PROJECT SUMMARY/ABSTRACT The purpose of this Ruth L. Kirschstein National Research Service Award is to provide support for Ms. Sanna Darvish, a PhD student in Dr. Douglas Seals’ laboratory at the University of Colorado Boulder, to conduct research that will prepare her to become an independent investigator in the field of cerebrovascular aging. As part of her proposed training plan, she will learn a variety of new technical, conceptual, intellectual, and professional skills and refine research skills currently under development. To do so, she will add outcomes to an ongoing NIH R01-funded clinical trial led by her Sponsor to investigate the efficacy of the mitochondrial-targeted antioxidant, MitoQ, for improving cerebrovascular function in older adults and the mechanism(s) of action. She will also assess the effects of MitoQ on fluid cognitive function. Cardiovascular diseases (CVD) are the leading cause of mortality in the U.S. Cerebrovascular diseases represent 37% of all CVD and, when considered alone, are the 5th most common cause of death. Aging is the primary risk factor for CVD, cerebrovascular diseases, Alzheimer’s disease and related dementias. Decreased cerebrovascular function (i.e., reduced cerebrovascular reactivity [CVR] and cerebral blood flow) is a key mechanism contributing to the age-related increase in risk for these diseases and is mediated in part by decreases in the vasodilatory molecule nitric oxide (NO), leading to cerebral endothelial cell (EC) dysfunction. Excessive reactive oxygen species production by mitochondria (mtROS) is an important contributor to cerebrovascular dysfunction as mtROS can scavenge NO and impair EC function. As such, establishing novel strategies to decrease mtROS to improve cerebrovascular function in older adults is an important biomedical research priority. Supported by a strong scientific premise and compelling preliminary results, Ms. Darvish will use innovative translational approaches to determine if three months of MitoQ treatment (versus placebo; n=30/group) in older adults (60 years of age) Aim 1) improves cerebrovascular function; Aim 2) if the improvements are mediated by a) reductions in tonic suppression of cerebrovascular function by mtROS, and b) beneficial changes in the circulating milieu that improve cerebral EC function; and Aim 3) if MitoQ improves fluid cognition and if improvements are associated with enhanced cerebrovascular function. The proposed research will be the first to assess the efficacy of MitoQ treatment for improving cerebrovascular function in older adults, a group at elevated risk for cerebrovascular diseases, Alzheimer’s disease and related dementias. This F31 fellowship project addresses important NIA research priorities to: 1) identify effective interventions aimed at preventing age-related diseases, and 2) investigate biological mechanism(s) involved in aging using translational, systems-based approaches. Under the supervision of her mentors, Ms. Darvish will complete the proposed research and training plan to advance an independent line of investigation and facilitate development towards becoming a successful independent scientific investigator.

PROJECT NARRATIVE The risk of developing cerebrovascular diseases, Alzheimer’s disease and related dementias increases with advancing age, largely due to declines in cerebral blood vessel function, which is influenced by age-related increases in mitochondrial oxidative stress. As the aging population is projected to increase in the coming years, establishing effective strategies to improve cerebrovascular function in older adults by decreasing mitochondrial oxidative stress is an urgent biomedical research priority. This project will investigate the efficacy of a new therapeutic intervention - mitochondrial-targeted antioxidant supplementation, MitoQ - for improving cerebral blood vessel function, assess the possible mechanism(s) contributing to these benefits and determine whether MitoQ improves cognitive function in older adults.