Abstract

Age-related cognitive decline is a major health concern in aging populations and a key feature of neurodegenerative diseases such as Alzheimer’s. While several studies have shown that systemic interventions—such as heterochronic parabiosis and young plasma infusion—can restore hippocampal function and improve cognition in aged mice, the identity and source of protective circulating factors remain incompletely understood. Recent findings from our lab and others suggest that organs outside the brain, such as the liver and platelets, can secrete factors that promote brain rejuvenation. Notably, females exhibit greater cognitive resilience with age than males, raising the possibility that female-specific organs like the ovary may contribute to brain aging. Indeed, ovary transplantation extends lifespan in aged mice, and ovariectomy accelerates cognitive decline, independent of sex hormones. In this proposal, we aim to identify and characterize ovary-derived plasma factors that drive sex-specific resilience to brain aging and protect against age-related cognitive impairment. Ultimately, this work holds significant translational potential by identifying ovary-derived circulating factors enriched in young females as novel therapeutic targets to combat brain aging and reduce the risk of neurodegenerative diseases