To address this question, we evaluated the ability of worms to control bacterial accumulation as a functional Selleckchem Tofacitinib marker of intestinal immunity. We considered the effect on longevity of the bacterial species used as nutrient source, as well as host age and host genotype. We studied genes directly related to intestinal immunity and those that are not known to be related. We found a strong inverse relationship between intestinal
bacterial accumulation and C. elegans longevity, operating across a range of host genotypes. These results suggest that intestinal (commensal) bacterial load is an age and host genotype-related phenotype that can be used to predict C. elegans lifespan. By analysis of mutants, Selleck PU-H71 we begin to establish a hierarchy of the host immune genes that have greatest effect on the intestinal milieu, and thus on longevity. Figure 1 Signaling pathways
important for C. elegans intestinal defenses against bacterial proliferation. A. DAF-2 insulin/IGF-I like signaling pathway. Activation of the DAF-2 receptor results in the phosphorylation of the phosphatidyl inositol 3 kinase (AGE-1) which catalyses the conversion of phosphatidylinositol biphosphate (PiP2) into phosphatidylinositol triphosphate (PiP3). The kinases PDK-1 and AKT-1/AKT-2 are activated by PiP3, which inhibits the transcription factor DAF-16. Relief of this inhibition leads to the expression of a set of stress response and antimicrobial genes. B. p38 MAPK pathway. PMK-1 is homologous to the mammalian p38 MAPK and acts downstream of NSY-1/MAKK kinase kinase and SEK-1/MAPK kinase. No interaction between TOL-1 and TIR-1 has been demonstrated. C. TGF-β pathway. The TGF-β homologue DBL-1 binds to the heterodimeric receptor SMA-6/DAF-4 and signals through the Smad proteins SMA-2, SMA-3 and SMA-4, which activate the transcription of genes involved
in regulation of body size and ARN-509 supplier innate immunity. The expression of lysozyme gene lys-1 is under the control of the p38 MAPK pathway and the DBL-1/TGF-β pathway. D. Mitochondrial enzymes. CLK-1 Amine dehydrogenase is an enzyme required for the biosynthesis of ubiquinoe CoQ9, an acceptor of electrons from both complexes I and II in C. elegans cells. Decreased complex I-dependent respiration of clk-1 mutants leads to decreased ROS production with lengthening lifespan and slowing development. TRX-1 is a mitochondrial oxidoreductase with important roles in lifespan regulation and oxidative stress response. Results Role of DAF-2 insulin-signaling pathway on C. elegans lifespan Under typical laboratory conditions at 25°C on NGM agar plates with a lawn of E. coli strain OP50, a culture of wild type (N2) C. elegans has a lifespan of ~ 2 weeks [20]. Lifespans are shorter when lawns are composed of bacteria that are more pathogenic for humans [21]; conversely, host mutations that increase resistance to bacterial infection prolong C. elegans lifespan [22].