Insulin/IGF‐1‐mediated longevity is marked by reduced protein metabolism

Abstract

Abstract Mutations in the daf‐2 gene of the conserved Insulin/Insulin‐like Growth Factor (IGF‐1) pathway double the lifespan of the nematode Caenorhabditis elegans. This phenotype is completely suppressed by deletion of Forkhead transcription factor daf‐16. To uncover regulatory mechanisms coordinating this extension of life, we employed a quantitative proteomics strategy with daf‐2 mutants in comparison with N2 and daf‐16; daf‐2 double mutants. This revealed a remarkable longevity‐specific decrease in proteins involved in mRNA processing and transport, the translational machinery, and protein metabolism. Correspondingly, the daf‐2 mutants display lower amounts of mRNA and 20S proteasome activity, despite maintaining total protein levels equal to that observed in wild types. Polyribosome profiling in the daf‐2 and daf‐16;daf‐2 double mutants confirmed a daf‐16‐dependent reduction in overall translation, a phenotype reminiscent of Dietary Restriction‐mediated longevity, which was independent of germline activity. RNA interference (RNAi)‐mediated knockdown of proteins identified by our approach resulted in modified C. elegans lifespan confirming the importance of these processes in Insulin/IGF‐1‐mediated longevity. Together, the results demonstrate a role for the metabolism of proteins in the Insulin/IGF‐1‐mediated extension of life.

Keywords

• ageing
• high‐throughput analysis
• metabolism
• protein metabolism
• translation