PROJECT SUMMARY/ABSTRACT Aging drives regenerative and cognitive impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. One exciting possibility is to harness the regenerative capacity of stem cells in the adult brain to reverse normal aging and ameliorate cognitive dysfunction by enhancing neurogenesis. We, and others, have shown that systemic manipulations such as heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) or young plasma administration can partially reverse age-related impairments in neural stem/progenitor cell (NPC) function and loss of cognitive faculties in the aged brain. Interestingly, heterochronic parabiosis studies have revealed an age-dependent bi-directionality in the influence of the systemic environment indicating anti-aging factors in young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that mitigating the effect of pro-aging factors may also provide an effective approach to rejuvenate aging phenotypes, however functional investigation of individual pro-aging factors is lacking. Recently my lab identified β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a systemic pro-aging factor that negatively regulates regenerative and cognitive functions in the adult hippocampus. The purpose of the proposed study is to gain mechanistic insight into the pro-aging effects of MHC I molecules on the aging brain, and ascertain the therapeutic potential of targeting these molecules at old age. Specifically, our hypothesis is that B2M in concert with classical MHC I molecules act as pro-aging factors driving age-related regenerative and cognitive impairments in the adult hippocampus. We will test this theory with Three Specific Aims: 1: Characterize age-related molecular mechanisms downstream of B2M and MHC I underlying regenerative and cognitive enhancements in the adult brain. 2: Determine effectiveness of reducing cell surface MHC I expression to ameliorate age-related regenerative and cognitive impairments. 3: Investigate classical MHC I molecules, H2-Kd and H2-Db, as pro-aging negative regulators of regenerative and cognitive function in the brain. Successful completion of these studies will have significant translational potential, identifying molecular pathways that could be targeted for novel therapies to ameliorate dementia-related neurodegenerative disorders and their downstream consequences in terms of impaired regenerative and cognitive functions.