The decline in female fertility as women age has often been attributed to the diminishing quality and quantity of eggs. However, recent research led by UC San Francisco (UCSF) and Chan Zuckerberg Biohub San Francisco suggests that the environment within the ovary—including supporting cells, nerves, and connective tissue—also plays a significant role in fertility loss.
Diana Laird, PhD, professor of Obstetrics, Gynecology & Reproductive Sciences at UCSF and senior author of the study published in Science on October 9, 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.”
The research team developed a three-dimensional imaging technique to observe eggs in mouse and human ovaries without slicing the organs. In mice that correspond to 30- to 40-year-old humans, they observed a notable decline in both immature and growing eggs. These mice also showed reduced success with in vitro fertilization, similar to women in their 30s.
When imaging human ovaries, researchers found that eggs cluster in pockets rather than being evenly distributed. As women age, these pockets lose density. 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.”
The study also examined gene activity in aging ovary cells by isolating individual eggs and analyzing nearly 100,000 mouse and human cells. They identified 11 major cell types in the ovaries, including glia—support cells typically found in the brain. Sympathetic nerves, which are involved in the body’s stress response, were found to increase in density with age. When these nerves were removed in mice, more eggs remained in reserve but fewer matured, indicating a regulatory role for nerves in egg development.
Other support cells, such as fibroblasts, were shown to change with age, leading to inflammation and scarring in the ovaries earlier than seen 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 similarities between mouse and human ovaries observed in the study support using mice as models for human reproductive research. 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 research provides a new framework for investigating how ovarian aging occurs under different conditions. Laird’s team is now exploring whether drugs could influence the timing or rate of ovarian aging. The goal is to find ways to slow or delay ovarian aging, which could affect fertility as well as reduce the risk of diseases common after menopause.
“The fountain of youth may actually be the ovary,” said Eliza Gaylord PhD, a postdoctoral fellow at UCSF who is co-first author of the study. “Delaying ovarian aging could promote healthier aging overall.”
The study was funded by several sources, 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, W.M. Keck Foundation, Simons Foundation International, the Juno Fund, and individual donors.
