Journal Article

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

Snijders, Dorien S, Betist, Marco C, Essers, Paul B, MacInnes, Alyson W, Kolkman, Annemieke, Brenkman, Arjan B, Stigter, Edwin C A, Mulder, Klaas W, van den Broek, Niels J F, Stout, Gerdine J, Korswagen, Hendrik C

2013

Overview

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. Quantitative proteomics, lifespan analysis, and biochemical assays were utilized to show that Insulin/IGF‐1‐mediated longevity in C. elegans is strongly associated with a daf‐16 dependent global reduction in protein metabolism. Synopsis Quantitative proteomics, lifespan analysis, and biochemical assays were utilized to show that Insulin/IGF‐1‐mediated longevity in C. elegans is strongly associated with a daf‐16 dependent global reduction in protein metabolism. A daf‐16 dependent global reduction in protein translation is observed in daf‐2 long‐lived mutant. The reduction in active translation is independent of germline activity A role for protein metabolism is identified in the Insulin/IGF‐1‐mediated extension of life.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Ltd,EMBO Press,Nature Publishing Group,Springer Nature
• Subject: ageing / Animals / Autophagy / Caenorhabditis elegans - genetics / Caenorhabditis elegans - metabolism / Caenorhabditis elegans Proteins - antagonists & inhibitors / Caenorhabditis elegans Proteins - genetics / Caenorhabditis elegans Proteins - metabolism / Dietary restrictions / EMBO31 / EMBO32 / Forkhead protein / Forkhead Transcription Factors / Gene expression / Gene Expression Regulation / Genes / Genotype / Growth factors / high‐throughput analysis / Immunoglobulins / Insulin / Insulin - metabolism / Insulin-Like Growth Factor I - genetics / Insulin-Like Growth Factor I - metabolism / Insulin-like growth factors / Laboratories / Life span / Longevity / Longevity - genetics / Metabolism / mRNA processing / Mutants / Mutation / Nematodes / Peptides / Phenotype / Phenotypes / Proteasome Endopeptidase Complex - genetics / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Protein Biosynthesis / Protein metabolism / Protein turnover / Proteins / Proteomics / Receptor, Insulin - antagonists & inhibitors / Receptor, Insulin - genetics / Receptor, Insulin - metabolism / Regulatory mechanisms (biology) / RNA transport / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA, Small Interfering - genetics / RNA-mediated interference / Signal Transduction / Stress response / Transcription Factors - antagonists & inhibitors / Transcription Factors - genetics / Transcription Factors - metabolism / translation