Neuronal autophagy activity is essential for insulin growth factor signaling-regulated lifespan extension in C. elegans

The conserved insulin growth factor IGF signaling pathway is one of the major regulators of lifespan in
many species including C. elegans. In C. elegans the insulin/IGF-like receptor is encoded by the daf-2
gene, mutations in which result in lifespan extension. The daf-2 activity in the nervous system controls
these phenotypes cell nonautonomously. Interestingly, the longevity phenotype of daf-2 mutant worms
is dependent on macroautophagy hereafter autophagy. Autophagy is a highly conserved lysosomal
degradation pathway involved in the removal of long-lived proteins and cytoplasmic organelles. During
autophagy, cellular components are sequestered into the double-membrane autophagosomes and
delivered to lysosomes for degradation. Increasing evidence has emerged that the autophagy process
is a central regulator of lifespan that is required for the effects of DAF-2 signaling, dietary restriction and
some mitochondrial mutations on C. elegans longevity. It is unknown however whether autophagy
activity in every tissue or in a single tissue mediates the influence of these longevity signals. To
address this question, we examined the tissue requirement of the autophagy gene atg-18 for the
lifespan of wild type animals and the daf-2 mutant. We discovered that neurons and intestinal cells are
two key tissues where atg-18 mediates the effect of DAF-2 insulin-like signaling on lifespan, suggesting
autophagy acts cell nonautonomously in controlling C. elegans adult longevity. Moreover, we found that
neuronal release of neuropeptides is required for the cell non-autonomous function of neuronal
autophagy activity in controlling C. elegans lifespan.