The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan

Dietary restriction (DR) and reduced insulin growth factor (IGF) signaling extend lifespan in Caenorhabditis elegans and other eukaryotic organisms. Autophagy, an evolutionarily conserved lysosomal degradation pathway, has emerged as a central pathway regulated by various longevity signals including DR and IGF signaling in promoting longevity in a variety of eukaryotic organisms. However, the mechanism remains unclear. Here we show that the autophagy protein ATG-18 acts cell non-autonomously in neuronal and intestinal tissues to maintain C. elegans wildtype lifespan and to respond to DR and IGF-mediated longevity signaling. Moreover, ATG-18 activity in chemosensory neurons that are involved in food detection sufficiently mediates the effect of these longevity pathways. Additionally, ATG-18-mediated cell non-autonomous signaling depends on the release of neurotransmitters and neuropeptides. Interestingly, our data suggest that neuronal and intestinal ATG-18 acts in parallel and converges on unidentified neurons that secrete neuropeptides to regulate C. elegans lifespan through the transcription factor DAF-16/FOXO in response to reduced IGF signaling.

Author summary Restriction of dietary food without malnutrition robustly extends lifespan in more than twenty species. It was also reported that fruit flies (Drosophila melanogaster) deficient in olfactory function live longer and that the longevity induced by food restriction is partially due to decreased olfaction. These observations suggest food assimilation through the gastrointestinal tract and food smell detected by olfactory neurons influence lifespan. The insulin growth factor signaling pathway is regulated by nutrient levels and has been shown to mediate the lifespan extension conferred by food restriction and defective gustatory neurons in the nematode Caenorhabditis elegans. However, the mechanism remains unclear. Autophagy is a lysosomal degradation pathway and is sensitive to nutrient availability. We found autophagy activity in the intestine and food sensory neurons acts in parallel to mediate food restriction and insulin signaling regulated lifespan extension in Caenorhabditis elegans. Moreover, intestinal and neuronal autophagy converges on unidentified neurons to control the secretion of neuropeptides that regulate lifespan. These data suggest autophagy is an essential component in a neuroendocrine pathway that coordinates how environmental food cues detected by sensory neurons and food nutrients assimilated by the intestine influence lifespan. These findings may contribute to understanding the aging process in mammals.