Life‐span extension by dietary restriction is mediated by NLP‐7 signaling and coelomocyte endocytosis inC. elegans

Abstract

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.

Genetic Mechanisms of Coffee Extract Protection in aCaenorhabditis elegansModel of β-Amyloid Peptide Toxicity

“…We considered the possibility that coffee extract might trivially provide protection by inhibiting C. elegans feeding and secondarily inducing a protective dietary restriction response. Mutations in eat-2 slow pharyngeal pumping (Raizen et al 1995) thereby producing a genetic dietary restriction model that shows SKN-1-dependent life-span extension (Park et al 2010). We directly measured pharyngeal pumping in response to coffee exposure but found no effect ( Figure 6A).…”

“…The role of skn-1 in dietary restriction-induced life-span extension depends solely on expression of SKN-1 in the ASI neurons (Bishop and Guarente 2007), implying that it is likely there are intercellular signaling events downstream of skn-1 activation modulating life span. Indeed, a neuropeptide-like hormone, NLP-7, has been recently shown to act downstream of skn-1 to promote life-span extension by dietary restriction (Park et al 2010). It is also interesting to note that astrocyte activation of Nrf2 is sufficient to convey neuronal protection in mouse models of PD and ALS (Vargas et al 2008;Chen et al 2009), demonstrating that Nrf2-dependent neuroprotection in mammals can also be non-cell autonomous.…”

Genomic approaches for the understanding of aging in model organisms

“…However, the induction of heat shock genes by oxidative stress is not SKN-1-dependent. Surprisingly, two SKN-1-dependent oxidative-stress-responsive genes, nlp-7 and cup-4, are specifically required for lifespan extension by DR (35). NLP-7 is a neuropeptide-like protein expressed in neurons while CUP-4 is a coelomocyte-specific ion channel essential for endocytosis by coelomocytes (36,37).…”

Logarithmic bacterial gradient chip for analyzing the effects of dietary restriction on C. elegans growth

“…Thus, DR is most commonly used method of retarding senescence and reducing mortality at present. Understanding the mechanism underlying this environmental intervention on lifespan is of vital importance [4,5]. Although numerous hypotheses have been proposed to explain the extension of DR to longevity, the exact mechanisms of regulatory role of DR in aging and lifespan is still poorly understood due to technical difficulties in precise dietary control.…”