Brain aging leads to cognitive decline and is the main risk factor for sporadic forms of neurodegenerative diseases including Alzheimer’s disease. While brain cell- and tissue-intrinsic factors are likely key determinants of the aging process recent studies document a remarkable susceptibility of the brain to circulatory factors. Thus, blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice and, vice versa, factors from old mice are detrimental for young mice and impair cognition. We found evidence that the cerebrovasculature is an important target of circulatory factors and that brain endothelial cells show prominent age-related transcriptional changes in response to plasma. Furthermore, plasma proteins are taken up broadly into the young brain through receptor mediated transport which declines with aging. At the same time, brain derived proteins are detectable in plasma allowing us to measure physiological changes linked to brain aging in plasma. We are exploring the relevance of these findings for neurodegeneration and potential applications towards therapies.