Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice

Colin Selman, Steven Lingard, Agharul I. Choudhury, Rachel L. Batterham, Marc Claret, Melanie Clements, Faruk Ramadani, Klaus Okkenhaug, Eugene Schuster, Eric Blanc, Matthew D. Piper, Hind Al-Qassab, John R. Speakman, Danielle Carmignac, Iain C. A. Robinson, Janet M. Thornton, David Gems, Linda Partridge, Dominic J. Withers

Research output: Contribution to journalArticle

434 Citations (Scopus)


Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, in several mouse mutants, impairment of the growth hormone (GH)/IGF1 axis increases life span and also insulin sensitivity. However, the intracellular signaling route to altered mammalian aging remains unclear. We therefore measured the life span of mice lacking either insulin receptor substrate (IRS) 1 or 2, the major intracellular effectors of the IIS receptors. Our provisional results indicate that female Irs1(-/-) mice are long-lived. Furthermore, they displayed resistance to a range of age-sensitive markers of aging including skin, bone, immune, and motor dysfunction. These improvements in health were seen despite mild, lifelong insulin resistance. Thus, enhanced insulin sensitivity is not a prerequisite for IIS mutant longevity. Irs1(-/-) female mice also displayed normal anterior pituitary function, distinguishing them from long-lived somatotrophic axis mutants. In contrast, Irs2(-/-) mice were short-lived, whereas Irs1(+/-) and Irs2(+/-) mice of both sexes showed normal life spans. Our results therefore suggest that IRS1 signaling is an evolutionarily conserved pathway regulating mammalian life span and may be a point of intervention for therapies with the potential to delay age-related processes.

Original languageEnglish
Pages (from-to)807-818
Number of pages12
JournalThe FASEB Journal
Issue number3
Early online date10 Oct 2007
Publication statusPublished - Mar 2008


  • aging
  • longevity
  • insulin signaling
  • insulin-receptor gene
  • caloric restriction
  • caenorhabditis-elegans
  • dwarf mice
  • mouse models
  • body-weight
  • expression
  • IGF-1
  • insights


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