Unlocking bat biology to extend ovarian health and reproductive longevity in women - The ovary is the fastest aging organ in humans. Some of the leading challenges to women’s health, including fertility decline, menopause, and aging-related diseases, are the inevitable consequences of this phenomenon. Identifying mechanisms that drive ovarian aging and developing strategies for their mitigation, therefore, have the potential to dramatically improve women’s health. Bats, which maintain reproductive health throughout their exceptionally long lifespans, offer a unique and powerful mammalian model for identifying mechanisms of ovarian resilience. Unlike traditional models such as mice, which experience rapid ovarian decline, many female bats sustain ovarian function and fertility into old age, despite being among the longest-lived mammals for their body size. However, the mechanisms underlying bats’ prolonged reproductive health remain poorly known, in part due to historical challenges in estimating age in wild bats. This project overcomes this limitation by utilizing newly developed methylation-based clocks that allow accurate chronological age estimation in wild bats. Long-term goals of this research are to develop bats as new models for ovarian aging and leverage their unique traits to develop bat-informed strategies to extend ovarian health-span in women. As a first step toward these goals, this project will pursue two aims. The first aim is to establish select bat species as models for ovarian aging in long-lived mammals, following three criteria. In preliminary fieldwork, eight bat species were identified that meet the first two criteria. This project will interrogate these species’ fit to the third criterion: they have long, sampleable lifespans over which they minimize ovarian aging. The hypothesis is that some of these bat species fulfill all criteria for adoption as long-lived, mammalian models for ovarian aging. To test this, for all sampled bats, chronological age will first be estimated with the new methylation-based clocks, and ovarian aging then characterized using markers of fibrosis, inflammation, and senescence. The second aim is to characterize primordial follicle dynamics in all sampled bats. In preliminary work, an abundance of primordial follicles was noted in the ovarian cortex of adult bats, far exceeding that typical in adult mice and humans. This is highly significant, as the primordial follicle pool is the ovarian reserve. Building on this, the hypothesis is that extended ovarian health in bats is associated with sustained maintenance of quiescent primordial follicles in the ovarian reserve with age. To test this, follicular quiescence, activation, and apoptosis and the proportion of primordial, transitioning, and primary follicles will be assayed over time in bat ovaries, using CB6F1 mouse ovaries as controls. This project is expected to establish select bats as transformative models for ovarian aging with the potential to uncover biological insights beyond the reach of traditional, short-lived models like mice. This project is also expected to characterize the dynamics of the primordial follicle pool in bats, identifying mechanisms that could sustain ovarian reserves and reproductive health. Ultimately, this project is expected to seed future NIH R01 proposals to develop bat-inspired therapies to extend women’s health and fertility.
