The relationship between environment and longevity is perhaps best illustrated by the effect of temperature on lifespan across multiple species. Contrary to previous thought, it has been shown that temperature mediates its effects on lifespan in part through highly coordinated genetic pathways (Lee et al. 2009, Xiao et al. 2013). We have recently reported that the N-acylethanolamine (NAE) system in worms reduces C. elegans lifespan at 25oC but not at 15oC (Harrison et al. 2014), phenocopying the effect of ablation of the AFD thermosensory neuron (Lee et al. 2009). Here we show that deletion of
faah-1, an NAE hydrolyzing enzyme, recapitulates the effect of over-expression of the biosynthetic enzyme
nape-1. We also find that the effect of
faah-1 deletion on lifespan is dependent on
daf-9 and
daf-12, indicating that the NAE signal acts via the same mechanism as that described for thermosensory mutants (Lee et al. 2009). In other systems, NAEs act as short-range signaling molecules and thus we hypothesized that NAEs directly influence neuronal activity to control lifespan cell non-autonomously. In accordance with this, we observed that genetic ablation of the ASJ neuron by cell-specific caspase expression rescues the effect of
faah-1 on lifespan at 25oC. We are currently evaluating the requirement for thermosensory neurons in mediating the effects of
faah-1 deletion.We are also interested in determining which specific NAEs are responsible for signaling this effect. NAEs are synthesized from phospholipid precursors and differ in their fatty acid moiety. We have previously reported that eicosapentaenoyl ethanolamine (EPEA), a C20:5n3-containing NAE, influences dauer entry and suppresses DR-induced longevity in worms. To test if this molecule could be responsible for the temperature-dependent effects of NAEs, we crossed
nape-1 over-expressers into a
fat-1 mutant, which lacks the fatty acid precursor needed for EPEA production. In this background we found that
fat-1 is not required for the effects of
nape-1 over-expression on lifespan, indicating that the effect of the NAE system on temperature-dependent longevity is independent of EPEA. We are currently trying to identify the specific NAE(s) responsible for this effect, as well as further defining the mechanism by which the NAE system affects lifespan in a temperature dependent manner.