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.
Please note: Abstract shown here should NOT be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.
The Genetics Society of America
9650 Rockville Pike, Bethesda, MD
Phone: 301-634-7300, Fax: 301-634-7079
Questions and Comments: firstname.lastname@example.org