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

Lipid signals and lifespan extension Dietary restriction can extend lifespan in model organisms such as the nematode Caenorhabditis elegans . Although a number of key players in lifespan extension have been identified, little is known about the signals that coordinate the metabolic response of the organism. The endocannabinoid system is one candidate for the role, as it is known to regulate nutrient intake and energy balance in mammals. These pathways, and cannabinoid receptors, are absent in C. elegans , but a possible alternative has now been identified in this important model for ageing studies. Abundance of a class of lipid-derived signalling molecules, the N -acylethanolamines (NAEs), is reduced in C. elegans by dietary restriction, and NAE deficiency alone is sufficient to extend lifespan. In mammals, an arachidonic acid containing NAE elicits many — though not all — of its effects through cannabinoid receptors. Dietary restriction is a robust means of extending adult lifespan and postponing age-related disease in many species, including yeast, nematode worms, flies and rodents 1 , 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 process 3 , 4 , 5 , including the nutrient-sensing target of rapamycin (TOR) pathway 6 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 balance 8 . 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 analysis 9 . 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 e