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N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans


Dietary restriction is a robust means of extending adult lifespan and postponing age-related disease in many species, including yeast, nematode worms, flies and rodents1,2. Studies of the genetic requirements for lifespan extension by dietary restriction in the nematode Caenorhabditis elegans have implicated a number of key molecules in this process3,4,5, including the nutrient-sensing target of rapamycin (TOR) pathway6 and the Foxa transcription factor PHA-4 (ref. 7). However, little is known about the metabolic signals that coordinate the organismal response to dietary restriction and maintain homeostasis when nutrients are limited. The endocannabinoid system is an excellent candidate for such a role given its involvement in regulating nutrient intake and energy balance8. Despite this, a direct role for endocannabinoid signalling in dietary restriction or lifespan determination has yet to be demonstrated, in part due to the apparent absence of endocannabinoid signalling pathways in model organisms that are amenable to lifespan analysis9. N-acylethanolamines (NAEs) are lipid-derived signalling molecules, which include the mammalian endocannabinoid arachidonoyl ethanolamide. Here we identify NAEs in C. elegans, show that NAE abundance is reduced under dietary restriction and that NAE deficiency is sufficient to extend lifespan through a dietary restriction mechanism requiring PHA-4. Conversely, dietary supplementation with the nematode NAE eicosapentaenoyl ethanolamide not only inhibits dietary-restriction-induced lifespan extension in wild-type worms, but also suppresses lifespan extension in a TOR pathway mutant. This demonstrates a role for NAE signalling in ageing and indicates that NAEs represent a signal that coordinates nutrient status with metabolic changes that ultimately determine lifespan.

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Figure 1: NAE levels in C. elegans are modulated by FAAH activity.
Figure 2: NAEs affect reproductive growth and dauer formation.
Figure 3: Reduced NAE levels are associated with dietary restriction and are sufficient to confer lifespan extension.
Figure 4: EPEA suppresses the effects of dietary restriction on lifespan.


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Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). We would like to thank N. J. Harrison, A. Olsen and P. Kapahi. M.L. was supported by NIH training grant T32 AG000266 and NIH grant R01 AG029631. GC-MS analysis was made possible through the Mass Spectrometry and Imaging Technologies Core supported by NIH grant PL1-AG032118. This work was supported by a Larry L. Hillblom Foundation grant and NIH grants to G.J.L. (UL1 DE019608, supporting the Interdisciplinary Research Consortium on Geroscience and R01 AG029631) and by NIH grants R21 AG030192 and R01 AG036992 to M.S.G.

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M.L., J.M.H., B.W.G., G.J.L. and M.S.G. conceived of and planned experiments. M.L., M.C.V., I.M.K., J.B.G. and M.S.G. performed experiments. M.L. and M.S.G. wrote the manuscript.

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Correspondence to Matthew S. Gill.

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Lucanic, M., Held, J., Vantipalli, M. et al. N-acylethanolamine signalling mediates the effect of diet on lifespan in Caenorhabditis elegans. Nature 473, 226–229 (2011).

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