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Mol Syst Biol. 2013 Jul 2;9:679. doi: 10.1038/msb.2013.35.

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

Author information

1
University Medical Center Utrecht, Wilhelmina Children's Hospital, Department of Molecular Cancer Research, Section Metabolic Diseases, Utrecht, The Netherlands.

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.

PMID:
23820781
PMCID:
PMC3734508
DOI:
10.1038/msb.2013.35
[Indexed for MEDLINE]
Free PMC Article

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