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Aging drives regenerative and cognitive impairments in the adult brain. It is imperative to gain mechanistic insight into what drives aging phenotypes in the brain to maintain functional integrity in the elderly. We, and others, have shown that systemic manipulations, such as heterochronic parabiosis, can partially reverse age-related impairments in neural stem/progenitor cell (NPC) function and loss of cognitive faculties in the aged brain. Interestingly, these studies have revealed an age-dependent bi-directionality in the influence of the systemic environment indicating pro-youthful factors in young blood elicit rejuvenation while pro-aging factors in old blood drive aging. It has been proposed that introducing pro-youthful factors or mitigating the effect of pro-aging factors may provide effective strategies to rejuvenate aging phenotypes. Despite this potential, much is unknown as to the systemic and molecular mechanisms regulating pro-youthful and pro-aging effects of blood-borne factors on NPC function in the aged brain. I will discuss work from my research group that begins to provide mechanistic insight into the molecular drivers promoting regenerative and cognitive rejuvenation in the aging brain.