The IRS2 Gly1057Asp variant is associated with human longevity.

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.

[1]  V. Basevi.  Diagnosis and Classification of Diabetes Mellitus , 2011, Diabetes Care.

[2]  R. Bellazzi,et al.  Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. , 2009, Rejuvenation research.

[3]  Stefan Schreiber,et al.  Association of FOXO3A variation with human longevity confirmed in German centenarians , 2009, Proceedings of the National Academy of Sciences.

[4]  R. Maccioni,et al.  Insulin resistance and Alzheimer's disease: molecular links & clinical implications. , 2008, Current Alzheimer research.

[5]  Katsuhiko Yano,et al.  FOXO3A genotype is strongly associated with human longevity , 2008, Proceedings of the National Academy of Sciences.

[6]  R. Westendorp,et al.  Insulin/Insulin-like growth factor-1 signaling and cognitive function in humans. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[7]  M. White,et al.  Response to Comment on "Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis" , 2008, Science.

[8]  M. White,et al.  Insulin-like signaling, nutrient homeostasis, and life span. , 2008, Annual review of physiology.

[9]  G. Paolisso,et al.  Metabolic aspects of the extreme longevity , 2008, Experimental Gerontology.

[10]  P. Zimmet,et al.  Diagnosis and classification of diabetes mellitus , 2002 .

[11]  T. Hofer,et al.  Molecular mechanisms of life- and health-span extension: role of calorie restriction and exercise intervention. , 2007, Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme.

[12]  K. Yaffe.  Metabolic syndrome and cognitive decline. , 2007, Current Alzheimer research.

[13]  V. Mohan,et al.  The G1057D polymorphism of IRS-2 gene and its relationship with obesity in conferring susceptibility to type 2 diabetes in Asian Indians , 2007, International Journal of Obesity.

[14]  T. Perls.  The different paths to 100. , 2006, The American journal of clinical nutrition.

[15]  G. Wolf.  Calorie restriction increases life span: a molecular mechanism. , 2006, Nutrition reviews.

[16]  C. Bogardus,et al.  Metabolic effects of the Gly1057Asp polymorphism in IRS-2 and interactions with obesity. , 2003, Diabetes.

[17]  G. Sesti,et al.  Defects of the insulin receptor substrate (IRS) system in human metabolic disorders , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  C. Lautier,et al.  Role of allelic variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in moderate-to-severe insulin resistance of women with polycystic ovary syndrome. , 2001, Diabetes.

[19]  G. Reaven,et al.  Insulin resistance as a predictor of age-related diseases. , 2001, The Journal of clinical endocrinology and metabolism.

[20]  R. Mariani-Costantini,et al.  Interaction between the G1057D variant of IRS-2 and overweight in the pathogenesis of type 2 diabetes. , 2000, Human molecular genetics.

[21]  P. Zimmet,et al.  Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[22]  O. Pedersen,et al.  Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians. , 1998, Diabetes.

[23]  G. Shulman,et al.  Disruption of IRS-2 causes type 2 diabetes in mice , 1998, Nature.

[24]  G. Paolisso,et al.  Body composition, body fat distribution, and resting metabolic rate in healthy centenarians. , 1995, The American journal of clinical nutrition.