Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse

Mech Ageing Dev. 2002 May;123(9):1245-55. doi: 10.1016/s0047-6374(02)00037-4.

Abstract

Mutations in Caenorhabditis elegans and mice have identified candidate genes that increase their lifespan via hormonal signal transduction, i.e. the insulin/IGF-1-like pathway. In this study we propose that longevity of the Snell dwarf (Pit1(dw)/Pit1(dw)) mouse is associated with a decrease of the insulin/IGF-1 signaling pathway caused by the Pit1 mutation. We recently demonstrated that the growth hormone deficiency of the dwarf mouse alters circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway, which is a determining factor in the increased nematode lifespan. The decreased activity of the insulin/IGF-1 signaling pathway is indicated by decrease of (a) IRS-two pool levels; (b) docking of p85 alpha to IRS-2; (c) docking of p 85 alpha to p110 alpha or p110 beta, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InR beta-IRS-1-PI3K pathway is attenuated in the Snell dwarf mouse liver. Our data show that the PI3K activity associated with IRS-1, the docking of IRS-1 to InR beta and the docking of p85 alpha to IRS-1 are attenuated in the aged Snell dwarf. Our studies suggest that the Pit1 mutation results in a decreased activity of the insulin/IGF-1 pathway; that this plays a key role in the longevity of the Snell dwarf mouse and conforms to the nematode longevity paradigm.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging
  • Animals
  • Caenorhabditis elegans / genetics
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Dwarfism, Pituitary / genetics
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / metabolism
  • Liver / metabolism
  • Longevity / genetics*
  • Mice
  • Mice, Mutant Strains
  • Mutation*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Receptor, Insulin / metabolism
  • Signal Transduction*
  • Transcription Factor Pit-1
  • Transcription Factors / genetics*
  • Transcription Factors / physiology

Substances

  • DNA-Binding Proteins
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Pit1 protein, mouse
  • Transcription Factor Pit-1
  • Transcription Factors
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin