During the last 20 years, the insulin-like/daf-2 signaling pathway has emerged from genome-wide RNAi screens as the most potent regulator of lifespan in C. elegans; it is a significant aging axis in mammals as well. Our full genome screens for lifespan regulatory processes have also revealed that the second rank of longevity regulation surveils core components of cells, for example, the ribosome, and if deficits are detected, couples to an endocrine system of immunity and longevity control that is distinct from the insulin-like pathway. In fact, detoxification pathways are coupled to lifespan regulation in mice as well. The remarkable ability of rapamycin to extend the lifespan of mice is likely to be based on its ability to engage this surveillance/longevity control system. Eukaryotes live in microbe-rich environments and are continuously challenged by microbial attacks. In the past grant cycle we have greatly expanded our genetic analysis of how C. elegans, and we believe that eventually this will be shown to apply across all eukaryotes, surveils its core cellular components, most especially in this grant, the ribosome, for attacks and signals such attacks to innate immune and detoxification responses as well as to longevity programs. We were initially drawn to these experiments by our work on regulation of longevity and our finding that gene inactivations of core cellular processes such as translation potently induce increased longevity. The major activity of this grant proposal is to test whether the many mutants we have isolated which either inappropriately activate detoxification pathways or fail to activate such pathways have consequences on the lifespan and measures of aging of the animal. The coupling of longevity control to detoxification and immunity provides a satisfying explanation for why human females live longer than males: we hypothesize that females have a higher set point for detoxification to protect the fragile developing fetus. Variation in these same pathways will reveal how humans respond appropriately and inappropriately to drugs or bacterial pathogens, or activate drug detoxification pathways in the absence of a triggering drug, perhaps inducing a false endocrine state of poisoning. Our proposal to study how the microbial flora attempt to subvert these pathways will also reveal how variation in the microbiome may underlie variation in human longevity.
Our full genome screens for lifespan regulatory processes have revealed two major axes of longevity regulation, an insulin-like signaling pathway and a pathway that surveils core components of cells, for example, the ribosome, and couples to an endocrine system of immunity and longevity control. Our new discoveries on the regulation of longevity by systems that surveil microbial attacks will be as influential for understanding human longevity as our work on the C. elegans insulin pathway has been over the past two decades. The human homologues of the genes we identify promise to explain how rates of aging change so dramatically between species or between human males and females.
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