PROJECT SUMMARY The overarching goal of this proposal is to provide the applicant with selected additional skills required for an applicant to become an independent NIH-funded investigator capable of designing and implementing early phase geroscience-guided clinical trials that have the potential to extend healthy lifespan by targeting biological aging. This custom-designed learning experience will be enhanced by three unique components. First, a Patterson Trust-funded study “The Mito-Frail Trial: Effects of MitoQ on Vasodilation, Mobility and Cognitive Performance in Frail Older Adults” will provide a research platform. Second, the NIA Translational Geroscience Network (R33 AG061456) and its Facility for Geroscience Analysis has agreed to provide learning experiences and subsidized measurements of biomarkers permitting a much broader and deeper analysis of biological hallmarks of aging. Third, the NIA Geroscience Education and Training Network (R25 AG073119) will permit the candidate to fulfill the requirements for a Certificate in Geroscience at UConn, one of the network's current five sites. Chronic diseases and associated declines in physical and cognitive performance contribute greatly to lost independence with aging. In addition to a lack of effective interventions other than exercise to address either problem, few studies have examined strategies for targeting both conditions in frail individuals who may experience difficulties with both walking and memory. Use of geroscience-guided therapies permits us to target mechanisms shared by aging with chronic conditions for which aging represents a major risk factor. Thus, instead of focusing on one single disease at a time, it may be possible to delay the onset and progression of disability involving multiple functional domains including those caused by Alzheimer's disease and other dementias. We have recently shown that MitoQ, a mitochondria-targeted antioxidant known to improve endothelial function and Nitric Oxide (NO) bioavailability, may also restore impaired flow-mediated vasodilation in frail older adults, enhancing gait speed. In the Mito-Frail study we now wish to explore the hypothesis that MitoQ attenuates aging- related declines in flow-mediated vasodilation involving both peripheral and cerebral blood vessels. At the same time, we will obtain feasibility and pilot data involving measures of physical mobility and cognitive performance that may help us design and power a future clinical trial. Ultimately, we seek to develop strategies for preventing or slowing the progression of Alzheimer's disease and the vascular contribution to dementia. Therefore, Aim 1 will assess peripheral and cerebral NO bioavailability and mitochondrial reactive oxygen species (mtROS) levels in older adults who are healthy, others who are frail with slow walking speed and those who meet criteria for mild cognitive impairment (MCI). Aim 2 will determine whether MitoQ supplementation can improve vasodilation wi...