Workshop: Sex Differences Impacting Human Health Across the Lifespan

Purpose and Background

Recent preclinical data from the Molecular Transducers of Physical Activity Consortium ( MoTrPAC ) demonstrates that significant sex differences exist in many organ responses to exercise based on multi-omics analyses in rat models. In addition, most clinical diagnostics remain predominantly based on data generated from males, while 80% of drugs withdrawn from the market between 1997 and 2000 were removed due to adverse effects observed in women. This demonstrates that sex differences are much more prevalent than previously recognized. There is a fundamental need to understand how sex differences affect normal organ function, epidemiology, pathophysiology, clinical manifestations, disease progression, and treatment responses in humans. Understanding the molecular mechanisms of organ sex differences will significantly improve clinical diagnostics for all.

With the growing evidence of sex as a critical biological variable, the Division of Aging Biology at NIA convened this workshop, and invited experts from academic institutions, NIH, and other federal agencies, to examine the mechanistic bases of sex differences in organ functions across multiple organs and ages, and the subsequent impacts on health outcomes. The workshop focused on major systems and identified unmet research needs and promising scientific opportunities related to sex differences impacting human health across the lifespan.

Date and Location

December 4, 2025 | 8:00 a.m. – 5:45 p.m. ET

Workshop Recording

The workshop recording is available on the NIH Videocast platform .

Speaker Abstracts

Fabrisia Ambrosio, Ph.D., MPT

Topic: Sex-specific aging trajectories of the musculoskeletal system

Menopause represents a defining inflection phase at which sex-specific differences often manifest. This is particularly true for musculoskeletal tissues, where women experience a disproportionate pathological burden relative to age-matched men, for reasons poorly understood. A barrier to mechanistic understanding of the effects of menopause has been the dearth of models that faithfully reflect key features of this transition in humans. Unlike women, who experience a gradual and progressive decline in sex hormones, most rodents sustain some ovarian sex hormone production even into older age. As such, preclinical studies often fail to capture the impact of menopause on tissue health. For example, older women display greater incidence and severity of osteoarthritis (OA) than age-matched men, while aged male, but not female, mice display progressive OA. To evaluate the role of sex hormones on cartilage integrity, we employed a model of menopause using ovarian-specific toxin (4-vinylcyclohexene, VCD) injections in mice. Following model validation, we performed proteomic profiling of cartilage across the menopause transition. Upregulation of estrogen and progesterone receptors characterized mid-perimenopause, suggesting early hormonal sensitization. A crisis management phase marked menopause onset, evidenced by pro-survival and stress-response signaling. A decompensation phase defined late menopause, reflected by cellular senescence and extracellular matrix remodeling, hallmark features of OA. In vivo and in vitro validation supported computational analyses. These data suggest that ovarian dysfunction, rather than mechanical wear-and-tear alone, is a driver of OA. This menopause model has similarly revealed female aging mechanisms, both tissue-conserved and tissue-specific, in other musculoskeletal organs. Collectively, these findings suggest that the ovaries govern the health of the greater musculoskeletal physiological network.

Elizabeth Barr, Ph.D.

Topic: Frontiers in sex differences research

Sex-linked biology is a critical variable influencing health and disease across molecular, cellular, organ, and systemic levels throughout the human life course. Accumulating evidence demonstrates that sex differences are dynamic, often emerging, amplifying, or reversing with aging, thereby shaping disease risk, progression, and treatment response. Although substantial progress has been made in characterizing sex-linked biological mechanisms, major gaps remain in integrating findings across organ systems, understanding sex–age interactions in older adults, and translating mechanistic insights into effective clinical and public health interventions. Addressing these challenges is central to the mission of the National Institutes of Health (NIH) Office of Research on Women’s Health (ORWH), which advances research rigor, discovery, and innovation across the full health research continuum. This presentation highlights three emerging frontiers in sex differences research. First, cross-disciplinary and cross-sector collaboration is essential for linking mechanistic studies with clinical, epidemiological, community, and population research. The ORWH-led Specialized Centers of Research Excellence on Sex Differences (SCORE) program exemplifies this model through coordinated basic, translational, and clinical investigations spanning aging, neurodegenerative disease, cardiometabolic health, mental health, microbiome biology, and exercise physiology. Second, interdisciplinary research - integrating expertise, methods, and perspectives from multiple fields - can accelerate innovation in understanding the multilevel mechanisms by which sex influences health and disease. When paired with life course and social determinants of health frameworks, this approach supports translation into scalable interventions and clinical practice. Third, advancing the health of communities requires real-world implementation of evidence-based approaches, ensuring that sex differences research informs prevention, diagnostics, and therapeutics across a variety of settings. Together, these three frontiers illuminate a strategic framework for accelerating sex differences research and improving health outcomes across the life course.

Dena Dubal, M.D., Ph.D.

Topic: X Chromosome-derived Mechanisms of Sex Differences in Longevity and Cognitive Aging

Women live longer than men worldwide and exhibit less cognitive aging. A major source of sex difference is sex chromosome complement: females have two X chromosomes and males have one. This difference generates unique X-derived mechanisms that are sex-specific. In mammalian development, one X chromosome randomly inactivates in XX cells, resulting in an active X (Xa) and inactive X (Xi), whereas males harbor only an Xa. Thus, reactivation of silent Xi genes may contribute to sex differences.

Using allele-specific, single-nucleus RNA sequencing, we found that aging preferentially altered gene expression on the X relative to autosomes, across hippocampal cell types. Select genes on Xi underwent activation with age, generating new escape across cells including in those critical to learning and memory. Expression of the Xi escapee Plp1, a myelin component, was increased in the aging hippocampus of female mice and parahippocampus of women. AAV-mediated Plp1 elevation improved cognition in aging male and female mice.

A second X-derived mechanism is cellular mosaicism: females express either a maternally-derived (Xm) or paternally-derived X (Xp) in each cell, while males express only Xm. We found that restricting expression in aging females to only Xm – mirroring males – accelerated cognitive decline and epigenetic brain aging, indicating that Xm is harmful and that female mosaicism (Xm+Xp) buffers deleterious aging processes. Xm selectively imprinted several genes in hippocampal neurons, suggesting silencing of cognitive loci, and CRISPR-mediated activation of these X-linked genes improved cognition. Targeting X chromosome-based pathways may counter deficits in cognitive aging in males, females, or both.

Passley Hargrove-Grimes, Ph.D.

Topic: New Approach Methodologies (NAMs) for Sex Differences Research

Drug development is extremely slow and costly, with a single drug often taking over 10 years and approximately $2.6 billion to reach the market, including the cost of failures. Despite major advances in computational methods and in vitro biology and toxicology over the past two decades, only about 5–7% of human diseases currently have effective therapies. These limitations suggest that existing preclinical models—such as 2D cell cultures and animal models—do not accurately replicate human organ and tissue responses.

As a result, there is a critical need for human-relevant model systems that can better predict health outcomes influenced by sex, age, genetics, population diversity, and interindividual variability. Human tissue chips, also known as microphysiological systems (MPS), are an emerging new approach methodology (NAM) that can recapitulate key functional aspects of human organs and tissues.

Tissue chips are particularly valuable for advancing sex differences research by enabling realistic, human-specific studies of how diseases and drugs affect males and females differently, helping to address the historical male bias in preclinical research. The NIH Tissue Chip Program has supported women’s health research by modeling the female reproductive system on chips, testing drug safety and efficacy using female-derived cells, and examining how factors such as sex and age contribute to variable drug responses. This work supports the development of more personalized and effective medical treatments.

Emily Jacobs, Ph.D.

Topic: Sex -Specific Factors that Influence the Central Nervous System

Despite women facing nearly twice the risk of anxiety, depression, stroke-related disability, and dementia, women’s brain health remains chronically underfunded and under-researched. Among neuroimaging papers published since the 1990s, <0.5% consider health factors specific to the female body (Jacobs, Nature 2023). The menstrual cycle, pregnancy, and menopause are accompanied by coordinated shifts of the endocrine, immunological, and vascular systems. Decades of evidence from animal models and emerging research in humans also point to coordinated shifts in the nervous system. Recent advancements in precision imaging allow us to map the mammalian brain with exquisite temporal resolution across these endocrine transitions. This body of work is revealing the human brain's capacity for rapid reorganization and gonadal hormones' potent role in shaping this process. Together, these insights inform our understanding of menarche, matrescence, and menopause as health inflection points that shape long-term aging trajectories. Currently, the field lacks a standardized method to capture women’s reproductive health experiences over their lifespan—an issue that limits the reproducibility and scale of research efforts, and leaves the field hungry for a universal approach to collecting data relevant for women’s brain health. To address this gap, the Ann S. Bowers Women’s Brain Health Initiative is developing a standardized reproductive health history questionnaire, designed with the goal to improve the rigor, reproducibility, and scalability of women’s health research.

C. Noel Bairey Merz, M.D.

Topic: Sex differences in cardiovascular disease through the lifespan

Cardiovascular disease (CVD) accounts for more deaths in women than breast cancer, lung cancer and chronic lung disease combined with a comparable mortality to that of men. Despite this, many women and physicians do not identify CVD as a prominent cause of major morbidity and mortality in women, resulting in significant delays in diagnosis and treatment. While advances have been made in the diagnosis, treatment and outcomes of CVD in women, there often remains insufficient evidence to guide effective, lifesaving care of women. Sex-specific and traditional CVD risk factors and risk enhancing factors in women identifies areas of knowledge gaps to consider for investigation aimed at risk prediction of cardiovascular health during a woman’s lifespan. Specific focus on the coronary vasculature reveals anatomical differences and physiological differences of clinical relevance resulting in differing disease mechanisms which can be interrogated. As CVD is the expression of the influence of traditional risk factors and emerging risk enhancing factors, a focus of research on detection of preclinical cardiovascular disease may be of particular importance for women. This may be even more important in pre-menopausal women as this dominantly remains is considered a healthy period of life with few predictors of cardiovascular health. A focus on awareness and implementation of the existing knowledge of sex-specific risk factors and sex-specific thresholds to educate women and physicians working with female patients is needed. The anticipated life course of women supports a broadening focus on CVD health toward that of lifelong care and emphasizes key transitional stages for women – early risk factor onset, pregnancy, menopausal transition, and the aged. Re-envisioning health system approaches for lifelong prevention, detection, and treatment of CVD in women is needed.

Jennifer Pluznick, Ph.D.

Topic: Sex differences in the renal system

Sex differences have clear impacts on kidney function, and many of these sex differences are modified by age. Notably, these sex differences include differences in transporter abundance along the nephron, with males relying more on the proximal nephron for transport, and females relying more on the distal segments. These changes have functional consequences, with females excreting a saline load more rapidly and achieving sodium homeostasis on a high salt diet more quickly. Of note, clinical lab values also differ both between sexes and by age. For example, equations to estimate glomerular filtration rate (eGFR) based on plasma creatinine take into account both sex and age. In addition, other common clinical values are also altered by sex and age: for example, plasma K+ tends to be lower in females, and, to increase with age in both sexes. Of note, the kidney is a master controller of blood pressure, and sex differences in blood pressure emerge at puberty, with females having blood pressure that is ~10mmHg lower than that of males during the reproductive years. As males and females age, blood pressure increases with a steeper slope in females, such that women have higher blood pressure than men during the post-menopausal years. A recent study revealed that an olfactory G protein-coupled receptor expressed in the vasculature, OLFR558 (mice)/OR51E1 (humans), is required for sex differences in blood pressure during the reproductive years: when OLFR558 is deleted in mice, sex differences in blood pressure are absent. Furthermore, a rare missense variant in the human OR51E1 gene has a statistically significant sex interaction with diastolic blood pressure.

Marta Rodriguez-Garcia, M.D., Ph.D.

Topic: Sex differences in immune responses and protection against infections

Biological sex and aging impact immune responses and protection against infections. Women have enhanced systemic immune responses compared to men, clear pathogens faster and display stronger vaccine responses but are more prone to inflammation and autoimmune diseases. Susceptibility to mucosal infections, such as respiratory and genitourinary infections, increases with age, with differential incidence between men and women; however, little is known about how sex and age modify mucosal immune protection and what is the additional contribution of menopause, a critical event in women’s aging process. Our group investigates immune aging in the human female genital tract (FGT) and susceptibility to genital infections, including HIV. Women of all ages acquire HIV primarily through sexual contact, meaning the FGT is a primary site for viral entry, and that mucosal immune responses are critical for prevention. Before menopause, immune responses in the FGT are precisely regulated by sex hormones to shape conditions for reproduction. However, following menopause, immune function dramatically changes. We have identified enhanced genital dendritic cell function with age, but impaired neutrophil function (critical for defense against infections), and decreased presence of innate lymphoid cells (involved in epithelial barrier maintenance and coordination of antiviral responses). Pregnancy also modifies the immune milieu in the FGT with effects lasting decades afterwards. Postmenopausal and age-dependent changes contribute to enhanced baseline inflammation and reduced protection against genital infections. Future studies need to compare samples by sex, and incorporate sex hormone information, menopause, and reproductive history into their analyses to understand how sex and age influence immune protection and uncover opportunities for intervention.

Michael Stout, Ph.D.

Topic: Sex differences in reproductive processes across the lifespan

Sex differences in mammal health has myriad of underlying mechanisms, several of which originate during development. Sex in mammals is determined by sex chromosome compliments, which in turn initiates sexual differentiation of the gonads. In XY embryos, the activation of the Sry gene triggers a cascade of molecular and cellular events that commit the bipotential genital ridge to a testis fate (PMID: 1695712; PMID: 2374589). In XX embryos, the absence of Sry promotes an ovarian differentiation program that also actively suppresses testis formation through several parallel transcriptional mechanisms (PMID: 27481580). Once gonadal differentiation has been initiated, sex hormone production soon follows. Androgen production in testis and estrogen production in ovaries both occur during gestation and postnatally, but peak at different times while also displaying different amplitudes during the first few months of life (PMID: 32318025). The early secretion of sex hormones from the gonads initiate the development of the hypothalamus-pituitary gonadal (HPG) axis, which eventually controls secondary sex characteristics, puberty, and differences in metabolic homeostasis between the sexes (PMID: 28591630). The developmental effects of sex hormones are commonly referred to as ‘organizational’ in nature because they permanently change the structure and function of organs, thereby leading to persistent effects throughout life. At the onset of puberty, sex hormone production ramps up dramatically in both sexes, which elicits organ-specific effects that promote the development of secondary sexual characteristics and sex differences in everything from transcription to behavior. After sexual maturation is complete, sex hormones continue to elicit broad sex-specific outcomes, which are referred to as ‘activational’ in nature because the effects are reversible if hormone production ceases, as seen in conditional such as menopause in female and late-onset hypogonadism in males. The aforementioned differences in sexual developmental and exposure to hormones play major roles in rendering susceptibility to certain diseases, which is why males and females often display differing incidences of chronic conditions and diseases. These differences will be discussed further throughout this perspective.

Barbara Stranger, Ph.D.

Topic: Big Data, AI, and the Next Generation of Sex Differences Research

Sex differences shape human health across molecular, cellular, physiological, and clinical scales, yet their dynamic origins and consequences remain incompletely understood. The convergence of large-scale biomedical data and modern analytics now makes it possible to characterize sex differences across genes, tissues, organ systems, and the lifespan with unprecedented resolution. Contemporary datasets include genomics and other omics, electronic health records, imaging, clinical laboratory measures, wearable biosensors, and deeply phenotyped longitudinal cohorts. Together, these data enable integrated modeling of biology in motion rather than static snapshots.

Longitudinal and multimodal analyses support a new generation of computational models, including machine learning, network-based modeling, agent-based and multiscale systems models, that capture nonlinear, age-dependent, and context-specific sex effects. These approaches reveal sex-specific trajectories across development, reproductive aging, menopause, and later-life aging; identify early warning signals for diseases such as heart failure, metabolic disorders, and cognitive decline; uncover sex-specific disease subtypes; and enable construction of sex-aware risk prediction models with improved accuracy, calibration, and interpretability. Together, they expose critical age × sex × context interactions and generate mechanistic insight across biological layers.

Clinical applications in heart failure with preserved ejection fraction and Alzheimer’s disease illustrate how these methods uncover sex-differentiated phenotypes, risk patterns, and progression pathways that remain hidden to traditional analyses. These same analytic advances provide the foundation for next-generation frameworks such as digital twins, computational representations of biological systems used to predict individual disease trajectories and responses to intervention, and a promising path toward precision medicine when built with explicit sex-aware data and modeling.

Realizing this potential requires confronting key challenges, including unbalanced datasets across sex and age, missing sex-relevant metadata such as menopause, pregnancy, and hormone exposure, small context-dependent effect sizes, algorithmic bias, and the absence of standardized best practices for sex-aware modeling. Addressing these challenges through improved data standards, harmonization across cohorts, fairness auditing in AI pipelines, and interdisciplinary collaboration will accelerate progress.

Advancing this paradigm is essential for improving prevention, diagnosis, and treatment across the lifespan and for delivering truly data-driven precision medicine for all.

Dan Theodorescu, M.D., Ph.D.

Topic: Sex differences in cancer

Loss of the Y chromosome (LOY) in peripheral blood mononuclear cells (PBMCs) is the most common somatic alteration with aging in men while LOY in tumor cells a frequent occurrence across multiple malignancies, including 10-40% of bladder cancers. Research employing genomic studies, CRISPR-Cas9 targeted deletions, and pan-cancer analyses of human tumor types reveal a contrast in biological behavior: while Y-positive (Y+) and Y-negative (Y-) cells exhibit similar growth rates in vitro, Y- tumors are significantly more aggressive in immune-competent hosts. This heightened malignancy is fundamentally T cell-dependent, as LOY in cancer cells trigger a striking shift toward exhaustion in CD8+ T cells within the tumor microenvironment. High-dimensional flow cytometry and spatial proteomic evaluations confirm that these alterations promote a state of immunosuppression. Furthermore, LOY is not restricted to malignant cells; it is also prevalent in tumor stroma and PBMCs, where its presence is associated with higher mortality from epithelial cancers. Studies using autochthonous and syngeneic mouse models indicate that LOY in malignant epithelial cells can actually predict LOY in benign cells in the tumor stroma, and in patients the magnitude of LOY in CD4+ and CD8+ T cells predicts survival with individuals with concurrent LOY in both epithelial and T cells experiencing the worst clinical outcomes. However, a significant "silver lining" exists: because of the specific way LOY promotes T cell exhaustion, Y- tumors exhibit an increased response to anti-PD-1 immune checkpoint blockade therapy compared to Y+ tumors. By establishing a clear link between the genetic status of immune cells and malignant cell behavior, these findings position LOY as a pivotal biomarker for personalizing immunotherapy and driver of cancer mortality.

Organizing Committee

Co-Chairs:

  • Francesca Duncan, Ph.D., Northwestern University
  • Fei Wang, Ph.D., Division of Aging Biology, NIH NIA
  • John Williams, Ph.D., Division of Aging Biology, NIH NIA

Members:

  • NIH
    • Elizabeth Barr, Ph.D., NIH Office of Research on Women’s Health (ORWH)
    • Rafael de Cabo, Ph.D., Experimental Gerontology Section, NIH NIA
    • Patrice Desvigne-Nickens, M.D., NIH National Heart, Lung, and Blood Institute (NHLBI)
    • Chelsea Haakenson, Ph.D., Division of Neuroscience, NIH NIA
    • Mihoko Kai, Ph.D., NIH National Cancer Institute (NCI)
    • Maja Maric, Ph.D., Division of Neuroscience, NIH NIA
    • Christine Maric-Bilkan, Ph.D., NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    • Sunila Nair, Ph.D., NIH National Institute on Drug Abuse (NIDA)
    • Kristy Nicks, Ph.D., NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
    • Mercy Prabhudas, Ph.D., NIH National Institute of Allergy and Infectious Diseases (NIAID)
    • Tracy Rankin, Ph.D., M.P.H., NIH, NIDDK
    • Susan Taymans, Ph.D., NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
    • Jean Yuan, Ph.D., Division of Extramural Activities, NIH NIA
  • Kimberlee Potter, Ph.D., U.S. Department of Veterans Affairs (VA)

Contact Information

Please contact Dr. John Williams at williamsj6@mail.nih.gov with any questions you may have about the workshop.