Project description:Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we investigate the phosphoproteomic landscape of Caenorhabditis elegans with severe mitochondrial deficiency in the context of insulin signaling inhibition.
Project description:Inhibition of insulin/IGF-1 signaling (IIS) represents a promising avenue for the treatment of mitochondrial diseases, although many of the molecular mechanisms underlying this beneficial effect remain elusive. Here, we investigate the proteomic landscape of Caenorhabditis elegans with severe mitochondrial deficiency in the context of insulin signaling inhibition.
Project description:Many studies have addressed the effect of dietary glycemic index on obesity and diabetes, but little is known about its effect on lifespan itself. We found that adding a small amount of glucose to the medium (0.1-2%) shortened the lifespan of C. elegans. Glucose shortened lifespan by inhibiting the activities of lifespan-extending transcription factors that are also inhibited by insulin signaling: the FOXO family member DAF-16 and the heat shock factor HSF-1. This effect involved the down-regulation of an aquaporin glycerol channel, aqp-1. We show that changes in glycerol metabolism are likely to underlie the lifespan-shortening effect of glucose, and that aqp-1 may act cell non-autonomously as a feedback regulator in the insulin/IGF-1 signaling pathway. Insulin down-regulates similar glycerol channels in mammals, suggesting that this glucose-responsive pathway might be conserved evolutionarily. Together these findings raise the possibility that a low-sugar diet might have beneficial effects on lifespan in higher organisms. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE18561: Adult C. elegans: Control daf-2 mutants treated with daf-16 RNAi vs. daf-2 mutants treated with empty vector RNAi GSE18562: Adult C. elegans: Control OP50 culture vs. OP50 + 2% glucose culture
Project description:Temperature is a prominent environmental stimulus that influences life span. Previous studies indicate that in Caenorhabditis elegans, thermosensory perception in the AFD neuron maintains life span at warm temperatures. How thermosensation is translated into neuronal signals that shape aging remains elusive. We found that the Caenorhabditis elegans CREB crh-1, as well as several key genes in AFD thermosensory transduction, were specifically required for normal life span at warm temperatures. crh-1 acted in the AFD to increase transcription of the CRE-containing neuropeptide gene flp-6 in a temperature-dependent manner. Both crh-1 and flp-6 were necessary and sufficient for longevity at warm temperatures, and their effects depended on the AIY interneuron. Moreover, flp-6 signaling downregulated ins-7/insulin and several insulin pathway genes, whose activity compromised life span. We postulate that temperature experience is integrated in the thermosensory neurons to generate CREB-dependent neuropeptide signals that antagonize insulin signaling and promote temperature-specific longevity.
Project description:Natural genetic variation is the raw material of evolution and influences disease development and progression. To analyze the effect of the genetic background on protein expression in the nematode C. elegans (Caenorhabditis elegans), the two genetically highly divergent wild-type strains N2 (Bristol) and CB4856 (Hawaii) were compared quantitatively. In total, we quantified 3,238 unique proteins in three independent SILAC (stable isotope labeling by amino acids in cell culture) experiments. The differentially expressed proteins were enriched for genes that function in insulin-signaling and stress response pathways.