Recent studies have shown that the rate of aging can be modulated by diverse interventions. Dietary restriction is the most widely used intervention to promote longevity; however, the mechanisms underlying the effect of dietary restriction remain elusive. In a previous study, we identified two novel genes,
nlp-7 and
cup-4, required for normal longevity in Caenorhabditis elegans.
nlp-7 is one of a set of neuropeptide-like protein genes;
cup-4 encodes an ion-channel involved in endocytosis by coelomocytes. Here, we assess whether
nlp-7 and
cup-4 mediate longevity increases by dietary restriction. RNAi of
nlp-7 or
cup-4 significantly reduces the life span of the
eat-2 mutant, a genetic model of dietary restriction, but has no effect on the life span of long-lived mutants resulting from reduced insulin/IGF-1 signaling or dysfunction of the mitochondrial electron transport chain. The life-span extension observed in wild-type N2 worms by dietary restriction using bacterial dilution is prevented significantly in
nlp-7 and
cup-4 mutants. RNAi knockdown of genes encoding candidate receptors of NLP-7 and genes involved in endocytosis by coelomocytes also specifically shorten the life span of the
eat-2 mutant. We conclude that two novel pathways, NLP-7 signaling and endocytosis by coelomocytes, are required for life extension under dietary restriction in C. elegans.