Gut-to-brain regulation of Drosophila aging through neuropeptide F, insulin and juvenile hormone

Dietary restriction slows aging in many animals, while in some cases the sensory signals from diet alone are sufficient to retard or accelerate lifespan. The digestive tract is a candidate location to sense nutrients, where neuropeptides secreted by enteroendocrine cells (EEC) produce systemic signals in response to food. Here we measure how Drosophila neuropeptide F (NPF) is secreted into adult circulation by enteroendocrine cells and find that specific enteroendocrine cells differentially respond to dietary sugar and yeast. Lifespan is increased when gut NPF is genetically depleted, and this manipulation is sufficient to blunt the longevity benefit conferred by dietary restriction. Depletion of NPF receptors at insulin producing neurons of the brain also increases lifespan, consistent with observations where loss of gut NPF decreases neuronal insulin secretion. The longevity conferred by repressing gut NPF and brain NPF receptors is reversed by treating adults with a juvenile hormone (JH) analog. JH is produced by the adult corpora allata, and inhibition of the insulin receptor at this tissue decreases JH titer and extends lifespan, while this longevity is restored to wild type by treating adults with a JH analog. Overall, enteroendocrine cells of the gut modulate Drosophila aging through interorgan communication mediated by a gut- brain-corpora allata axis, and insulin produced in the brain impacts lifespan through its control of JH titer. These data suggest that we should consider how human incretins and their analogs, which are used to treat obesity and diabetes, may impact aging. Significance StatementNeuropeptide F (NPF) produced in the Drosophila gut is an insulin-regulatory hormone (incretin) that is secreted into adult circulation in response to feeding and diet. Suppression of gut NPF extends Drosophila longevity, as does knockdown of Neuropeptide F receptors at the insulin-producing medial neurosecretory cells in the brain that control the titer of juvenile hormone. Gut hormones and brain insulin regulate lifespan because they control juvenile hormone titer, which itself is the master endocrine regulator of Drosophila aging. Gut NPF modulates Drosophila aging through the integration of nutrient sensing, insulin signaling and juvenile hormone. Given the role of incretin-mimetic drugs to treat diabetes and obesity, it may be time to consider how incretin analogs could impact human aging.