The discovery of neural stem/progenitor cells (NPCs) in the adult brain has incited possibilities for restoring cognitive dysfunction in the elderly by enhancing neurogenesis in the aging brain. However, advancements remain necessary in our understanding of how normal environmental changes during aging alter adult neurogenesis. Using heterochronic parabiosis (in which the circulatory systems of young and old animals are connected) we discovered that blood-borne factors present in the systemic environment inhibit or promote adult neurogenesis in an age dependent fashion in mice. Moreover, heterochronic parabiosis also resulted in changes in the activation state of microglia in the young and old brain. Interestingly, immune signaling has emerged as a key player in the negative regulation of adult neurogenesis, both by directly signaling to NPCs or indirectly by promoting changes in the activation state of resident immune cells. Employing a proteomic approach we identified the immune factor &beta2-Microglobulin (B2M) as a potential regulator of neurogenesis and microglia activation during aging. We observed a decrease in neurogenesis in the adult hippocampus after local administration of exogenous B2M, which could be mitigated in the absence of major histocompatibility complex I (MHC I) expression in vivo. Furthermore, local exposure to B2M resulted in impairments in hippocampal dependent learning and memory. Lastly, we observed an age-dependent enhancement in hippocampal neurogenesis, and associated cognitive processes, in old mice lacking endogenous B2M expression. Cumulatively, our data indicate that systemic age-related immune factors negatively regulate adult hippocampal neurogenesis and associated cognitive process during aging.