Serotonin signaling mediates protein valuation and aging.

Research into how protein restriction improves organismal health and lengthens lifespan has largely focused on cell-autonomous processes. In certain instances, however, nutrient effects on lifespan are independent of consumption, leading us to test the hypothesis that central, cell non-autonomous processes are important protein restriction regulators. We characterized a transient feeding preference for dietary protein after modest starvation in the fruit fly, Drosophila melanogaster, and identified tryptophan hydroxylase (Trh), serotonin receptor 2a (5HT2a), and the solute carrier 7-family amino acid transporter, JhI-21, as required for this preference through their role in establishing protein value. Disruption of any one of these genes increased lifespan up to 90% independent of food intake suggesting the perceived value of dietary protein is a critical determinant of its effect on lifespan. Evolutionarily conserved neuromodulatory systems that define neural states of nutrient demand and reward are therefore sufficient to control aging and physiology independent of food consumption.