The decline in female fertility with age has traditionally been attributed to the quality and quantity of eggs. However, new research from UC San Francisco and Chan Zuckerberg Biohub San Francisco indicates that the environment surrounding the eggs—including supporting cells, nerves, and connective tissue—also plays a significant role in the aging of ovaries and the decrease in fertility.
“We’ve long thought of ovarian aging as simply a problem of egg quality and quantity,” said Diana Laird, PhD, professor of Obstetrics, Gynecology & Reproductive Sciences at UCSF and senior author of the study, which appears in Science on Oct. 9. “What we’ve shown is that the environment around the eggs — the supporting cells, nerves, and connective tissue — is also changing with age.”
The research team developed a new three-dimensional imaging technique to study ovarian aging in both mice and humans. They found that as mice aged—at stages equivalent to 30 to 40 human years—there was a significant drop in both immature and growing eggs. These older mice also showed reduced success with in vitro fertilization, mirroring patterns seen in women in their 30s.
The study also revealed that human eggs are not evenly distributed throughout the ovary. Instead, they cluster in pockets surrounded by areas without eggs. With age, the density of eggs in these pockets decreases. “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, explained, “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.”
Through genetic analysis of nearly 100,000 mouse and human ovarian cells, the team identified 11 major cell types, including glia—support cells usually associated with nerves and the brain. The study also found that sympathetic nerves, which are part of the body’s stress response system, become more dense in ovaries as they age. Removing these nerves in mice led to more eggs in reserve but fewer that matured, suggesting that nerves play a role in egg development.
Other support cells called fibroblasts were found to change with age as well, contributing to inflammation and scarring in ovaries of women in their 50s—well before such changes typically 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,” Laird said. “It tells us that ovarian aging is not just about the egg cells but about their whole ecosystem.”
The research also highlighted the similarities between mouse and human ovaries, which supports using mice as models for human ovarian aging studies. Laird noted, “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. 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 provide a new roadmap for understanding ovarian aging and could inform future studies on drugs that might slow or alter the process. Eliza Gaylord, PhD, co-first author of the study, said, “The fountain of youth may actually be the ovary. Delaying ovarian aging could promote healthier aging overall.”
The study involved researchers from UCSF, Chan Zuckerberg Biohub San Francisco, Buck Institute for Aging, and Oregon Health and Science University. Funding was provided by several organizations, including the National Institutes of Health and the Bia-Echo Foundation.
