The IRS2 Gly1057Asp variant is associated with human longevity. Michelangela Barbieri, Maria Rosaria Rizzo, Michela Papa, Virginia Boccardi, Antonietta Esposito, Morris F. White, and Giuseppe Paolisso conducted a study to evaluate whether a common polymorphism (Gly1057Asp) in the human IRS2 gene is associated with human longevity. Reduced insulin and insulin-like growth factor-1 (IGF-1) signaling have been found to extend the lifespan of invertebrates and mammals. Recently, reduced insulin receptor substrate-2 (IRS2) signaling was found to be associated with increased longevity in mice. The study included 677 participants between 16 and 104 years of age who were categorized as long-lived or controls and genotyped for Gly1057Asp-IRS2 locus variability (rs1805097). The whole population showed that homozygous IRS2Asp/Asp participants were more represented among long-lived versus control participants. The association between the IRS2 gene polymorphism with longevity was independent of anthropometric and metabolic covariates. Categorizing participants into percentiles by age showed that IRS2Asp/Asp participants were more likely to reach extreme old age. 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 these findings in an independent larger population group with sufficient power before the association between the 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. The key words are: IRS2 gene polymorphism, Longevity, Insulin signaling. 

Deletion causes mild glucose intolerance until middle age. Conversely, old hemizygous mice are more insulin-sensitive and glucose-tolerant than wild-type mice. Moreover, IRS2+/ mice live nearly 18% longer than wild-type mice. The disruption of insulin and IGF-1 signaling cascade can significantly extend life span in diverse living species from yeast to rodents. A recent study demonstrated that systemic or neural-specific reduction of the insulin receptor substrate-2 (IRS2) can extend the life span of mice. However, it is difficult to determine directly whether IRS2 signaling regulates human longevity. In humans, a number of polymorphisms have been identified in the IRS2 gene, including the Gly1057Asp variant that occurs with an allelic frequency of 34%. Some studies have indicated a role for such variant in the pathogenesis of obesity and obesity-associated insulin resistance. In some populations, obesity and IRS2Asp have been found associated with infertility, reduced pancreatic b-cell function, and increased type 2 diabetes susceptibility. 

In humans, insulin resistance ordinarily develops with age and is an important risk factor for various metabolic disorders such as hypertension, atherosclerosis, obesity, and type 2 diabetes strongly affecting morbidity, disability, and mortality among the elderly participants. By contrast, people aged between 85 and 90 years and older display relatively high insulin sensitivity and glucose tolerance, and centenarians are remarkably insulin sensitive. Because the metabolic profile of long-lived participants resembles that of IRS2+/ mice, the authors investigated whether the IRS2Asp variant is associated with human longevity.

The study included 677 Caucasians (388 females and 289 males) from northern, central, or southern Italy who volunteered for the study. Participants were categorized into two groups by splitting the whole sample at the age of 85: healthy people aged 85 years and younger were grouped under the denomination of control people; healthy people aged from 85 to 104 years were collected in the group of long-lived people. The impact of the IRS2 gene polymorphism on longevity was assessed by comparing the expected genotypic frequencies based on the Hardy-Weinberg equilibrium with the actual frequencies observed in the long-lived and control groups separately. Insulin resistance (homeostasis Model Assessment [hOMA]-IR), insulin sensitivity (hOMA IS), and -cell function (hOMA-B cell) were calculated by the hOMA2 calculator v2.2. Plasma insulin, hOMA-IR, and hOMA-B cell were logarithmically transformed for use in all calculations and back-transformed for result presentations. All metabolic parameters were presented as mean  SD. Analysis of variance with Scheffes test was used for comparing the mean body mass index (BMI), hOMA2%B, and hOMA2 IR between control and long-lived male and female participants. A logistic regression analysis was used to test the association of IRS2 gene polymorphism with longevity independently of multiple covariates. Furthermore, participants were subdivided by age into 10 percentiles and used as ordinate dependent variables in multinomial regression with a logit link function to estimate the oddsIn order to assess the potential effect of population stratification, we compared genotype and allele frequency distributions of IRS2 gene variants between the three geographically different Italian regions. Indeed, no differences in allele and genotype frequency distributions of IRS2 gene polymorphism between northern, central, or southern Italy were found (data not shown). The allele and genotype frequencies observed were almost similar to those reported in previous studies among Caucasians. However, controlling for these covariates, the odds of reaching extreme old age were increased 2-fold for IRS2Asp/Asp participants and 1.5-fold for IRS2Gly/Asp participants (Table 3). As expected, women were more likely to be associated with the oldest participants, whereas a high BMI or hOMA2%B reduced significantly the odds of reaching the 90 percentile (Table 3).

Table 1. Clinical Characteristics of Study Population (n = 677) (90 percentile, 96-104 years).