PROJECT SUMMARY/ABSTRACT The ability to enhance cognition by targeting circulating factors in the systemic milieu provides a unique and underexplored therapeutic approach to brain aging. We and others have shown that systemic manipulations, including exposure to young blood through heterochronic parabiosis (in which the circulatory system of a young and old animal are joined) and young blood plasma administration, revitalize the aged hippocampus and ameliorate cognitive decline in aged mice. The rejuvenating effects of young blood mirror those observed with exercise, positing common bloodborne mechanisms of action by which broad systemic interventions exert their beneficial effects. Preliminary data from our labs indicate that systemic administration of platelet factors derived from either naïve young mice or exercised mice reverses age-related impairments in adult neurogenesis, deceases neuroinflammation and restores cognitive function in aged mice. Moreover, using proteomics, our two groups have independently identified CXCL4/platelet factor 4 (PF4)—a chemokine released from platelets, involved in coagulation and a variety of immunomodulatory functions—as a potential young blood-derived and exercise-induced anti-geronic circulating factor. The proposed study will investigate the rejuvenating and therapeutic effects of platelet factors on the aged brain. Specifically, our hypothesis is that systemic exposure to platelet factors rejuvenates adult neurogenesis, attenuates neuroinflammation and improves cognition, while ameliorating neurodegenerative phenotypes. We will test this theory with three specific aims: 1: Determine mechanisms downstream of PF4 underlying cognitive and regenerative rejuvenation in the aged hippocampus. 2: Examine the rejuvenating effects of PF4 on neuroinflammation in the aged hippocampus. 3: Investigate the beneficial effects of PF4 in a mouse model of Alzheimer’s disease. Successful completion of these studies will have significant translational potential, identifying platelet-derived circulating factors as candidate therapeutic targets to restore age-related cognitive dysfunction and potentially treat dementia-related neurodegenerative disorders such as Alzheimer’s disease.