The Role of Hypothalamic Dysfunction in Accelerating Aging in Humans

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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 accelerating aging, deter- mined by longitudinal assessments of neurocognitive scores, frailty index and all-cause mortality. Aim 2: To establish cross-sectional relationships between hypothalamic gliosis and accelerated aging (2a) and neuro- endocrine hypothalamic dysfunction (2b); and Aim 3: To identify circulating protein signatures of neuroen- docrine hypothalamic dysfunction (3a) and hypothalamic gliosis (3b). This proposal will establish the role of hypothalamic dysfunction in human aging and identify potential biological mechanisms that accelerate aging. My career goal is to establish the role of the neuroendocrine system in the regulation of aging in humans, and I have identified four main areas for further development over the 5-years of this K76 Award. These include advanced training in 1) neuroimaging, 2) geriatrics, 3) data analysis, and 4) leadership. I have devised, with input from my multidisciplinary team of mentors and collaborators, a comprehensive training plan to attain knowledge and skills necessary to become a highly competent translational aging scientist who will successfully compete for future R01 funding and lead the field of neuroendocrine regulation of human aging into the future.