Project Summary Aging is associated with age-related impairments in cognitive function and is the number one risk factor for a series of neurodegenerative disorders, including Alzheimer’s disease. However, aging is not isolated to the brain, but is instead a system wide process affecting multiple tissues and organ systems. A growing body of work has demonstrated that exposure to an aged circulatory system, which connects all organ systems that face age- related decline, drives hippocampal-dependent cognitive impairments during aging. Interestingly, there are known age-related changes in the peripheral immune system, which constitutes an integral portion of the aging circulatory system. T cells, a component of the adaptive immune system, are one of the immune cells most detrimentally affected by age. In addition to a decrease in the ability to respond to infections and increases in inflammatory cytokine secretion in the periphery, there is an emerging role posited for T cells in age-related brain dysfunction. While studies have identified an increase in T cell infiltration into select areas of the aged brain, the effect of age-related changes in circulating T cells on hippocampal-dependent cognitive function has not fully been explored. Therefore, I sought to delineate the role of peripheral, aged CD8+ T cells in driving age-related cognitive decline. Using single cell RNA sequencing, I identified age-associated CD8+ T cells, marked by elevated expression of Granzyme K (GZMK), in spleens of cognitively impaired aged mice and young mice exposed to an old circulatory system via heterochronic parabiosis. Interestingly, levels of secreted GZMK are increased in the plasma of aged mice. Functionally, adoptive transfer of aged CD8+ T cells into young mice resulted in cognitive deficits in hippocampal-dependent learning and memory, underlain by synaptic and neuronal changes. To explore the rejuvenating potential of targeting aged CD8+ T cells, I selectively depleted circulating CD8+ T cells in aged mice and observed amelioration of age-related impairments in learning and memory. Interestingly, bulk RNA sequencing identified differentially expressed genes enriched in neurons and endothelial cells. Consequently, this study aims to test the hypothesis that peripheral, age-associated CD8+ T cells are drivers of cognitive impairments in the aging hippocampus. In Aim 1, I will determine the molecular and cellular changes elicited by aged CD8+ T cells in the aged hippocampus. As depletion of circulating CD8+ T cells is sufficient to ameliorate cognitive decline, in Aim 2, I will investigate the role of CD8+ T cell-derived factors in promoting hippocampal-dependent cognitive decline, focusing on the pro-aging effects of GZMK. This study aims to identify molecular mechanism by which circulating aged CD8+ T cells drive cognitive impairments with age and identify potential therapeutic targets to counter aging-associated cognitive decline and dementia-related neurode...