Steroid signaling mediates longevity responses to the eat-2 genetic model of dietary restriction in Caenorhabditis elegans

Dietary restriction (DR) extends lifespan in a wide range of model organisms, including Caenorhabditis elegans. It is an interesting but yet to be addressed question whether hormones serve as a systemic mechanism that mediates this longevity response. We identified a requirement for steroid signaling in lifespan extension induced by DR, by studying two members of the conserved 3β-hydroxysteroid dehydrogenase (3β-HSD) family, HSD-2 and HSD-3. Specifically, we found that lifespan extension in the eat-2 genetic model of DR is completely suppressed by a deletion mutant of hsd-2. This suppression is independent of the decreased brood size and prolonged egglay timing of eat-2, as neither was affected by hsd-2, suggesting that the hsd-2-mediated steroid signal regulates longevity without influencing reproduction. Furthermore, hsd-2 suppressed the ability of eat-2 to resist acute heat shock; stress, as measured by survival after recovery, but only later in life (day 7 and day; 13 adults). This indicates a role for hsd-2 in age-dependent responses to DR, consistent with; hsd-2 expression, which is primarily in adults. Since hsd-2 did not affect DR-induced heat shock resistance in day 1 adults, we hypothesized that hsd-3, which is only expressed in larvae, might be functioning in that role. Indeed, we found that while a deletion mutant of hsd-3 does not appear to affect eat-2 overall lifespan, it completely suppressed its ability to resist heat shock stress as day 1 adults. Therefore, although both hsd-2 and hsd-3 contribute to stress resistance in eat-2 adults, only hsd-2 impacts lifespan, as though steroid signaling in older eat-2 adults is more important for lifespan extension than steroid signaling in larvae and young adults. Taken together, our results indicate that steroid signaling through these two steroidogenic enzymes, active at distinct times during the worm lifespan, is vital for the health and longevity conferred by DR.