Sirtuins, a family of NAD+ dependent histone deacetylases, have been implied as conserved regulators of lifespan and stress resistance; however, the underlying mechanisms are unclear. Previous work showed that chemosensation of hermaphrodite-produced pheromones ascr#2 and ascr#3 increases C. elegans adult lifespan and stress resistance (Ludewig 2013), whereas male-produced pheromones of unknown identity shorten hermaphrodite lifespan (Gems 2000, Maures 2014).
We show that the male-produced ascaroside ascr#10 decreases hermaphrodite lifespan, and that pheromone-mediated lifespan increase and decrease depend on two different sirtuins, SIR-2.1 and SIR-2.3. Whereas SIR-2.1 mutants are defective in pheromone mediated lifespan increase, the ascr#10-dependent lifespan phenotype is reversed in SIR-2.3 worms: male-produced ascr#10 decreases lifespan in wild-type worms but increases lifespan in SIR-2.3 mutants. We further show that lifespan regulation via sirtuins primarily depends on metabolism of co-factor (NAD+)-derived nicotinamide, which triggers generation of reactive oxygen species (ROS) in the mitochondria and activation of the transcription factor skn-1, a homolog of mammalian Nrf. Similar to the effects of SIR-2.1 over expression (Schmeisser 2013), ascaroside perception transiently increases ROS in mitochondria, followed by a long-term decrease of ROS activity for lifespan-increasing compounds. In sir-2.1 mutants, longevity-promoting ascarosides do not increase ROS, indicating a direct connection between sirtuin-dependent mitochondrial ROS increase and longevity. Our work demonstrates that sirtuins regulate lifespan in a non-over expression background (i.e WT) via ROS generation, and that sex-specific endogenous small molecules modulate lifespan through this mechanism. Furthermore, our results link SIR-2.1, the homolog of mammalian SIRT1, to increased lifespan, whereas the SIRT4 homolog SIR-2.3 appears to promote shorter lifespan.
Lastly, our work shows that a seemingly minor modification of the chemical structure of an endogenous small molecule, namely the addition of a double bond, can drastically change its signaling properties: a lifespan-decreasing (ascr#10, no double bond) signal turns into a lifespan extending (ascr#3, with double bond) signal. Both ascr#3 and ascr#10 accumulate on C. elegans plates, suggesting confounding effects of population density on C. elegans lifespan studies.
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