The decline in female fertility with age has long been attributed to a reduction in the quality and quantity of eggs. However, new research led by UC San Francisco (UCSF) and Chan Zuckerberg Biohub San Francisco suggests that the surrounding cells and tissues within the ovary play a significant role in this process.
The study, published in Science on October 9, was conducted by a team including Diana Laird, PhD, professor of Obstetrics, Gynecology & Reproductive Sciences at UCSF. Laird stated, “We’ve long thought of ovarian aging as simply a problem of egg quality and quantity. What we’ve shown is that the environment around the eggs — the supporting cells, nerves, and connective tissue — is also changing with age.”
Researchers used advanced three-dimensional imaging to observe ovaries in both mice and humans. This approach allowed them to see eggs in the ovary without slicing the organ, providing new insights into how eggs are distributed and how their environment changes over time. The study found that eggs tend to cluster in “pockets” within the ovary, and that the density of eggs in these pockets declines with age.
“This was a surprise. We assumed eggs would be distributed more evenly based on what we see in the developing ovary,” said Laird. “These pockets suggest that even within one ovary, the environment around an egg may influence how long it lasts and how well it matures.”
Norma Neff, PhD, director of the Genomics Platform at the San Francisco Biohub, collaborated on the research. She noted, “By combining the Laird lab’s cutting-edge imaging with the Biohub’s expertise in two kinds of single-cell sequencing, we were able to understand the ovary in unprecedented detail. This technology-driven approach let us uncover new cell types, providing a foundation for future discoveries in reproductive health.”
The study also explored genetic activity in ovary cells as they aged. The team identified 11 major cell types, including glia—support cells typically associated with nerves and most often studied in the brain—within the ovary. They also found that sympathetic nerves, which are involved in the body’s “fight or flight” response, become denser with age in the ovary. When these nerves were removed in mice, there were more eggs in reserve but fewer that matured, indicating a possible role for nerves in regulating egg growth.
Other supporting cells, such as fibroblasts, were found to change with age, leading to inflammation and scarring in the ovaries of women in their 50s—well before similar changes appear in other organs.
“This all points to a brand-new line of inquiry about how nerves, blood vessels, and other cell types communicate with eggs,” Laird said. “It tells us that ovarian aging is not just about the egg cells but about their whole ecosystem.”
One important outcome of this research is the confirmation that mice can serve as effective models for studying human ovarian aging, given the similarities observed between species. “Until now, it was somewhat unclear whether we could use mice as a model for humans when it comes to the ovaries — we have quite different reproductive windows,” Laird explained. “But the similarities we saw in this study make us confident that we can move forward in mice and apply those lessons to humans.”
The findings may have broader implications beyond fertility, as slowing ovarian aging could potentially reduce risks for age-related diseases that rise after menopause or ovary removal.
“The fountain of youth may actually be the ovary,” said Eliza Gaylord, PhD, a postdoctoral fellow at UCSF and co-first author of the study. “Delaying ovarian aging could promote healthier aging overall.”
The research was funded by several organizations, including the National Institutes of Health, UCSF Discovery Fellowship, Hillblom/BARI Graduate Student Fellowship Award, CZ Biohub Investigator funds, The Global Consortium for Reproductive Health through the Bia-Echo Foundation, the W.M. Keck Foundation, the Simons Foundation International, and the Juno Fund.
