Project Abstract – MAE-WEST SCORE CEC Over the course of life, chronic stressors contribute to multi-organ aging and dysfunction and, ultimately, the development of clinical disease. Sex remains a critical determinant of the nature and pace of aging and ultimately longevity. With advancing chronologic age in humans, differences in biological aging between women and men become even more pronounced, culminating in the female predominance for a number of important morbid disease conditions, including notably Alzheimer’s disease and related dementias (ADRD), heart failure with preserved ejection fraction (HFpEF), progressive chronic kidney disease (CKD), and in turn systemic frailty. Mechanisms underlying the female predominance for these major morbidities remains unknown and are not explained by variations in sex hormones or survival bias. Our preliminary work supports a central hypothesis that sexual dimorphism in inflammatory eicosanoid mediators contribute to sex differences in microvascular dysfunction and, in turn, to sex differences in age-related multi-organ disease, including for ADRD, HFpEF and CKD. Elucidating a common pathophysiologic basis for the female predominance of ADRD, HFpEF, and CKD holds the key to effective interventions for reducing the excess burden of age-related disease in women. Motivated our findings and the critical need to understand the determinants and drivers of sex differences in major age-related disease outcomes, we propose to establish the Microvascular Aging and Eicosanoids – Women’s Evaluation of Systemic aging Tenacity (MAE-WEST) (“You are never too old to become younger!”) Specialized Center of Research Excellence (SCORE) on Sex Differences, in response to NIH RFA-OD-19-013. Our goal is to form a robust and sustainable structure of academic activities centered on systematically interrogating sex differences in the relationship among eicosanoids, microvascular dysfunction, and age-related end-organ disease, with an initial focus on the microvascular aging effects on brain, heart, and kidney function. This goal will be achieved by an outstanding collaborative team of clinician-scientists (with expertise in geriatrics, cardiology, and nephrology), epidemiologists, basic and translational scientists, analytical chemists, biostatisticians, and bioinformaticians. Leveraging our collective experience, resources, and infrastructure, we will advance the scientific enterprise through 3 foundational projects aligned and complementary yet independent. To promote and enhance the development of the next generation of early career investigators who are committed to studying sex differences in biomedicine, our MAE-WEST SCORE program will provide a robust, multi-disciplinary Career Enhancement Core. Methodological expertise areas include: epidemiology, clinical trials, basic science, analytical chemistry, biostatistics and bioinformatics, neurocognitive testing, integrated physiology, and global functional assessments. Content and clinical areas of expertise that will maximize the potential for translation of research findings to practice include: geriatrics and gerontology, neurology and neuro- ophthalmology, cardiology, nephrology, and women’s health.

Project Narrative – MAE-WEST SCORE CEC With advancing age, women and men age differently; women suffering more from Alzheimer’s disease and related dementias, heart failure with preserved ejection fraction, chronic kidney disease, and frailty. Recent work suggests that small blood vessel-related aging driven by chronic low-grade inflammation may be responsible for these aging disparities for women. The Career Enhancement Core (CEC) in the Microvascular Aging and Eicosanoids – Women’s Evaluation of Systemic aging Tenacity (MAE-WEST) (“You are never too old to become younger!”) Specialized Center of Research Excellence (SCORE) on Sex Differences will provide expert training in areas that include: population health, clinical trials, basic science, chemistry, biostatistics and bioinformatics, dementia testing, physiology, and frailty measurement, expanding the reach of the SCORE, and training the next generation of researchers to continue to improve public health.