Project Summary/Abstract The world population is aging. Despite our advances in extending lifespan, there is tremendous individuality in age-related morbidity and mortality. It is recognized that the breakdown of the blood-brain barrier (BBB) in hippocampus marks an early event of cognitive impairment in aging. However, how aging affects BBB in the hypothalamus, and its ensuring metabolic consequences is not well understood. The goal of this study is to test whether the age-related decline of tanycyte number contributes to the weakening of the BBB in the hypothalamus and its impact on metabolic impairment and mortality. We will determine if proliferative capacity of tanycytes decreases with age, leading to age-dependent loss of tanycytes. We will explore if inadequate tanycyte proliferation leads to weakened BBB in the mediobasal hypothalamus and its consequences. We will evaluate if aging of the AgRP neurons outside the BBB marks the decline of AgRP neuronal function and metabolic derailment in advanced aging. Lifespan is influenced by both genetic and environmental factors. Given the essential roles of the AgRP neurons in metabolic control and their unique anatomical localization outside the BBB, information obtained from this study will establish the importance of the hypothalamic BBB in metabolic control and longevity in advanced aging.