title: Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice.
abstract: 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.
authors.affiliation: Centre for Diabetes and Endocrinology, Department of Medicine, Rayne Institute, University College London, University St., London, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Selman
authors.forename: Steven
authors.initials: S
authors.lastname: Lingard
authors.forename: Agharul I
authors.initials: AI
authors.lastname: Choudhury
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Batterham
authors.forename: Marc
authors.initials: M
authors.lastname: Claret
authors.forename: Melanie
authors.initials: M
authors.lastname: Clements
authors.forename: Faruk
authors.initials: F
authors.lastname: Ramadani
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Eugene
authors.initials: E
authors.lastname: Schuster
authors.forename: Eric
authors.initials: E
authors.lastname: Blanc
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Piper
authors.forename: Hind
authors.initials: H
authors.lastname: Al-Qassab
authors.forename: John R
authors.initials: JR
authors.lastname: Speakman
authors.forename: Danielle
authors.initials: D
authors.lastname: Carmignac
authors.forename: Iain C A
authors.initials: IC
authors.lastname: Robinson
authors.forename: Janet M
authors.initials: JM
authors.lastname: Thornton
authors.forename: David
authors.initials: D
authors.lastname: Gems
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D005260:Female; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008136:Longevity / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins