A new hypothesis for aging puts women at the center of understanding — and potentially extending — human health span.

Reproduction and longevity should be understood in conjunction with each other, not as opposing forces, according to the “reproductive resilience hypothesis” published in Cell. The idea is that reproductive tissues actively drive systemic resilience (the body’s ability to recover after stress or trauma).

The paper comes as longevity science turns to the ovary as a central driver of aging and a key target for improving health span. Studies on rapamycin in mice indicate that the immunosuppressant can slow ovarian aging, with human clinical trial results expected soon. This line of study offers medicine a new way to evaluate female disease risk as evolutionary thinking takes center focus in longevity research.

“The reproductive resilience hypothesis starts from an evolutionary question: Why do females often live longer than males, despite bearing a much greater physiological burden of reproduction?” said Pankaj Kapahi, PhD, professor at the Buck Institute for Research on Aging in Novato, California, and co-author of the new paper.

Historically, reproduction has been thought to speed aging by pulling resources away from body maintenance and repair. But from an evolutionary view, that doesn’t square with species whose survival relies on repeated reproduction and caregiving.

“If remaining healthy and resilient allows an animal to reproduce repeatedly, successfully raise offspring, or contribute to the survival of descendants, then longevity itself can enhance reproductive fitness,” Kapahi said. “Under those circumstances, natural selection could favor mechanisms that couple reproductive success to maintenance and repair of the body.”

The framework builds on the idea that natural selection doesn’t necessarily optimize the body for lifelong health, Kapahi said. Aging is an afterthought to mating. That could help explain why late-in-life mothers tend to live longer than women who give birth at younger ages. When a child’s survival depends on mom, evolution may enhance her “somatic maintenance rather than trading it off,” the authors wrote. 

The hypothesis offers a compelling synthesis of known evidence in the field, said Yousin Suh, PhD, director of reproductive aging at Columbia University in New York City. (Suh was not involved with the paper.) There’s a genetic component as well, she said. Not only do women with later menopause tend to live longer than women with earlier menopause — their brothers do too. “The mechanisms that we discover…will benefit not just women but men as well,” Suh said.

Bringing Reproductive Resilience Into the Lab — and the Clinic

Most preclinical lab work relies on male or virgin female animal models, avoiding the variability of reproductive hormones. “They say the hormones create a lot of noise, but they don’t,” Kapahi said. “I mean, you’re trying to capture biology. Going through reproduction, lactation will actually make the biology more interesting.”

Males and females face different selective pressures, he added. Factors such as pregnancy and menopause have no direct physiologic equivalents in males. Even caregiving can influence aging. In primate species where males are the dominant caregiver, they live longer.

“Males in many species, their job is really to find the mate and essentially pass on the sperm,” Kapahi said. “Once you’re done with that, the male job is kind of over. But the female has to live longer for anything to happen for that species. And that’s the part that’s been missing.” Including reproductive health in research could lead to more tailored treatments for women vs men and for menopausal women vs premenopausal women. 

Even without new data, clinicians can act now by taking more comprehensive reproductive histories. Questions such as: When did you start puberty? When did you have your first pregnancy? How many children have you had? Did you have any side effects during pregnancy?

“These are all very important variables that medicine thus far [has] failed to collect,” Suh said. “This is a good way to start, so then we will have much better understanding of this reproductive history, which can then be incorporated into management.” 

The Ovary ‘Runs the Show’

The new hypothesis places the ovary at the forefront of systemic resilience.

“There’s lots of signaling between the ovary and every tissue. Every tissue is talking to the ovary,” Kapahi said. “I would even argue [the] ovary runs the show. From an evolutionary point of view, everything else is beholden to that.”

The ovary is one of the first organs to age in the human body, beginning its decline 10-15 years before menopause, and it influences overall health, Suh said. Genes that promote later menopause have an impact across all tissues.

Drug and nutritional interventions have extended lifespan in animal models, but scientists have yet to translate that to humans. In mice, replacing older ovaries with younger ones prolongs lifespan and health span, “suggesting that young ovaries have pro-longevity benefit,” Suh said. (The practice of transplanting ovarian tissue to delay menopause has already sparked debate in reproductive medicine.)

Columbia University’s VIBRANT study, co-led by Suh, is looking at whether rapamycin can delay menopause, which could slow declines in mitochondrial function or genome maintenance. “Aging drives major chronic diseases,” Suh said. “So targeting aging itself will address age-related diseases simultaneously.”

Kapahi sees implications for modern family planning as well. “As society is changing, this is another reason to empower women with the choice to have pregnancy later,” he said. Often, the choice is made for social, professional, or financial reasons, but Kapahi suggests delaying pregnancy could have unexpected health benefits. “There’s even long-lasting effects on the body for them to make that choice... They could have better health.”

Kapahi is the founder of Juvify Bio, a company focused on anti-glycation and health aging. Suh reported having no relevant disclosures.