Aging Reshapes the Ovary Long Before Reproductive Function Ends

Aging affects every organ in the body, yet we still know little about how the ovary changes over time. In a new study published in Nature Aging, Yale researchers created one of the most detailed maps of the aging ovary to date, examining how its cellular organization changes across the reproductive lifespan.

For decades, ovarian aging has largely been viewed through the lens of egg depletion—the gradual loss of the finite pool of eggs women are born with that ultimately leads to menopause. However, according to Hattie Chung, PhD, assistant professor of medicine (cardiovascular medicine) at Yale School of Medicine and senior author of the study, focusing on egg loss alone provides an incomplete picture of how the ovary ages.

As a hormone-producing organ, the ovary influences many aspects of women's health, including cardiovascular, metabolic, and bone health. "We like to think of the ovary as the physiological rheostat for the female body," says Chung. "It has so many important endocrine functions beyond just reproduction."

The ovary is composed of many different cell types that work together to support reproductive and hormonal function. Oocytes, or egg cells, develop within structures called follicles, which nurture and support their growth until ovulation. Within and surrounding the follicles themselves, the ovary also contains immune, vascular, connective tissue, and hormone-producing cells that work together to regulate ovulation, remodel tissue, and produce hormones that affect health throughout the body.

Maintaining the precise organization and communication among these cell populations is critical for ovarian function, yet how this cellular architecture changes with age has remained poorly understood.

“At the menopause transition, humans typically still have about 1,000 eggs remaining,” says Chung. “That suggests it's not just the eggs themselves, but also the surrounding ecosystem that changes with age.”

To examine these age-related changes more closely, Chung and her team used preclinical animal models and advanced spatial transcriptomic techniques to create high-resolution maps of the ovary across different stages of the reproductive lifespan, allowing the researchers to track changes in tissue organization, gene expression, and cell-to-cell communication over time.

The researchers found that age-related changes begin to emerge in the ovary well before reproductive cycles cease. While older animals continued to cycle, their ovarian tissue showed early signs of degeneration and a loss of the cellular synchrony that normally coordinates follicle development, ovulation, and tissue remodeling. These disruptions were accompanied by altered immune cell dynamics, increased inflammatory signaling, and a broader breakdown in tissue organization.

Several mechanisms may contribute to this breakdown in ovarian organization, says Chung. Aging cells may become less capable of carrying out the precise molecular changes required throughout the reproductive cycle, while communication between cells becomes less coordinated. The researchers also found evidence of impaired tissue clearance, a hallmark of aging in many organs, suggesting that the ovary becomes less efficient at removing damaged cells and maintaining healthy tissue over time.

The findings may help researchers identify biomarkers of ovarian aging. “If there are tissue signatures that signal a breakdown in ovarian organization, we'd love to be able to detect those through noninvasive methods,” says Chung. “Establishing that the tissue itself is dysregulated provides a really strong foundation for that direction in the future.”

“The next obvious step for us is to conduct these analyses in human tissues,” says Chung. “We're really keen on working with patient specimens to understand how these cellular interactions may be altered with aging and in pathologic conditions.” Since completing the study, Chung and her colleagues have begun collaborating with Yale obstetrics and gynecology researchers to collect ovarian samples from patients across a range of ages.

For Chung, the work highlights the need to study the ovary as more than a reproductive organ. “Understanding how its complex cellular ecosystem changes with age may ultimately provide insights into women's health far beyond fertility alone,” she says.

The Department of Internal Medicine at Yale School of Medicine is among the nation's premier departments, bringing together an elite cadre of clinicians, investigators, educators, and staff in one of the world's top medical schools. To learn more, visit Internal Medicine.