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

Ching Chyuan Hsieh, James H. DeFord, Kevin Flurkey, David E. Harrison, John Papaconstantinou

Research output: Contribution to journalArticle

58 Scopus citations

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 (Pit1dw/Pit1dw) 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 p85α to IRS-2; (c) docking of p85α to p110α or p110β, and (d) IRS-2-associated PI3K activity. In this study we present data suggesting that the InRβ-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 InRβ and the docking of p85α 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.

Original languageEnglish (US)
Pages (from-to)1245-1255
Number of pages11
JournalMechanisms of Ageing and Development
Volume123
Issue number9
DOIs
StatePublished - May 27 2002

Keywords

  • AKT
  • IRS-1
  • Insulin receptor
  • Insulin signaling
  • Liver
  • PI3K
  • Snell dwarf

ASJC Scopus subject areas

  • Aging
  • Developmental Biology

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