Ovarian aging: mechanisms and intervention strategies

Abstract

Ovarian reserve is essential for fertility and influences healthy aging in women. Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes. The molecular mechanisms and various contributing factors underlying ovarian aging have been uncovered. In this review, we highlight some of critical factors that impact oocyte quantity and quality during aging. Germ cell and follicle reserve at birth determines reproductive lifespan and timing the menopause in female mammals. Accelerated diminishing ovarian reserve leads to premature ovarian aging or insufficiency. Poor oocyte quality with increasing age could result from chromosomal cohesion deterioration and misaligned chromosomes, telomere shortening, DNA damage and associated genetic mutations, oxidative stress, mitochondrial dysfunction and epigenetic alteration. We also discuss the intervention strategies to delay ovarian aging. Both the efficacy of senotherapies by antioxidants against reproductive aging and mitochondrial therapy are discussed. Functional oocytes and ovarioids could be rejuvenated from pluripotent stem cells or somatic cells. We propose directions for future interventions. As couples increasingly begin delaying parenthood in life worldwide, understanding the molecular mechanisms during female reproductive aging and potential intervention strategies could benefit women in making earlier choices about their reproductive health.

Biomarkers of aging

“…Reduced steroid synthesis and expression of antioxidant genes, elevated inflammatory response, apoptosis, autophagy, and advanced glycation end products in granulosa cells surrounding the oocytes within the follicles or in follicular fluid provide convenient non-invasive biomarkers to indicate oocyte quality with increasing maternal age. (Zhu et al, 2022c). Ovarian biopsies are not an adequate technique for the assessment of ovarian reserve due to the irregular distribution of ovarian NGFs within the ovarian cortex (Lass, 2004).…”

“…Many factors significantly contribute to the poor oocyte quality associated with maternal aging. Among them, mitochondrial dysfunction, ROS, recombination failure, cohesin deterioration and spindle assembly checkpoint dysregulation are the leading causes of oocyte aneuploidy (Charalambous et al, 2023;Mikwar et al, 2020;Zhu et al, 2022c).…”

Integrative Bioinformatics Analysis for Identifying the Mitochondrial-Related Gene Signature Associated with Immune Infiltration in Premature Ovarian Insufficiency

“…Accumulating evidence suggests that mitochondrial events, contributing to negative effects such as changes in the mitochondrial metabolic pathway, triggering of in ammatory responses, disruption of reactive oxygen species (ROS) homeostasis, and induction of cell apoptosis, can eventually lead to the further development of POI[6-8]. Additionally, dysfunctional mitochondria are implicated in driving ovarian aging through mechanisms like impaired mitochondrial dynamics, accumulation of mitochondrial DNA (mtDNA) mutations, and defective electron transport chain function [9]. Speci cally, mitochondria play a crucial role in meeting the energetic needs of oogenesis and follicle maturation while also being essential in follicular atresia [10,11].…”

Aging hallmarks of the primate ovary revealed by spatiotemporal transcriptomics

“…As an important component of the female reproductive system, the ovary generates oocytes and is the major provider of steroid sex hormones ( Adashi, 1994 ). Several cohort studies demonstrate that female fertility starts to decline around the late 20s to early 30s and declines more rapidly after the age of 35 ( Zhu et al, 2022 ). Thus, ovarian aging is the primary cause of age-associated infertility in women.…”

“…The major characterization of ovarian aging is massive reductions in the quantity and quality of oocytes ( Ahmed et al, 2020 ; Broekmans et al, 2009 ; Wang et al, 2020 ; Zhu et al, 2022 ). In addition, aging-associated hostile ovarian microenvironment that comprises ovarian somatic cells including granulosa cells, impairs follicle growth and maturation and serves as a primary confounding factor to ovarian functional decline, further leading to subfertility even infertility with advancing age ( Ahmed et al, 2020 ).…”