The Role of Hypothalamic Dysfunction in Accelerating Human Aging Sandra Aleksic, MD, M.S. Mentor: Sofiya Milman, MD, M.S. Co-mentors: Michael Lipton, MD, PhD; Joe Verghese, MBBS, MS Abstract: Mechanisms underpinning biological aging in humans remain incompletely understood. The hypothalamus integrates key metabolic and neuroendocrine longevity pathways; therefore, hypothalamic dysfunction could accelerate aging in humans. Recent studies in rodents identified aging-related hypothalamic microinflam- mation, referred to as gliosis, which was characterized by accumulation and activation of microglia and astrocytes. Gliosis caused hypothalamic dysfunction and accelerated aging, but prevention of hypothalamic gliosis delayed aging. Despite growing evidence that the hypothalamus may regulate the aging process, its role in human aging has not been investigated. My hypothesis is that hypothalamic dysfunction accelerates aging in humans. To test this hypothesis, we have devised a unique approach tailored to human aging cohorts. We will test two different measures of hypothalamic dysfunction as predictors of cognitive decline, frailty, and reduced lifespan, which are features of accelerated aging: 1) Neuroendocrine hypothalamic dysfunction is a functional measure, represented by hypothalamic dysregulation of gonadal axis. 2) Hypothalamic gliosis is a structural measure, established by neuroimaging MRI-DTI parameters. This proposal leverages an established prospective cohort of adults age ≥65 (n=1,200), LonGenity, with detailed biochemical and phenotypic assessments, including high-quality brain MRIs (n=240), which will be analyzed with a novel automated MRI processing pipeline developed by our group to efficiently and objectively study hypothalamic gliosis. My hypothesis will be addressed through the following Specific Aims: Aim 1: To establish the role of neuroendocrine hypothalamic dysfunction, represented by hypothalamic dysregulation of gonadal axis at study baseline, in