PROJECT SUMMARY/ABSTRACT Identifying novel therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing elderly population. Exercise has been shown to rejuvenate regenerative capacity and cognition in the aged brain in animal models. Moreover, exercise has been shown to improve learning and memory in Alzheimer’s disease patients. Excitingly, our lab recently demonstrated that systemic administration of blood plasma derived from exercised mice reverses age- related impairments in adult neurogenesis and cognition in aged mice. We identify glycosylphosphatidylinositol specific phospholipase D1 (Gpld1) as a liver-derived exercise blood factor – the plasma levels of which correlate with improved cognitive function in aged mice, and the levels of which are increased in active healthy elderly humans. Functionally, we show that increasing liver-derived systemic Gpld1 in aged mice ameliorates age- related regenerative and cognitive impairments. These data raise fundamental questions as to the function of liver-derived systemic Gpld1: How long lasting are the rejuvenating effects of systemic Gpld1 on the aged brain? What is the role of systemic Gpld1 in mediating the rejuvenating effects of exercise on the aged brain? 3. What molecular mechanisms underly the rejuvenating effects of systemic Gpld1 in the aged brain? The purpose of the proposed study is to investigate the rejuvenating effects of systemic Gpld1 on the aged brain. Specifically, our hypothesis is that exercise-induced liver-derived systemic Gpld1 elicits long lasting rejuvenation of regenerative and cognitive functions in the aged hippocampus. We will test this theory with Three Specific Aims: 1: Characterize the kinetics of brain rejuvenation following increased liver-derived systemic Gpld1. 2: Investigate the necessity of exercise-induced systemic Gpld1 in mediating the rejuvenating effects of exercise on the aged brain. 3: Determine molecular mechanisms underlying the rejuvenating effects of liver-derived systemic Gpld1 in the aged brain. Successful completion of these studies will have significant translational potential, revealing pathways that could be targeted for novel therapies to ameliorate age-related neurodegenerative diseases such as Alzheimer’s disease.