The decline in female fertility as women age has often been attributed to the diminishing quality and quantity of eggs. However, new research from UC San Francisco (UCSF) and Chan Zuckerberg Biohub San Francisco suggests that the surrounding ovarian environment, including supporting cells, nerves, and connective tissue, also plays a key role in this process. The study, published in Science on October 9, was supported by the National Institutes of Health.
“We’ve long thought of ovarian aging as simply a problem of egg quality and quantity,” said Diana Laird, PhD, professor at UCSF and senior author of the study. “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 imaging techniques to study the ovaries in both mice and humans. They found that in mice, which serve as models for human reproductive aging, there was a significant drop in both immature and maturing eggs as they aged. These older mice also showed reduced fertility with in vitro fertilization, similar to patterns seen in women in their 30s.
The study also discovered that eggs are not evenly distributed within the ovary. Instead, they are grouped in clusters or “pockets,” with egg density declining inside these pockets over time. Laird explained, “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 Chan Zuckerberg Biohub San Francisco and collaborator on the project, highlighted the technological advancements that enabled this research: “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 team identified 11 major cell types in mouse and human ovaries through genetic analysis. Notably, they found glia cells—typically associated with nerves—in ovarian tissue. The study also showed that sympathetic nerves become denser with age. When these nerves were removed from mice, more eggs remained in reserve but fewer matured, indicating a role for nerves in egg development.
Additionally, fibroblast support cells changed as women aged, causing inflammation and scarring in ovaries by their 50s—much earlier than similar changes occur 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,” said Laird. “It tells us that ovarian aging is not just about the egg cells but about their whole ecosystem.”
Laird emphasized similarities between mouse and human ovaries found in this study. She said these findings validate using mice as models for studying human ovarian aging.
Future research will explore whether certain drugs can alter or slow ovarian aging. The hope is to find ways to delay ovarian aging to impact fertility and reduce risks for age-related diseases common after menopause.
“The fountain of youth may actually be the ovary,” said Eliza Gaylord PhD, postdoctoral fellow at UCSF and co-first author of the study. “Delaying ovarian aging could promote healthier aging overall.”
The study included authors from UCSF, Chan Zuckerberg Biohub San Francisco, Buck Institute for Aging, and Oregon Health and Science University.
Funding came from multiple sources including grants from the National Institutes of Health, fellowships at UCSF, support from CZ Biohub Investigator funds, foundations such as W.M. Keck Foundation and Simons Foundation International, as well as individual donors.
