Why do women, on average, live longer than men, yet often face a greater burden of chronic disease later in life? Why do some of the most fertile animals in nature, including queen bees and naked mole-rat queens, also live exceptionally long lives?
A perspective, to be published on August 6 th in Cell, introduces the Reproductive Resilience Hypothesis (RRH), a new way to think about these questions. The hypothesis, developed by Buck professor Pankaj Kapahi, PhD and senior postdoc Parminder Singh, PhD, proposes that reproduction and longevity, often seen as opposing biological forces, may be tightly linked in the context of life history. The authors posit that women could be the key players in efforts to discover ways to extend human healthspan.
“If we wish to understand why organisms age, nature points us toward studying women, the sex in which reproduction most profoundly shapes the course of aging,” says Buck professor Pankaj Kapahi, PhD, senior author of the paper.
“The Reproductive Resilience Hypothesis is a new evolutionary framework for understanding why reproduction accelerates aging in some biological settings but is associated with exceptional longevity in others,” says Singh. “The central question is not simply how much an organism reproduces. It is whether continued survival remains important for future reproductive success, offspring survival, caregiving, or inclusive fitness.”
Reframing the relationship between reproductive investment and aging
Classical evolutionary theories of aging often describe reproduction and longevity as a trade-off. Because organisms have limited energy, investing heavily in reproduction should leave fewer resources for maintaining the body over time. The authors say that while this explanation is useful, it does not fully account for a recurring pattern across nature: in many species, the sex that invests most heavily in pregnancy, lactation, offspring care, or colony reproduction is also the longer-lived sex.
RRH proposes that when reproductive success depends on surviving long enough to reproduce repeatedly, care for offspring, or support kin and social groups, evolution may favor biological programs that strengthen the body’s ability to withstand stress. In these settings, reproduction and long-term maintenance may become linked rather than opposed.
“Our perspective helps explain why female mammals often outlive males, why queen insects can combine extraordinary fertility with longevity, and why male lifespan can equal or exceed female lifespan in species where fathers provide substantial infant care,” says Singh, who leads the research in the Kapahi lab.
A new lens on menopause and female healthspan
The framework also provides a new way to interpret human menopause and the female health-survival paradox. Women generally live longer than men, yet they often spend a greater proportion of later life with chronic disease, disability, or frailty.
The authors propose that menopause should not be viewed only as the end of fertility. Instead, it may represent an important inflection point in the progressive loss of reproductive resilience.
During reproductive life, ovarian signals are integrated with systems controlling metabolism, bone maintenance, immune regulation, brain function, stress responses, tissue repair, and communication among organs. As ovarian function declines, this reproductive-somatic communication network may become destabilized, exposing vulnerabilities that were previously buffered.
In this framework, menopause is not simply the loss of estrogen. It represents a broader disruption of the signals and physiological networks that connect reproductive function with whole-body maintenance.
“The ovary should not be viewed only as an organ that produces eggs and sex hormones,” Singh says. “It may also function as a communication hub whose endocrine, metabolic, immune, and paracrine signals help coordinate the physiological state of distant organs. When this communication declines, the consequences may extend far beyond fertility.”
The authors emphasize that RRH is not an estrogen-only explanation of female aging. Estrogen has complex, tissue-specific effects that depend on receptor type, timing, genetic background, inflammatory state, and disease stage. Aging also proceeds through processes such as DNA damage, protein aggregation, mitochondrial dysfunction, stem-cell exhaustion, and tissue-specific degeneration that may occur independently of reproductive state.
“We are not proposing that ovarian aging is the sole cause of systemic aging,” Kapahi said. “Rather, ovarian decline may remove an important layer of physiological coordination. That loss can interact with chronological aging, genetics, inflammation, metabolism, environmental exposures, and tissue-specific damage.”
Loss of reproductive resilience as a sex-specific hallmark of aging
The authors propose that loss of reproductive resilience should be considered a sex-specific hallmark-level process in aging. Like other hallmarks, it appears during normal aging, and its acceleration can worsen age-related decline. Interestingly, restoring aspects of ovarian function or signaling in experimental models has been shown to improve health-related outcomes.
Calling loss of reproductive resilience a sex-specific hallmark changes how we interpret reproductive aging, Singh said. It is not merely a marker that fertility has ended. It may be an upstream and temporally defined transition that changes the trajectory of several tissues and aging mechanisms at the same time.
Kapahi says RRH challenges a longstanding limitation in biomedical research. “For decades, many preclinical studies relied largely on male animals or young female animals that had never been pregnant. Yet pregnancy, lactation, menopause, ovarian surgery, and reproductive history can produce lasting changes in metabolism, immunity, the brain, and other organs. Treating these features only as sources of experimental variability may cause researchers to miss fundamental mechanisms of resilience and disease vulnerability.”
From evolutionary hypothesis to experimental discovery
Building on this framework, Singh and Kapahi are investigating how the ovary communicates with distant organs, including the brain, bone, immune system, and metabolic tissues. Their work aims to understand how reproductive aging disrupts this communication and whether beneficial ovarian signals can be restored without relying exclusively on conventional hormone replacement.
The broader goal is to determine whether the mechanisms that evolved to preserve females through reproduction, caregiving, and physiological stress can be identified and used to protect health later in life.
“Studying females is not a specialized branch of aging research,” Kapahi said. “It is an opportunity to discover biological mechanisms that evolution has already developed to preserve survival under the demanding conditions of reproduction and caregiving.”
“Female biology should be prioritized not only to correct a longstanding gap in biomedical research,” Singh added, “but because it may reveal resilience mechanisms that help us understand how to extend healthspan in both women and men.”
Rethinking the future of research on aging
The authors outline 11 ramifications of RRH that could reshape how research on aging is designed and translated into medicine. They call for human studies to routinely document reproductive history, including puberty, pregnancy, lactation, menopause, hormone therapy, and ovarian surgery. Animal studies, they say, should also move beyond comparisons between males and virgin females by including reproductively experienced, post-reproductive, and ovarian-signal-loss models.
“Reproductive history should not be treated simply as experimental variability,” said Singh. “It may reveal important mechanisms of resilience, disease vulnerability, and treatment response that conventional studies have overlooked.”
The authors also propose developing sex- and reproductive-state-specific biomarkers, mapping how reproductive transitions affect aging across organs, and identifying ovary-derived signals beyond classical sex hormones. These discoveries could guide interventions aimed at preserving systemic health without necessarily extending fertility. Comparative studies of queen insects, naked mole-rats, and other unusually resilient species may also reveal naturally evolved mechanisms that connect reproduction with long-term somatic maintenance.
“These ramifications provide a roadmap for converting the hypothesis into testable experiments and more precise interventions,” said Kapahi. “To fully understand aging, we need to consider not only biological sex, but also reproductive state and life history.”
Citation : Why Studying Females Reveals More About Aging: The Reproductive Resilience Hypothesis as an Evolutionary Framework for Studying Sex-Specific Aging
DOI: 10.1016/j.cell.2026.07.013
Other collaborators include:
Vineeta Tanwar, Yifan Xiang, Lizabeth Enriquez Najera, Buck Institute, and Steven N. Austad, Department of Biology, The University of Alabama at Birmingham, Alabama.
Acknowledgements:
The work was supported by grants from the National Institute of Health (R01AG068288, R01AG061165) as well as the Larry L. Hillblom Foundation and the Hevolution Foundation.
About the Buck Institute for Research on Aging
At the Buck, we aim to end the threat of age-related diseases for this and future generations. We bring together the most capable and passionate scientists from a broad range of disciplines to study mechanisms of aging and to identify therapeutics that slow down aging. Our goal is to increase human health span, or the healthy years of life. Located just north of San Francisco, we are globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer’s, Parkinson’s, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer. Our success will ultimately change healthcare. Learn more at: https://buckinstitute.org
Cell
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Why Studying Females Reveals More About Aging: The Reproductive Resilience Hypothesis as an Evolutionary Framework for Studying Sex-Specific Aging
6-Aug-2026
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