Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm

Mech Ageing Dev. 2002 May;123(9):1229-44. doi: 10.1016/s0047-6374(02)00036-2.

Abstract

Mutation analyses in the nematode, Caenorhabditis elegans, and mice have identified genes that increase their life-span via hormonal signal transduction, i.e. the insulin/insulin-like growth factor-1 (IGF-1) pathway in nematodes, and the growth hormone (GH)-thyriod stimulating hormone (TSH)-prolactin system in Snell dwarf mouse mutants. We have shown that the GH deficiency due to Pit1 mutation in the long-lived Snell dwarf mice may decrease circulating insulin levels, thereby resulting in a decreased activity of the insulin/IGF-1 signaling pathway. The data presented are consistent with our hypothesis that the decreased circulating insulin levels resulting from the Pit1 mutation mimics a physiological state similar to that proposed to occur in the long-lived C. elegans, daf-2 mutant. Our studies demonstrate a series of changes in components of the insulin/IGF-1-signaling pathway that suggest a reduction-of-function of this pathway in the aged dwarf. These include a decreased IRS-2 pool level, a decrease in PI3K activity and its association with IRS-2 and decreased docking of p85alpha to IRS-2. Our data also suggest a preferential docking of IRS-2-p85 alpha -p110 alpha in the aged dwarf liver and IRS-2-p85 alpha -p110 beta in the aged control. We speculate that the preference for the p110 alpha-containing complex may be a specific characteristic of a downstream segment of the longevity-signaling cascade. We conclude that the Pit1 mutation may result in physiological homeostasis that favors longevity, and that the Snell dwarf mutant conforms to the nematode longevity paradigm.

Publication types

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

MeSH terms

  • Aging
  • Animals
  • Blood Glucose / analysis
  • Blotting, Western
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / physiology*
  • DNA-Binding Proteins / genetics
  • Dwarfism, Pituitary / genetics
  • Growth Hormone / deficiency
  • Growth Hormone / genetics
  • Immunosorbent Techniques
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / metabolism
  • Intracellular Signaling Peptides and Proteins
  • 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

Substances

  • Blood Glucose
  • DNA-Binding Proteins
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Phosphoproteins
  • Pit1 protein, mouse
  • Transcription Factor Pit-1
  • Transcription Factors
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin