A major National Institute on Aging workshop is putting a once-overlooked question at the center of aging science: why does health change differently in women and men across the lifespan? The meeting, summarized in a new article in Nature Aging, brought together researchers to examine how biological sex influences disease risk, resilience, treatment response and the pace of aging from early development through old age. Rather than treating sex as a simple demographic label, the workshop framed it as a biological variable that can shape nearly every stage of health. The discussion arrives as researchers increasingly recognize that findings derived primarily from male animals, male cells or male participants may not fully explain how diseases develop or how therapies work in half of the population.
The workshop’s central message is that sex differences are not confined to reproductive biology. They can emerge in the immune system, metabolism, cardiovascular function, brain aging, skeletal health and the body’s response to stress. These differences may be influenced by sex chromosomes, hormones, gene regulation and the organization of tissues, but they are also shaped by nutrition, physical activity, occupation, caregiving, exposure to pollutants, access to medical care and social expectations. The result is a complex biological and social interaction that changes over time. A mechanism that protects health during one period of life may become less influential later, while a new vulnerability may appear after puberty, pregnancy, menopause or other major physiological transitions.
One of the most important scientific challenges is separating the effects of sex chromosomes from the effects of reproductive hormones. Females typically carry two X chromosomes, while males generally carry one X and one Y chromosome, but the biology is more complicated than this binary description suggests. Some genes on the X chromosome escape the normal process that silences one copy in female cells, potentially altering immune activity, metabolism and cellular maintenance. The Y chromosome also carries genes with functions beyond sex determination. At the same time, hormones such as estrogen, progesterone and testosterone bind to receptors throughout the body, changing gene expression in organs that include the heart, brain, liver, muscle and bone. Their concentrations fluctuate across puberty, reproductive life, pregnancy, menopause and later aging, creating a moving biological landscape rather than a fixed difference.
These mechanisms may help explain why some diseases show strikingly different patterns in women and men. Women are more likely to develop autoimmune disorders, in which the immune system attacks the body’s own tissues, whereas men often experience cardiovascular disease at younger ages. Alzheimer’s disease and other dementias also raise difficult questions about sex differences because women represent a large proportion of people living with these conditions. The gap cannot automatically be attributed to women living longer. Researchers are investigating whether differences in immune signaling, vascular injury, brain connectivity, hormonal transitions, genetic risk and lifetime exposure to social or economic stress contribute to the pattern. The workshop emphasized that these questions require studies designed to test mechanisms, not simply count cases.
Aging itself may alter the meaning of sex differences. The decline of ovarian hormone production during menopause, for example, occurs at a different time and with a different biological profile from the gradual changes in androgen production often seen in aging men. Yet neither process affects only the reproductive system. Hormonal transitions can influence bone remodeling, fat distribution, muscle maintenance, sleep, mood, vascular function and cognition. In women, the years surrounding menopause may coincide with changes in cardiovascular and metabolic risk, while in men, declining testosterone and changes in body composition may interact with frailty and chronic disease. These trajectories are not universal, and they are strongly modified by genetics, health conditions and environment. Treating them as identical—or assuming that one sex represents the default human pattern—can conceal important opportunities for prevention.
The workshop also highlighted the need to understand sex differences across the entire life course rather than studying older adults in isolation. Conditions in the womb, early childhood nutrition, puberty, reproductive events and cumulative exposure to illness can influence health decades later. This life-course perspective is particularly important for diseases that emerge in old age, because aging is not a single event but the result of long-term changes in cells, organs and physiological systems. Researchers are increasingly studying how inflammation, mitochondrial dysfunction, cellular senescence and changes in the epigenome accumulate differently across sexes. The epigenome consists of molecular marks that regulate gene activity without changing the DNA sequence, and it can respond to hormones, diet, stress and environmental exposures. Mapping these changes may reveal why two people with similar chronological ages can have very different biological ages and disease risks.
Better science will require better study design. The workshop called attention to the importance of including both sexes in basic and clinical research, analyzing results separately when biologically justified and reporting sex-specific findings transparently. Statistical adjustment for sex is not always enough: if researchers simply place sex into a model as a control variable, they may erase the very differences they need to understand. Experiments should be powered to detect meaningful interactions between sex and treatment, age, disease stage or exposure. Researchers also need to distinguish sex, a set of biological attributes, from gender, which encompasses social roles, identity and lived experience. These factors can interact, but they cannot be treated as interchangeable. A rigorous approach must also account for racial and ethnic diversity, socioeconomic conditions, disability, sexual orientation and other dimensions that influence health and access to care.
The implications extend directly to medicine. A therapy that performs well in a mixed study population may produce different benefits or side effects in women and men, especially when body composition, drug metabolism, immune activation or hormonal status varies. Clinical trials that recruit diverse participants and report outcomes with appropriate detail can help clinicians make more precise decisions about prevention, diagnosis and treatment. The same principle applies to artificial intelligence and biomedical data science: algorithms trained on unbalanced datasets may reproduce or amplify existing health disparities. Researchers therefore need datasets that capture sex, gender, age, hormonal status and relevant social exposures without reducing patients to simplistic categories. The workshop’s broader vision is a form of precision medicine that recognizes biological variation while avoiding assumptions about any individual based solely on sex.
The report presents sex-difference research not as a niche field, but as a foundation for understanding healthy aging. Its message is especially timely as populations grow older and chronic diseases place increasing pressure on health systems. Discovering why certain people remain resilient while others develop frailty, dementia, cardiovascular disease or immune disorders could lead to earlier interventions and more effective therapies. Achieving that goal will require collaboration among endocrinologists, neuroscientists, immunologists, gerontologists, epidemiologists, clinicians and social scientists. It will also require long-term studies that follow people through major biological and social transitions instead of capturing health at a single moment. By making sex and gender central to lifespan research, the National Institute on Aging workshop points toward a more complete picture of aging—one that treats differences not as statistical noise, but as clues to the mechanisms that determine who stays healthy and who becomes vulnerable.
Subject of Research: Sex differences in health, disease, aging and biological processes across the lifespan
Article Title: A National Institute on Aging workshop on sex differences in health across the lifespan
Article References: Pea, J., Addie, S., Ambrosio, F. et al. A National Institute on Aging workshop on sex differences in health across the lifespan. Nature Aging (2026). https://doi.org/10.1038/s43587-026-01194-z
Image Credits: AI Generated
DOI: 10.1038/s43587-026-01194-z
Keywords: sex differences, healthy aging, lifespan health, women’s health, men’s health, hormones, sex chromosomes, immune system, dementia, cardiovascular disease, precision medicine, National Institute on Aging
