Lifespan regulation in α/β posterior neurons of the fly mushroom bodies by Rab27.

Brain function has been implicated to control the aging process and modulate lifespan. However, continuous efforts remain for the identification of the minimal sufficient brain region and the underlying mechanism for neuronal regulation of longevity. Here, we show that theDrosophilalifespan is modulated byrab27functioning in a small subset of neurons of the mushroom bodies (MB), a brain structure that shares analogous functions with mammalian hippocampus and hypothalamus. Depletingrab27in the alpha/beta p neurons of the MB is sufficient to extend lifespan, enhance systemic stress responses, and alter energy homeostasis, all without trade-offs in major life functions. Within the alpha/beta p neurons,rab27KOcauses the mislocalization of phosphorylated S6K thus attenuates TOR signaling, resulting in decreased protein synthesis and reduced neuronal activity. Consistently, expression of dominant-negative S6K in the alpha/beta p neurons increases lifespan. Furthermore, the expression of phospho-mimetic S6 in alpha/beta p neurons ofrab27KOrescued local protein synthesis and reversed lifespan extension. These findings demonstrate that inhibiting TOR-mediated protein synthesis in alpha/beta p neurons is sufficient to promote longevity.