Does reduced IGF-1R signaling in Igf1r+/- mice alter aging?

PLoS One. 2011;6(11):e26891. doi: 10.1371/journal.pone.0026891. Epub 2011 Nov 23.

Abstract

Mutations in insulin/IGF-1 signaling pathway have been shown to lead to increased longevity in various invertebrate models. Therefore, the effect of the haplo-insufficiency of the IGF-1 receptor (Igf1r(+/-)) on longevity/aging was evaluated in C57Bl/6 mice using rigorous criteria where lifespan and end-of-life pathology were measured under optimal husbandry conditions using large sample sizes. Igf1r(+/-) mice exhibited reductions in IGF-1 receptor levels and the activation of Akt by IGF-1, with no compensatory increases in serum IGF-1 or tissue IGF-1 mRNA levels, indicating that the Igf1r(+/-) mice show reduced IGF-1 signaling. Aged male, but not female Igf1r(+/-) mice were glucose intolerant, and both genders developed insulin resistance as they aged. Female, but not male Igf1r(+/-) mice survived longer than wild type mice after lethal paraquat and diquat exposure, and female Igf1r(+/-) mice also exhibited less diquat-induced liver damage. However, no significant difference between the lifespans of the male Igf1r(+/-) and wild type mice was observed; and the mean lifespan of the Igf1r(+/-) females was increased only slightly (less than 5%) compared to wild type mice. A comprehensive pathological analysis showed no significant difference in end-of-life pathological lesions between the Igf1r(+/-) and wild type mice. These data show that the Igf1r(+/-) mouse is not a model of increased longevity and delayed aging as predicted by invertebrate models with mutations in the insulin/IGF-1 signaling pathway.

Publication types

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

MeSH terms

  • Aging / drug effects
  • Aging / physiology*
  • Animals
  • Female
  • Gene Expression Regulation / drug effects
  • Glucose Tolerance Test
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Insulin / pharmacology
  • Insulin-Like Growth Factor Binding Protein 5 / genetics
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism
  • Insulin-Like Growth Factor I / pharmacology
  • Longevity
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction* / drug effects

Substances

  • Insulin
  • Insulin-Like Growth Factor Binding Protein 5
  • RNA, Messenger
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3