The Secrets of Aging Are Hidden in Your Ovaries
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science
May 2023
The ovary is a time machine. It travels to the future, reaching old age ahead of the rest of the body. At birth, each ovary contains around a million follicles--tiny, fluid-filled sacs that hold immature eggs. But the decline of these follicles is immediate and unceasing. By puberty, only about 300,000 remain. By age 40, the vast majority are gone. And by 51, the average age of menopause in the United States, virtually none are left.
Humans are an oddity in this regard. Most mammals remain fertile up to the end of their lives; the only species known to experience menopause naturally are humans and some whales. In humans, the loss of hormones during menopause sets off a cascade of negative health effects: Bones get brittle; metabolism slows; and the risk of cardiovascular disease, diabetes, stroke, and dementia increases. Paradoxically, women live longer than men on average but spend more of their older years in poor health.
Jennifer Garrison has a hunch that the ovaries are the culprit. "That cocktail, that orchestra of chemicals that the ovaries make, is really important to overall health," says Garrison, an assistant professor at the Buck Institute for Research on Aging in Novato, California. "When it goes away at menopause, it has a dramatic effect." On the other hand, having working ovaries for longer seems to carry longevity benefits. One study of 16,000 women found that later menopause made it more likely someone would live to age 90.
Despite the fact that half the world's population experiences ovarian aging--including cisgender women and trans and nonbinary people--longstanding gender bias in science means it has remained an understudied field. But that's starting to change.
Garrison leads the Buck Institute's Center for Reproductive Longevity and Equality, a first-of-its-kind facility established in 2018 with a $6 million gift from attorney and philanthropist Nicole Shanahan. In 2019, the institute launched a related effort, the Global Consortium for Reproductive Longevity and Equality, to fund outside researchers. An initial 22 researchers received inaugural grants totaling $7.4 million. Their goal is to understand why the ovaries seem intricately connected to health and longevity. Unraveling these mysteries could mean extending a person's reproductive years--and potentially lifespan--by delaying menopause.
In 2018, the field of reproductive longevity was so nascent that Garrison had a hard time finding faculty to interview, let alone hire, to staff the center. Few people were actively researching it, partly because the only other mammals that experience it are whales--which can't exactly be studied in a lab. It's also hard to study ovarian aging in such long-lived species--killer whales, for example, can live up to 90 years in the wild. Instead, researchers have often tried to crack menopause and its link to aging by proxy: by observing chemotherapy's effects on fertility, by studying a common menopause treatment that mimics female hormones, or by experimenting on mice, which are imperfect stand-ins for humans.
Five years later, the Buck Institute's efforts are starting to deliver results. Researchers might not have figured out how to slow reproductive aging yet, but they've spurred interest in a long-overlooked organ and opened a new avenue of inquiry that could have implications for how everyone ages--not just people with ovaries. "If we can understand what's happening in the ovary," Garrison says, "that will probably tell us something about aging in the rest of the body, and could also give us a handle on how to intervene."
To work out how fast ovaries age, you need to look at a lot of cells. At Columbia University in New York, geneticist Yousin Suh and her colleagues have been collecting and analyzing cells taken from the ovaries of women in their twenties and those in their late forties and early fifties who haven't yet gone through menopause. What they found shocked them. Cells from the ovaries of middle-aged women often resembled cells in other tissues from people in their seventies and older.
In cell type after cell type, Suh's team found unmistakable signatures of aging. They saw damaged DNA and dysfunctional mitochondria--the energy powerhouses within cells. Communication between cells broke down. They stopped dividing. A key regulator of cell growth and metabolism, called mTOR, was also overactive. Too much mTOR is associated with cancer and aging, and drugs that suppress it are used to slow tumor growth. For Suh, it was "crystal clear" evidence that the ovary is aging faster than the rest of the body at the molecular and cellular levels. Suh and her team posted their findings online last year, and the paper is currently undergoing peer review.
The mTOR discovery was particularly intriguing. Blocking the protein has already been shown to increase lifespan in flies, worms, and mice. Now Suh wonders if the same benefits could extend to human ovaries.
Over at Northwestern University in Illinois, Kara Goldman, an associate professor of obstetrics and gynecology, has also been exploring the link between mTOR and ovarian aging. She was interested in whether mTOR inhibitors could protect the ovaries against fertility loss caused by chemotherapy.
In a 2017 study, she gave the drugs to otherwise healthy female mice that were also treated with chemotherapy. The hope was that the mTOR mice would be better protected against ovarian damage compared to mice that only received chemotherapy. And it worked. Both groups lost follicles because of the chemo, but the mice that received mTOR inhibitors had more of them left. Those mice went on to have more than twice as many offspring. In other words, the drugs seemed to preserve the ovaries, says Goldman, who serves as director of the clinical advisory board for the Buck's consortium.
Then Goldman took the research a step further. She wanted to see if these drugs could boost fertility in healthy mice. She gave daily oral doses of mTOR inhibitors to female mice for four weeks, beginning in young adulthood. When these mice mated, they produced twice as many pups over a seven-month period as a control group that didn't receive the drugs, suggesting they were better at reproducing than untreated mice.
Goldman and her team also wanted to make sure the drugs didn't have negative side effects--a drug to be used in otherwise healthy people to extend the lifespan of their ovaries would need to be extremely safe, she says. Her team monitored the health and fertility of the treated mice, as well as their first- and second-generation offspring, and thus far have found no ill effects. The researchers presented preliminary findings in 2021 and are still analyzing their data.
But will the same be true for humans? To find that out, Suh and her collaborator Zev Williams launched a trial to test whether the drug rapamycin, an mTOR inhibitor, can slow aging in the ovaries. They plan to enroll 50 women in their mid-thirties to early forties who don't plan on having any more children. For a year, half will take daily rapamycin pills and the other a placebo. Researchers will then test the number of healthy eggs the participants have left.
Their hope is that the group taking rapamycin will have more eggs. That would mean their ovaries are aging less rapidly than normal. "What we're trying to do is slow down the rate at which eggs get lost," says Williams, director of the Columbia University Fertility Center.
The fact that the ovaries age so much faster than other body tissues also makes them a valuable way to test anti-aging drugs. Studies like these could yield insights on a much shorter timescale than than those done on other tissues in the body--which could have implications for aging in both women and men.
Ultimately, Goldman sees a future in which women would take these drugs at an even younger age. "The moonshot idea is to not only protect fertility but prolong ovarian health span," she says.
No one knows for sure if it's possible to keep the ovaries functioning longer, or whether that will lead to a longer, healthier life. Mice, at least, seem to benefit when their ovaries stay healthy for longer. When researchers at Utah State University transplanted the ovaries of young mice into older ones, the recipients lived about 40 percent longer than their peers and also had healthier-looking hearts. But there's one problem with relying on mice as a stand-in for people: Like most other animals, mice don't go through menopause.
Berenice Benayoun, an assistant professor of gerontology at the University of Southern California, is trying to genetically engineer menopause into mice so scientists can study the biological mechanisms behind it and figure out how to offset it. "Menopause is basically the single most consequential event in a woman's life in terms of health," says Benayoun, who's funded by the Buck Institute.
Researchers elsewhere have tried inducing a menopause-like state in two- to three-month-old mice by removing their ovaries or injecting them with a chemical to stop the ovaries from working. But Benayoun says that's like trying to suddenly make young adults menopausal. The animals don't show a gradual loss of ovarian function over time like humans do.
Benayoun and her team have knocked out a gene in mice that, in humans, leads to early menopause. In mice, it led to a more gradual loss of hormones. The research has not been published yet, but Benayoun thinks it may offer a closer approximation of what happens in humans: "We can get hormonal states that are very similar to what's described in human women," she says.
Even if researchers figure out how to delay a fake menopause in mice, that doesn't mean it would be safe to do so with people. "That's the big question," says Stephanie Faubion, medical director of the North American Menopause Society and the director of the Mayo Clinic Center for Women's Health. "Would there be any harms associated with it? We have no idea."
A common treatment for menopause may offer some clues. Hormone replacement therapy, or HRT, provides the body with estrogen and progesterone that stop getting made during menopause. While generally considered safe for most women, it can slightly increase the risk of blood clots and stroke, as well as some types of breast and ovarian cancers.
But the ovaries produce many more chemicals and signaling molecules than these two hormones. To Garrison, the issue with HRT is that it doesn't fully replicate the work of the ovary. While she calls HRT "the best Band-Aid treatment we have," she considers it "deeply imperfect" because it doesn't mimic every chemical the ovary makes. "We don't even know what they are, much less how to replace them," she says.
Perhaps the biggest mystery about menopause is why humans experience it at all. The "grandmother hypothesis," a concept proposed in the 1960s, suggests an evolutionary benefit. It argues that menopause allows older women to care for their grandchildren, thus boosting their kin's chances of survival and ensuring the continuation of their own lineage. By studying killer whales--which also experience menopause--researchers have found that the presence of a living grandmother increases the chances of survival for a calf.
If the theory is right, this evolutionary mechanism could still be helpful to human families--but less so to the individual. Humans are living longer and starting families later than ever before. People born today may live as much of their lives after menopause as they do before it. Why shouldn't those postmenopausal years start later and be healthier? "The reality is, the age of menopause is at odds with modern life," Goldman says.
Menopause may be inevitable, but Garrison thinks it's possible to at least stall it to help people remain healthier in older age. With her initiative at the Buck Institute, she's trying to fill in the huge gaps created by sexism in science and chronic underfunding of women's health research. Historically, investigators have relied too much on male lab animals and often excluded women from medical and toxicology studies, generalizing to women from data collected from men.
Today, clinical trials are more gender-balanced, and in 2014 the US National Institutes of Health announced an initiative to balance sex in cell and animal studies. Still, there's catching up to do. "We don't have a lot of basic knowledge because this area has been ignored by the biomedical research community for a very long time," Garrison says. Now, the field of female reproductive aging is finally getting the attention it deserves. "These are solvable problems," she adds. "We just need to do the work."
