Midlife Obesity, Neurovascular Senescence and Cognitive Decline

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Stefano Tarantini, PhD, is a junior aging researcher whose overarching goal is to develop an independent research program to understand and apply nutritional lifestyle interventions to the field of cerebrovascular aging to ameliorate age-related vascular cognitive impairment and dementias (VCID). To achieve this, the following K01 proposal aims to further Dr. Tarantini's training to enable him to explore the role of midlife obesity on neurovascular senescence as it relates to the development of vascular cognitive impairment and related dementias. Candidate: Dr. Tarantini is an Assistant Professor in the Dept. of Biochemistry and Molecular Biology at the University of Oklahoma HSC. This K01 proposal perfectly builds on his previous training and extends his research in a logical direction that is becoming growingly relevant in the field of cognitive aging. This proposal identifies 5 training goals: 1) Acquire novel training in the field of nutrition; 2) Receive training in data integration, biostatistics, single-cell transcriptomics, and analysis; 3) training in advanced intra-vital imaging techniques; 4) Improve skills in magnetic resonance imaging (MRI); 5) Establish and lead an independent research laboratory. Mentors/Environment: The mentoring team will assist the candidate to ensure his success through the K01 training and research activity. The proposed plan will leverage resources of the newly established Center for Geroscience and Healthy Brain Aging, the NIH supported Nathan Shock Center, and the NIGMS-funded CoBRE training grant. The department is fully committed to support Dr. Tarantini independently of the outcome of this K01 application. Research: Mid-life obesity promotes cellular senescence. Aging-induced senescence among cells of neurovascular unit (NVU) associates with neurovascular dysfunction and cognitive impairment. Yet, the impact of obesity-induced senescence on the cellular components of the NVU and its function is not understood. We hypothesize that obesity accelerates NVU senescence, impairing structural and functional qualities of the cerebral vasculature. The resulting decline in cerebral blood flow and increased neuroinflammation contribute to cognitive impairment. We predict that elimination of senescent cells rejuvenates the NVU, restoring its youthful functional and structural integrity, which confers cognitive benefits. This project aims to characterize mid-life obesity-induced senescence in the neurovascular unit (Aim 1), the effects of senescence on NVC responses, cerebral blood flow and cognition (Aim 2), and how senescence alters microvascular density and BBB integrity in mouse models of mid-life obesity (Aim 3). Summary: This K01 proposal utilizes advanced imaging and sophisticated sequencing and data integration techniques in a relevant model of mid-life obesity to detect senescence in the NVU of the brain. Understanding the relationship between brain cellular senescence and impaired BBB function and diminished cerebrovascular hemodynamic responses (which are responsible to maintain intact cognitive function) will be critical to address potential nutritional interventional therapies to avoid obesity-induced cognitive deficits in aging and develop an independent research direction.