title: The IRS2 Gly1057Asp variant is associated with human longevity.
abstract: BACKGROUND
  Reduced insulin and insulin-like growth factor-1 (IGF-1) signaling extends the life span of invertebrate and mammals. Recently, reduced insulin receptor substrate-2 (IRS2) signaling was found associated with increased longevity in mice. The aim of our study was to evaluate whether a common polymorphism (Gly1057Asp) in human IRS2 gene is associated with human longevity.
  
  
  METHODS
  Six hundred seventy-seven participants (289 males and 388 females) between 16 and 104 years of age, categorized as long lived (LL; >85 years old) or controls (C; <85 years old), were genotyped for Gly1057Asp-IRS2 locus variability (rs1805097). All participants, contacted at home or in their institution or selected from Italian geriatric and internal medicine or geriatric rehabilitation structures, underwent to a clinical, biochemical, and functional characterization, with particular attention to the insulin and IGF-1 signaling. Insulin resistance (Homeostasis Model Assessment [HOMA]-IR), insulin sensitivity (HOMA IS), and ss-cell function (HOMA-B cell) were calculated by the HOMA2 calculator v2.2 (www.dtu.ox.ac.uk/homa).
  
  
  RESULTS
  In the whole population, homozygous IRS2(Asp/Asp) participants were more represented among LL versus C participants (16.7% vs 12.0%; p = .04). The association between IRS2 gene polymorphism with longevity (being LL) was independent of anthropometric and metabolic covariates (odds ratio: 2.07, 95% confidence interval [CI] = 1.38-3.12; p = .001). Categorizing participants into percentiles by age, IRS2(Asp/Asp) participants were more likely to reach extreme old age (>or=90 percentile, 96-104 years; odds ratio: 2.03, 95% CI = 1.39-2.99; p = .0003).
  
  
  CONCLUSIONS
  These results support the hypothesis that the IRS2 branch of the insulin and IGF signaling is associated with human longevity. Further studies will be necessary for replicating our finding in an independent larger population group with sufficient power before the association between IRS2 gene polymorphism and longevity can be regarded as proven. Furthermore, studies of genetic and/or environmental background interactions may be useful after basic replication is complete.
authors.affiliation: Department of Geriatric Medicine and Metabolic Diseases, Second University of Naples, Piazza Miraglia 2, 80138, Naples, Italy.
authors.forename: Michelangela
authors.initials: M
authors.lastname: Barbieri
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Rizzo
authors.forename: Michela
authors.initials: M
authors.lastname: Papa
authors.forename: Virginia
authors.initials: V
authors.lastname: Boccardi
authors.forename: Antonietta
authors.initials: A
authors.lastname: Esposito
authors.forename: Morris F
authors.initials: MF
authors.lastname: White
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Paolisso
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D004247:DNA / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D007558:Italy; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D004247:DNA