Hallmarks of female reproductive aging in physiologic aging mice

Abstract

The female reproductive axis is one of the first organ systems to age, which has consequences for fertility and overall health. Here, we provide a comprehensive overview of the biological process of female reproductive aging across reproductive organs, tissues and cells based on research with widely used physiologic aging mouse models, and describe the mechanisms that underpin these phenotypes. Overall, aging is associated with dysregulation of the hypothalamic-pituitary-ovarian axis, perturbations of the ovarian stroma, reduced egg quantity and quality, and altered uterine morphology and function that contributes to reduced capacity for fertilization and impaired embryo development. Ultimately, these age-related phenotypes contribute to altered pregnancy outcomes and adverse consequences in offspring. Conserved mechanisms of aging, as well as those unique to the reproductive system, underlie these phenotypes. The knowledge of such mechanisms will lead to development of therapeutics to extend female reproductive longevity and support endocrine function and overall health.

Fig. 1 |. The phenotypes and hallmarks of female reproductive aging.

a, The major phenotypes of reproductive aging per organ or endpoint. Upward arrows indicate an increase, and downward arrows indicate a decrease. The adjacent wheels represent which hallmarks of aging are implicated in the mechanisms giving rise to the phenotypes. b, The 14 hallmarks of reproductive aging. These hallmarks are consistent with systemic aging mechanisms. Dysbiosis (gray) was not represented in the articles included in the Review. Asterisks indicate that matrix and vascular remodeling (tan) and impaired metal homeostasis (magenta) were added as novel hallmarks of reproductive aging. Genomic instability was amended to include cell cycle instability, as cell cycle progression defects are a major phenotype in oocytes, eggs and embryos from reproductively old mice.

Fig. 2 |. The mechanisms of female reproductive aging in mice.

Colors correspond to the hallmarks of reproductive aging shown in Fig. 1: Epigenetic alterations, telomere attrition, loss of proteostasis, chronic inflammation, genome and cell cycle instability, mitochondrial dysfunction, altered intercellular communication, cellular senescence, disabled macroautophagy, stem cell exhaustion, deregulated nutrient sensing, impaired metal homeostasis, matrix and vascular remodeling. Dysbiosis has been implicated in reproductive aging, but was not a focus of the references in this Review.