Why ovaries age and fertility drops with time

For years, scientists believed fertility faded mainly because eggs got old. But new research from UC San Francisco and the Chan Zuckerberg Biohub shows something deeper.

The ovary is not just a container for eggs. It is a living world of cells, nerves, and tissues that talk to each other. This hidden network shapes how eggs mature and how the organ itself ages.

How ovaries age

The team used powerful imaging and gene sequencing to look at ovaries in humans and mice. “We’ve long thought of ovarian aging as simply a problem of egg quality and quantity,” said Dr. Diana Laird, senior author and professor at UCSF.

“What we’ve shown is that the environment around the eggs – the supporting cells, nerves, and connective tissue – is also changing with age.”

This shift matters far beyond reproduction. When the ovary slows down, other organs follow. Heart disease, bone loss, and metabolism problems often rise after menopause.

The research team hopes that understanding these changes can lead to ways to extend both fertility and health.

Seeing the ovary alive

To explore how aging alters this organ, the team built a new 3D imaging technique. It lets scientists see the entire ovary without cutting it apart. Under this lens, the ovary comes alive in color and shape.

In young mice, eggs spread evenly through the tissue. Older mice had fewer eggs and struggled with conception, even with in vitro fertilization.

In humans, the pattern looked completely different. Eggs gathered in clusters, forming small “pockets” surrounded by empty zones. Over time, these pockets thinned.

“This was a surprise – we assumed eggs would be distributed more evenly based on what we see in the developing ovary,” said Dr. 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.”

Ovarian cells show aging

The team wanted to know what kinds of cells make up these pockets. They used single-cell sequencing to examine nearly 100,000 ovarian cells from mice and humans.

The results showed 11 main cell types – including glia, a kind of support cell usually found in the brain.

Fibroblasts and endothelial cells, both key to structure and blood flow, changed most with age. In older samples, these cells looked inflamed and scarred.

That scarring appeared much earlier in ovaries than in organs like the lungs or liver. The study shows that ovarian aging begins quietly, long before menopause.

“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,” said Norma Neff, Ph.D., director of the Genomics Platform at the Biohub.

The role of the nervous system

Something unexpected appeared in the data – nerves. Dense networks of sympathetic nerves, which control the body’s “fight or flight” response, ran through the ovaries. Their numbers increased with age.

When scientists blocked these nerves in mice, more eggs stayed dormant, but fewer matured. That finding showed nerves help decide which eggs wake up and which stay asleep.

Glial cells seemed to guide and protect these nerve fibers. Together, they formed a communication system inside the ovary. This network might explain how stress, hormones, and aging link together over time.

Scarring ages ovaries

The ovaries also stiffened with age. Fibrosis – the buildup of scar-like tissue – made the structure less flexible. Interestingly, fibroblasts appeared to dial down genes that produce collagen, perhaps to slow damage.

Humans showed these fibrotic changes earlier than mice. That difference helps explain why fertility drops faster in people than in lab animals.

The study also tracked shifting hormone patterns. In aging human ovaries, testosterone and cholesterol signaling weakened, while inflammation rose.

This imbalance may underlie hot flashes, bone changes, and other symptoms that appear as menopause nears.

Comparing mice and humans

Despite their differences, mice and humans shared many ovarian traits. The same basic cell types appeared in both species. Yet humans showed stronger fibrosis and nerve growth with age.

“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 Dr. 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.”

These comparisons help scientists understand when animal studies can reflect human fertility – and when they can’t.

Slowing age of ovaries

The study paints a new picture of ovarian life. The organ does not simply run out of eggs; it changes as an ecosystem. Cells, nerves, and hormones interact constantly. When one part weakens, the whole system feels it.

“The fountain of youth may actually be the ovary,” said Dr. Eliza Gaylord, co-first author of the study. “Delaying ovarian aging could promote healthier aging overall.”

By revealing how every cell connects, this work gives researchers a roadmap. It suggests that maintaining the ovarian environment – not just preserving eggs – could hold the key to longer fertility and stronger health throughout life.

The study is published in the journal Science.

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