"This IRG will support my return to the EU as a Senior Lecturer in Nutrition and Neuroscience at the Hebrew University of Jerusalem, bringing state-of-the-art science and technology, collaborations, and excellent prospects for reintegration and the enhancement of European competitiveness. My research aims to elucidate the metabolic basis of brain aging and develop interventions for preventing dementia and brain vascular disease. We address a timely and fundamental question regarding microvascular mechanisms of cognitive decline. Our central hypothesis is that impairment of brain microvascular plasticity due to age, diet or disease, is a pivotal mechanism of cognitive decline. Building on outstanding prior research, we predict that that folate deficiency and aging will limit brain circulation and oxygen delivery by diminishing microvascular plasticity, thus ultimately impairing cognition. Specific aims are to: 1) Test the hypothesis that impaired brain circulation and oxygen delivery due to aberrant microvascular plasticity impairs cognition in both folate-deficiency and aging; and 2) Identify folate- and age-responsive pathways that regulate brain microvascular plasticity. We will use a conceptually and technically innovative approach to measure cognitive function, brain microvascular plasticity, and brain circulation and oxygen delivery with our proprietary near infrared spectroscopy (NIRS) system. These studies will help delineate the role of microvascular plasticity in cognitive function; establish a new animal model of vascular cognitive impairment; establish quantitative anatomical and non-invasive functional measures of microvascular health for basic and pre-clinical research; and identify one or more diet-responsive microvascular signaling pathways. These outcomes are significant because they will provide actionable insight into the role of nutritional factors in modifying microvascular plasticity for the prevention of age-related cognitive decline."