PROJECT SUMMARY/ABSTRACT Candidate: Stefano Tarantini, PhD is a young assistant professor in the Center for Geroscience at the University of Oklahoma HSC. Dr. Tarantini’s research is focused on the role of age-related dysregulation of cerebral blood flow in the pathogenesis of Vascular Cognitive Impairment and Dementia (VCID). Dr. Tarantini’s long-term goal is to independently lead a federally funded laboratory with research focused on the underlying causes for the pathogenesis of VCID, and development of novel interventions for prevention targeting basic mechanisms of aging. Career Development: This R03 award will support Dr. Tarantini’s research efforts investigating a novel pilot study building on his past experience in cerebrovascular pathophysiology, advanced two-photon imaging, transcriptomics, bioinformatics, cognitive testing, redox biology and metabolic biology. Rich research environment: The Center for Geroscience at University of Oklahoma HSC is a leading center in VCID research and is an ideal environment for Dr. Tarantini’s career development, providing all the resources required to successfully complete the proposed studies. This proposal builds on the existing significant strengths: multidisciplinary expertise, cutting-edge core facility infrastructure, highly collaborative environment, and an exceptionally successful model for junior faculty mentoring. Research: The proposal aims to investigate the potential role of time-restricted feeding (TRF) against the development of age-related vascular cognitive impairment. Nutritional interventions such as caloric restriction (CR) have been shown to exert positive effects against endothelial dysfunction however poor adherence to CR and some deleterious effects in older individuals generate the need to investigate alternative translatable strategies against cognitive decline in the elderly. On the basis of extant preliminary data, the central hypothesis is proposed that TRF reverses age-induced endothelial dysfunction and improves CBF and NVC responses. It is predicted that the resulting neurovascular rejuvenation contributes to restoration of cognitive function. The following aims are proposed: 1) Determine how TRF regimen affects endothelium-mediated neurovascular coupling responses in aging; 2) Determine how TRF as a lifestyle intervention alters multiple cognitive domains in aging. The studies that have been highlighted in this proposal will investigate pathways that lead to the pathogenesis of VCID and offer potential therapeutic strategies to prevent the loss of cognitive function in the elderly. Deliverables: The results from the proposed studies will provide mechanistic insight into the endothelial contributions to age-related VCID and provide proof-of-concept for the development of nutritional lifestyle intervention strategies for prevention.