Ascarosides are small molecules that constitute major components of the dauer pheromone and act as social signals in C. elegans (Jeong, 2005; Butcher, 2007; Srinivasan, 2008). Chemical analyses have led to the identification of more than ten different ascarosides with dauer-inducing or other signalling activities (Pungaliya, 2009). We recently showed that ascarosides ascr#2 and ascr#3 increase adult lifespan in C. elegans by up to 50%, without reducing fecundity and feeding rate (Ludewig et al, submitted). Biosynthesis of the ascarosides depends on functional peroxisomal beta-oxidation, including
daf-22, which encodes a homolog of human sterol carrier protein SCPx and
dhs-28, which encodes a homolog of the human D-bifunctional protein.
daf-22 and
dhs-28 mutant worms do not make dauer-inducing ascarosides and are characterized by a reduced lifespan. These worms accumulate distinct fat granules in the intestine, presumably as a result of defective beta-oxidation of long-chained fatty acids. Here we report that in contrast to wild-type worms, lifespan of
daf-22and dhs-28 mutant worms is not increased by ascr#2 and ascr#3. Lifespan of
dhs-28(
tm2581) mutant worms is largely unaffected by treatment with ascarosides, whereas lifespan of
daf-22(
ok693) worms decreases in response to exposure to ascarosides.This lifespan decrease is associated by increased accumulation of lipid droplets. Pharyngeal structures are dissolved or greatly enlarged and body length is shortened by up to 30%. Hence, we conclude that peroxisomal beta-oxidation of long-chained fatty acids is required for lifespan extension via ascarosides. 1. P. Jeong et. al., Nature 433, 541-545 (2005). 2. R. Butcher et.al., Nature Chemical Biology 3, 420-422 (2007). 3. J. Srinivasan et.al., Nature 454, 1115-1118 (2008). 4. C. Pungaliya et.al., Proc Natl Acad Sci U S A 106, 7708-7713 (2009).