Lipids for a Long Life

Sci. Signal.  17 May 2011:
Vol. 4, Issue 173, pp. ec144
DOI: 10.1126/scisignal.4173ec144

Caloric restriction increases life span in several model organisms. Endocannnabinoids link nutrient intake to energy balance, leading Lucanic et al. to investigate the role of these lipid-derived signaling molecules in mediating the effect of dietary restriction on life-span extension. In mammals, N-acylethanolamines (NAEs) bind to cannabinoid receptors. Although the nematode Caenorhabditis elegans lacks clear orthologs of cannabinoid receptors, the authors found that they synthesize the NAEs eicosapentaenoyl ethanolamide (EPEA) and, as previously reported, arachidonoyl ethanolamide (AEA). FAAH1 (fatty acid amide hydrolase) degrades NAEs, and worms overexpressing faah-1 had lower concentrations of EPEA and AEA. Furthermore, these worms were developmentally delayed, a phenotype that was rescued by RNA interference directed against faah-1, prompting the authors to examine the relationship between NAE concentrations and dauer, a developmentally arrested state that C. elegans enter under adverse conditions. NAE concentrations were reduced during the transition to dauer and during dauer, and EPEA treatment suppressed the constitutive dauer phenotype of several mutant worm strains. Starved adult worms showed decreased NAE concentrations, which were restored upon refeeding. Worms overexpressing faah-1 were more resistant than wild-type to thermal stress and had longer adult life spans; longevity was increased only in well-fed mutant worms, not those subjected to caloric restriction, and not in worms lacking the FOXO transcription factor PHA-4, which is required for life-span extension by dietary restriction. Worms with a null mutation in rsks-1, which encodes the worm ortholog of S6 kinase in the TOR pathway, are long-lived, and Lucanic et al. showed that these worms had decreased concentrations of EPEA. Moreover, treatment of rsks-1 worms with EPEA attenuated their longevity phenotype. The receptor through which EPEA and other NAEs exert their effects on life span in worms in response to nutrient availability remains to be identified, but these data suggest that, in mammals, cannabinoid receptors may have a role in longevity (see De Petrocellis and Di Marzo for commentary).

M. Lucanic, J. M. Held, M. C. Vantipalli, I. M. Klang, J. B. Graham, B. W. Gibson, G. J. Lithgow, M. S. Gill, N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans. Nature 473, 226–229 (2011). [PubMed]

L. De Petrocellis, V. Di Marzo, Why fasting worms age slowly. Nature 473, 161–163 (2011). [PubMed]