N-acylethanolamine signaling mediates the effect of diet on lifespan in C. elegans

Dietary restriction (DR) is a robust means of extending adult lifespan and postponing age-related disease in many species, including yeast, worms, flies and rodents 1 , 2 . Studies of the genetic requirements for lifespan extension by DR in the nematode Caenorhabditis elegans (C. elegans) have implicated a number of key players in this process 3 – 5 , including the nutrient-sensing target of rapamycin (TOR) pathway 6 and the Foxa transcription factor PHA-4 7 . However, little is known about the metabolic signals that coordinate the organismal response to DR and maintain homeostasis when nutrients are limited. The endocannabinoid (EC) system is an excellent candidate to play such a role given its involvement in regulating nutrient intake and energy balance 8 . Despite this, a direct role for EC signaling in DR or lifespan determination has yet to be demonstrated, in part due to the apparent absence of EC signaling pathways in model organisms that are amenable to lifespan analysis 9 . N-acylethanolamines (NAEs) are lipid-derived signaling molecules, which include the mammalian EC arachidonoyl ethanolamide (AEA). Here we identify NAEs in C. elegans, show that NAE abundance is reduced under DR and that NAE deficiency is sufficient to extend lifespan through a DR mechanism requiring PHA-4. Conversely, dietary supplementation with the nematode NAE eicosapentaenoyl ethanolamide (EPEA) not only inhibits DR-induced lifespan extension in wild type animals, but also suppresses lifespan extension in a TOR pathway mutant. This demonstrates a role for NAE signaling in aging and suggests that NAEs represent a signal that coordinates nutrient status with metabolic changes that ultimately determine lifespan.