A cytoprotective perspective on longevity regulation.

There are many mechanisms of lifespan extension, including the disruption of insulin/insulin-like growth factor 1 (IGF-1) signaling, metabolism, translation, and feeding. Despite the disparate functions of these pathways, inhibition of each induces responses that buffer stress and damage. Here, emphasizing data from genetic analyses in Caenorhabditis elegans, we explore the effectors and upstream regulatory components of numerous cytoprotective mechanisms activated as major elements of longevity programs, including detoxification, innate immunity, proteostasis, and oxidative stress response. We show that their induction underpins longevity extension across functionally diverse triggers and across species. Intertwined with the evolution of longevity, cytoprotective pathways are coupled to the surveillance of core cellular components, with important implications in normal and aberrant responses to drugs, chemicals, and pathogens.