A proteomic atlas of insulin signalling reveals tissue-specific mechanisms of longevity assurance

Mol Syst Biol. 2017 Sep 15;13(9):939. doi: 10.15252/msb.20177663.


Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins). Expression of ribosome-associated proteins in the fat body was reduced in the mutant, with a corresponding, tissue-specific reduction in translation. Expression of mitochondrial electron transport chain proteins in fat body was increased, leading to increased respiration, which was necessary for IIS-mediated lifespan extension, and alone sufficient to mediate it. Proteasomal subunits showed altered expression in IIS mutant gut, and gut-specific over-expression of the RPN6 proteasomal subunit, was sufficient to increase proteasomal activity and extend lifespan, whilst inhibition of proteasome activity abolished IIS-mediated longevity. Our study thus uncovered strikingly tissue-specific responses of cellular processes to lowered IIS acting in concert to ameliorate ageing.

Keywords: ageing; insulin/IGF; mitochondria; proteasome; proteome.

MeSH terms

  • Aging / metabolism*
  • Animals
  • Drosophila / metabolism*
  • Drosophila Proteins
  • Fat Body / metabolism
  • Gene Regulatory Networks*
  • Insulin / metabolism
  • Intestinal Mucosa / metabolism
  • Models, Animal
  • Mutation
  • Organ Specificity
  • Proteomics / methods*
  • Ribosomal Proteins / metabolism


  • Drosophila Proteins
  • Insulin
  • Ribosomal Proteins