Cytoprotective Pathways that Contribute to Lifespan Extension in C. elegans

Stress tolerance and lifespan are intimately associated. Extension of lifespan is accompanied by increased tolerance of heat, oxidative stress, radiation and other stressors, while genetic perturbations that abrogate lifespan extension compromise stress tolerance. The consistency of this correlation suggests that the mechanisms of longevity extension and stress tolerance are intertwined. However, the contributions of individual cytoprotective mechanisms to lifespan extension under each of these conditions, and the cascades by which they are regulated, are largely unknown. Treatments that confer lifespan extension include the inhibition of feeding, insulin/IGF-1 signaling, metabolism and translation. We have examined diverse stress-responsive pathways to isolate those that contribute to one or more modes of longevity extension in C. elegans. Initial results revealed an association of longevity with mitochondrial and endoplasmic reticulum unfolded protein responses, oxidative stress response, xenobiotic detoxification and developmental arrest. To gain insight into the regulation of these responses in lifespan extension, we employed gene inactivation and mutagenic screens to identify the genetic pathways that couple the induction of cytoprotective pathways to longevity-regulatory programs. We have identified a set of 25 genes required for both cytoprotective response and lifespan extension. These genes elaborate the regulatory cascades that mediate longevity and provide insight into the complexity of cytoprotective networks.