The decline in female fertility with age has often been attributed mainly to the quality and quantity of eggs. However, a new study led by researchers at UC San Francisco and Chan Zuckerberg Biohub San Francisco suggests that the environment surrounding the eggs within the ovary plays a significant role as well. The findings were published in Science on October 9.
“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. “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 used advanced three-dimensional imaging to study the ovaries of both mice and humans. This allowed them to visualize eggs without slicing the organs into thin layers. They observed that, similar to women in their 30s, older mice had fewer immature and growing eggs and showed reduced success with in vitro fertilization.
In human ovaries, the study found that eggs cluster in specific pockets rather than being evenly distributed. As women age, the density of eggs within 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.”
The researchers also identified changes in other ovarian cells. They found glia, a type of support cell usually associated with nerves, present in the ovaries. Sympathetic nerves, which are part of the body’s “fight or flight” response, were found to form dense networks that become more pronounced with age. When these nerves were removed in mice, there were more eggs in reserve but fewer matured, indicating that these nerves may help regulate egg growth. Fibroblasts, another support cell type, were seen to trigger inflammation and scarring earlier than typically observed 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.”
Norma Neff, PhD, director of the Genomics Platform at the San Francisco Biohub, who collaborated on the research, said, “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 highlights the similarities between mouse and human ovaries, supporting the use of mice as models for further research. “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,” said Laird. “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 team plans to investigate whether certain drugs could affect the pace of ovarian aging. Their goal is to find ways to slow or delay ovarian aging, which could have implications for fertility and for reducing risks of diseases that increase 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 organizations including the National Institutes of Health, the UCSF Discovery Fellowship, the 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.
