Sensory neurons regulate the lifespan of several organisms, including C. elegans and Drosophila. In C. elegans, insulin/IGF-1 and steroid signaling pathways have been shown to mediate the longevity response by sensory neurons. Although it is established that perturbation of chemosensory neurons promotes longevity by activating DAF-16, upstream mediators of this activation are poorly understood. Here, we show that mutations in
tax-2 and
tax-4, which encode subunits of neural cGMP-gated channels, increase lifespan at low temperature via modulating the expression of several insulin-like peptides. After confirming
daf-16-dependency of longevity by
tax-2 mutations, we determined the tissues crucial for the action of DAF-16. We found that pan-neuronal, intestinal or hypodermal expression of DAF-16::GFP partially rescued the short lifespan of
tax-2 daf-16 double mutants, whereas muscle-specific expression did not. In addition,
tax-2 mutations increased nuclear localization of DAF-16 in non-neuronal tissues, including the intestine. Because the expression of
tax-2 and
tax-4 is restricted to neurons, these data suggest a tissue non-autonomous signaling between sensory neurons and other tissues. In addition, the expression of
sod-3,
dod-8 and
mtl-1, downstream target genes of DAF-16, was elevated in
tax-2;
tax-4 mutants, suggesting a transcriptional activation of DAF-16. Next, we reasoned that neuroendocrine signaling via insulin-like peptides may participate in the longevity of
tax-2 and
tax-4 mutants. Among 34 insulin-like peptide genes we examined,
daf-28 and
ins-6 were significantly repressed in
tax-2;
tax-4 mutants. We demonstrated the functional significance of this down-regulation by showing that overexpression of
ins-6 or
daf-28 suppressed the long lifespan of
tax-2 mutants. Together, we propose that sensory neurons modulate lifespan via neuroendocrine signaling mediated by insulin-like peptides that regulate the activity of DAF-16.