Reduced insulin/insulin-like growth factor signaling decreases translation in Drosophila and mice

Sci Rep. 2016 Jul 25;6:30290. doi: 10.1038/srep30290.

Abstract

Down-regulation of insulin/insulin-like growth factor signaling (IIS) can increase lifespan in C. elegans, Drosophila and mice. In C. elegans, reduced IIS results in down-regulation of translation, which itself can extend lifespan. However, the effect of reduced IIS on translation has yet to be determined in other multicellular organisms. Using two long-lived IIS models, namely Drosophila lacking three insulin-like peptides (dilp2-3,5(-/-)) and mice lacking insulin receptor substrate 1 (Irs1(-/-)), and two independent translation assays, polysome profiling and radiolabeled amino acid incorporation, we show that reduced IIS lowers translation in these organisms. In Drosophila, reduced IIS decreased polysome levels in fat body and gut, but reduced the rate of protein synthesis only in the fat body. Reduced IIS in mice decreased protein synthesis rate only in skeletal muscle, without reducing polysomes in any tissue. This lowered translation in muscle was independent of Irs1 loss in the muscle itself, but a secondary effect of Irs1 loss in the liver. In conclusion, down-regulation of translation is an evolutionarily conserved response to reduced IIS, but the tissues in which it occurs can vary between organisms. Furthermore, the mechanisms underlying lowered translation may differ in mice, possibly associated with the complexity of the regulatory processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drosophila / genetics
  • Drosophila Proteins / genetics*
  • Insulin / genetics
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins / genetics*
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Insulins / genetics*
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Longevity / genetics*
  • Mice
  • Oxidative Stress / genetics
  • Protein Biosynthesis*
  • Signal Transduction / genetics

Substances

  • Drosophila Proteins
  • ILP3 protein, Drosophila
  • Ilp5 protein, Drosophila
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Insulins
  • Intercellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I