Previous studies demonstrated that both C. elegans sexes excrete pheromones that alter development and lifespan in the worms. Hermaphrodites produce the dauer-inducing pheromones ascr#2 and ascr#3 which have been shown to increase C. elegans lifespan and stress resistance (Ludewig et al., 2013), whereas males produce compounds that shorten lifespan in both sexes (Gems et al., 2000, Maures et al., 2014) including the ascaroside ascr#10 and the recently identified nacq#1, a representative of a new class of pheromones derived from acylated amino acids (Ludewig et al., in revision). Here we aim to unravel the molecular mechanisms underlying lifespan regulation mediated by ascarosides signaling. We provide evidence that changes in lifespan after exposure to asccr#2, #3 and #10 required G-protein coupled receptors
srbc-64 and
srbc-66 as well as intact ASK and ASI amphid neurons. Downstream of chemosensory perception, we show that several sirtuins are required for ascaroside-mediated changes of lifespan. Sirtuins are a family of NAD+ dependent histone deacetylases that are involved with regulation of stress responses and longevity in many organisms. Sensing of lifespan-increasing ascarosides results in a sirtuin-dependent transient increase of reactive oxygen species (ROS) levels in the mitochondria. Furthermore, we show that ascaroside-mediated lifespan increase requires the transcription factor
skn-1/Nrf, a key regulator of responses to oxidative stress, consistent with a model in which sirtuin-dependent increase of mitochondrial ROS triggers
skn-1-activated longevity pathways. In addition, we present the effect of tissue-specific expression of
sir-2.1 in neuronal and intestinal cells on C. elegans lifespan. As part of a broader screen for targets of ascaroside signaling, we identified 35 genes differentially expressed in worms after treatment with asrc#3 and ascr#10 by RNAseq. References: Ludewig AH et al. PNAS 2013;110(14):5522-5527. doi:10.1073/pnas.1214467110 Gems D, Riddle DL. Genetics. 2000;154(4):1597-1610. Maures TJ et al. Science. 2013;343(6170):541-544. doi:10.1126/science.1244160