The decline in female fertility as women age has long been attributed to a reduction in the quality and number of eggs. However, new research from UC San Francisco (UCSF) and Chan Zuckerberg Biohub San Francisco indicates that the environment surrounding the eggs within the ovary also plays a significant role in fertility decline.
The study, published in Science on October 9, was led by Diana Laird, PhD, professor of Obstetrics, Gynecology & Reproductive Sciences at UCSF. Laird explained, “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 a novel three-dimensional imaging technique to study ovaries in both mice and humans. This method allowed them to visualize eggs in intact ovaries, revealing that eggs are not distributed evenly but instead cluster in specific pockets. With age, the density of eggs in these pockets decreases. Laird noted, “This was a surprise. We assumed eggs would be distributed more evenly based on what we see in the developing ovary. 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, highlighted the importance of combining advanced imaging with single-cell sequencing technologies. “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,” Neff said.
The study identified 11 major cell types in ovaries, including glia—support cells typically associated with nerves in the brain—and found that sympathetic nerves, which increase with age, form dense networks in ovaries. When these nerves were removed in mice, researchers observed more eggs in reserve but fewer maturing eggs, suggesting these nerves influence when eggs begin to grow.
Other supporting cells, such as fibroblasts, also changed with age, causing inflammation and scarring in older women’s ovaries 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,” Laird said. “It tells us that ovarian aging is not just about the egg cells but about their whole ecosystem.”
The findings also reinforce the validity of using mice as models for human ovarian aging research. Laird stated, “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 study provides a roadmap for understanding healthy ovarian aging and opens up new questions about whether drugs could affect the timing or speed of this process. Eliza Gaylord, PhD, co-first author and postdoctoral fellow at UCSF, said, “The fountain of youth may actually be the ovary. Delaying ovarian aging could promote healthier aging overall.”
The research was supported 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, the Juno Fund, and individual donors.
