Temperature is an important environmental cue that influences longevity. In the nematode Caenorhabditis elegans, the thermosensory neuron AFD is required for normal life span at warm temperatures, but how AFDs control temperature-specific longevity response remains elusive. We showed that crh-1, which encodes the C. elegans cyclic AMP response element binding protein (CREB), acted in the AFD to maintain a normal life span at warm temperatures. We also identified an FMRFamide-like neuropeptide, flp-6, as the crh-1 transcriptional target and act in the longevity control in response to temperature. crh-1 and flp-6 acted in the AFD for longevity control. Both crh-1 and flp-6 were necessary and sufficient for longevity control in a temperature-dependent manner, with flp-6 acting downstream of crh-1. The effects of crh-1 on longevity were independent of the heat shock response pathway, but may engage insulin signaling, as genetic analysis of longevity phenotype in crh-1, flp-6 and daf-16 suggested that crh-1 and flp-6 act in the daf-16 pathway. This is supported by our profiling of the flp-6 mutant transcriptome compared to that of the wild type, which identified several insulin pathway genes that were upregulated in the flp-6 mutant, including the insulin-like peptide (ILP) ins-7. crh-1/flp-6 mutation or overexpression increased or decreased ins-7 expression in the intestine, respectively. Furthermore, the ins-7 mutation completely suppressed longevity deficits of the flp-6 mutant. Together these experiments identify an flp-6/FLP-to-ins-7/ILP neuropeptide signaling circuit as an output from the thermosensory neuron for systemic longevity control in response to a rise in the ambient temperature. (supported by National Health Research Institutes NHRI-EX101-10119NC).
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