Rasal1: A candidate exercise mimetic to increase adult hippocampal neurogenesis in middle age

Physical exercise exerts several positive effects on the brain and is emerging as an approach for mitigating age-related functional decline. One benefit of exercise is the increase in adult hippocampal neurogenesis (AHN). However, physical exercise may not always be feasible in individuals due to physical or medical constraints which are more common in older age, highlighting the importance of understanding regulators of exercise-induced AHN. We demonstrate that Rasal1, a GTPase-activating protein, is downregulated in the dentate gyrus (DG) by voluntary running exercise in young adult rats. Middle age is recognised as a period of the lifespan prognostic of cognitive health in older age, and amenable to intervention. Lentiviral knockdown of Rasal1 in the DG promoted AHN and neurite growth in middle-aged rats that were otherwise reluctant to run. Treatment of hippocampal neuroprogenitor cells in vitro with serum from exercising animals mimicked the exercise-induced downregulation of Rasal1 and was associated with neuroprogenitor expansion. Lastly, multi-omic analysis of sera in conjunction with brain proteomics identified possible systemic mediators of Rasal1 downregulation. Taken together, our findings highlight Rasal1 as a novel candidate regulator of the pro-neurogenic effects of exercise. Identifying systemic factors underlying the Rasal1-driven effects of exercise could inform new therapies to enhance AHN and hippocampal function.