Inhibition of a small subset of sensory neurons can increase the lifespan of a whole organism, including C. elegans and mice. Perturbation of sensory neurons prolongs the lifespan of C. elegans by activating DAF-16/FOXO transcription factor. However, mechanisms by which sensory neurons transmit longevity signals to other body parts remain elusive. Here, we show that insulin-like peptides (ILPs) are neuro-endocrine factors that relay longevity signals from sensory neurons to non-neuronal tissues. Mutations in tax-2 and tax-4, subunits of a cyclic GMP-gated channel required for sensory neural functions, promote the longevity of C. elegans. We found that tax-2 or tax-4 mutations activated DAF-16/FOXO in multiple tissues, including neurons and non-neuronal tissues, intestine and hypodermis. This result indicates tissue-to-tissue regulation of DAF-16 activity by sensory neurons. Considering potential roles of neuroendocrine signaling via ILPs in lifespan regulation, we determined the expression of 34 C. elegans ILP genes. We found that down-regulation of two ILP genes, daf-28 and ins-6, mediated the longevity of sensory mutants. Further, daf-28 and ins-6 regulated the elevated nuclear localization and transcriptional activation of DAF-16 in tax-4 mutants. We also showed that ins-6 mediated the sensory longevity response by acting in two specific sensory neurons, ASI and ASJ. Optogenetic activation of either ASI or ASJ neurons was sufficient to alter subcellular localization of DAF-16 in the intestine. Finally, we identified food signals as sensory cues that regulated ILP expression. Cell-free E. coli supernatants, which acted as sensory food cues, increased ins-6 and daf-28 mRNA levels and caused the inactivation of DAF-16. Thus, food cues appear to regulate ILPs in sensory neurons, which relay the longevity signals to non-neuronal tissues by regulating the activity of DAF-16.
Research support: NRF-2012R1A4A1028200, NRF-2013R1A1A2014754, and Korean Health Technology R&D Project (HI14C2337) to S.-J.V.L. H.G.S. is supported by NRF-2012H1A2A1049108, and D.E.J. is supported by NRF-2013H1A8A1003751.
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