title: Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm.
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.
authors.affiliation: Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, 613 Basic Science Building, Rt. 0643, Galveston, TX 7755-0643, USA.
authors.forename: Ching-Chyuan
authors.initials: CC
authors.lastname: Hsieh
authors.forename: James H
authors.initials: JH
authors.lastname: DeFord
authors.forename: Kevin
authors.initials: K
authors.lastname: Flurkey
authors.forename: David E
authors.initials: DE
authors.lastname: Harrison
authors.forename: John
authors.initials: J
authors.lastname: Papaconstantinou
mesh_terms: D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004393:Dwarfism, Pituitary / Q000235:genetics; D013006:Growth Hormone / Q000172:deficiency / Q000235:genetics; D007163:Immunosorbent Techniques; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011972:Receptor, Insulin; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C526298:Irs2 protein, mouse; C494185:Pou1f1 protein, mouse