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Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed that SEPP1 and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) are required for the exercise-induced increase in adult hippocampal neurogenesis. In vivo selenium infusion increased hippocampal neural precursor cell (NPC) proliferation and adult neurogenesis. Mimicking the effect of exercise through dietary selenium supplementation restored neurogenesis and reversed the cognitive decline associated with aging and hippocampal injury, suggesting potential therapeutic relevance. These results provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippocampal NPCs and their subsequent recruitment into the neurogenic trajectory. [Display omitted] • Selenium mediates the exercise-induced increase in adult hippocampal neurogenesis • Selenium increases hippocampal precursor proliferation and adult neurogenesis • Selenium reverses cognitive decline in aging and in hippocampal injury Exercise increases new neuron generation in the hippocampus, a brain region with important learning and memory functions. Here, Leiter et al. report that this process is mediated by an increase in systemic selenium transport. Dietary selenium supplementation restored neurogenesis and reversed cognitive decline in aging and in a model of hippocampal injury, suggesting potential therapeutic relevance. [ABSTRACT FROM AUTHOR]