Establishing new age-relevant mouse models of menopause

Female reproductive lifespan is limited by the fixed number of ovarian reserves that women are born with. With age, the decline in quantity and quality of ovarian reserves leads to sterility and loss of ovarian function. Studies have shown that loss of endocrine function due to ovarian aging contributes to multisystem aging and frailty. Consistently, post-menopausal women are more susceptible to age-associated diseases, including neurodegeneration. However, despite overwhelming evidence of the health impact of ovarian aging, the underlying molecular mechanisms that drive ovarian aging are understudied. Repeated injections with 4-VinylCyclohexene Diepoxide (VCD) can promote selective atresia of primordial and primary ovarian follicles in rodents. Within approximately 100 days of a 15-days injection regimen, mice undergo an accelerated ovarian failure with hormonal states reminiscent of human peri- and post-menopause. However, VCD treatment has, thus far, been performed in very young 2-3 months old mice, which makes it difficult to evaluate the endocrine impact of menopause on an aged organism. In this study, we induced menopause-like states in 3 and 10 months old female mice. Ovaries were collected at 30 and 90 days post-injections (control vs. VCD) to capture the temporal changes in the genomic landscapes of ovaries via single-cell RNA-seq analysis.