased oocyte chromosome aneuploidy, and lower implantation rates [1][2][3]. Aging is associated with an imbalanced redox state in most organs, including the ovaries, with increased reactive oxygen species (ROS) relative to antioxidant signaling [4,5].…”

Euploid day 7 blastocysts of infertility patients with only slow embryo development have reduced implantation potential

“…Advanced maternal age was associated with a delay in blastocyst development, as patients who underwent transfer of a D6 or D7 blastocyst were older than those who received a transferred D5 blastocyst. Patients of advanced maternal age generally experience poorer reproductive outcomes following infertility treatment, and have increased rates of slowly developing blastocysts (Crawford and Steiner 2015, Llarena and Hine 2020, Lebovitz et al 2021. However, the lower live birth rate following transfer of D7 blastocysts was only partly due to advanced maternal age, as we also observed significantly compromised developmental potential of D7 euploid blastocysts compared to maternally age-matched D5 and D6 counterparts.…”

Human amnion-derived mesenchymal stem cells improved the reproductive function of age-related diminished ovarian reserve in mice through Ampk/FoxO3a signaling pathway

“…Primordial follicle pool is declining irreversibly until menopause, but exceeding activation of primordial follicles asynchronous with age can result in POF; for example, almost all of young women with cancer suffered POF after receiving radiation and chemotherapy [52][53][54]. The Pten/Akt/FoxO3a pathway is crucial in regulating quiescence or activation of primordial follicles [55][56][57][58][59]. The FoxO3a and phosphorylation FoxO3a are the critical factors, usually FoxO3a represses while phosphorylation FoxO3a activates the development of primordial follicles.…”