A variety of mutations in the nematode Caenorhabditis elegans extend lifespan, such as in insulin signaling, mitochondrial or other conserved cellular pathways. Our new findings on the regulation of reproduction and longevity by systems that surveil the core components of eukaryotic cells for microbial attack reveals a new paradigm for regulation of longevity. Our previous studies have shown that inhibition of these core cellular pathways can extend lifespan and activate xenobiotic detoxification and innate immune pathways and increase longevity. Consistent with this view, long lived dwarf mice as well as long lived daf-2 insulin like receptor mutant C. elegans strongly induce xenobiotic detoxification genes. 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 of the animal. We already have many of these mutant strains from our preliminary studies and we propose to test particular sets of mutants and combinations of mutants for lifespan effects of detoxification and immunity programs. We continue to focus on C. elegans in this proposal because compared to mouse genetics, C. elegans genetics is about 100x more economical. And we translate our findings to mouse and human by using our results as a prism through which the mammalian literature can be interpreted. For example, the coupling of longevity control to xenobiotic detoxification is a rather neat explanation for why human females live longer than human males: if females have a higher set point for detoxification, as suggested by the morning sickness of pregnant women and the huge gender bias of anorexia nervosa as well as autoimmune disease and migraines, all could be explained by induction of xenobiotic detoxification and innate immune programs in females rather than the self-destruction post reproductive programs. This would be most dramatic in centenarians. We also explore how the natural microbiome of C. elegans as well as the natural microbiome of humans interacts with these surveillance of core eukaryotic cellular process programs. Our early results established that particular bacterial species disrupt the response to mitochondrial or ribosome toxins or mutations. We propose to screen through collections of hundreds of bacterial strains for such activities and to initiate bacterial genetic analysis on those gene activities. We expect that this analysis will be a model for how to study the microbiome, not via the descriptive metagenomic analysis but by single bacterial species testing for microbiome bacterial countermeasures for other bacterial toxins.