Insulin networks in aging and obesity

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The insulin/IGF-1 signaling (IIS) pathway plays a fundamental role in regulation of the aging process and age-related disease. In the nematode, C. elegans, as with mammals, the IIS pathway modulates metabolism, growth and development in addition to life span. Although in C. elegans there is a single insulin/IGF-1 receptor, the C. elegans genome sequencing project revealed that there are 40 insulin- like peptides. To date, the function of these peptides remains largely unknown. This proposal uses C. elegans as a model system to uncover how insulin-like peptide networks modulate life span. C. elegans is an organism of choice for these studies since worms have a short, reproducible life span, and because systems approaches are feasible due to many available resources and techniques. The hypothesis is that differential expression and combinatorial function of insulin peptides is a major determinant of life span. Systems approaches are uniquely suited to address this hypothesis. In Aim 1, transgenic worm strains harboring insulin promoter:GFP fusion constructs for each of the 40 insulin genes will be visually analyzed for spatiotemporal gene expression by light microscopy and quantified using sensitive mRNA digital profiling technology called Nanostring (nCounter). In Aim 2, spatiotemporal expression of GFP and mRNA quantification of all 40 insulin genes will be analyzed under relevant metabolic and environmental conditions. Finally, in Aim 3, dosage of the insulin like peptides will be modulated to determine the effect on lifespan and fat metabolism. Data will then be integrated into a network that will provide the firs comprehensive analysis of insulin peptides in a metazoan organism and will result in greater into how insulin/IGF-1 signaling achieves specificity to regulate aging and age-related diseases.