The IRS2 Gly1057Asp Variant Is Associated With human Longevity

Michelangela Barbieri,1 Maria Rosaria Rizzo,1 Michela Papa,1 Virginia Boccardi,1 Antonietta esposito,1 Morris F. White,2 and Giuseppe Paolisso1

1Department of Geriatric Medicine and Metabolic Diseases—II University of Naples, Italy. 2howard hughes Medical Institute, Division of endocrinology, Children’s hospital Boston, harvard Medical School, Massachusetts.

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 lon- gevity 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 characteriza- tion, 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 cal- culator v2.2 (www.dtu.ox.ac.uk/homa).

Results. In the whole population, homozygous IRS2Asp/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, IRS2Asp/Asp participants were more likely to reach extreme old age (≥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. Further- more, studies of genetic and/or environmental background interactions may be useful after basic replication is complete.

Key Words: 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 (5). Moreover, IRS2+/− mice live nearly 18% longer than wild-type mice (5).

like growth factor-1 (IGF-1) signaling attracted substan- tial attention on the basis of several evidences showing that disruption of insulin and IGF-1 signaling cascade can signifi- cantly extend life span in diverse living species from yeast to rodents (1–4). A recent study demonstrated that systemic or neural-specific reduction of the insulin receptor substrate-2 (IRS2) can extend the life span of mice (5). however, it is difficult to determine directly whether IRS2 signaling regulates human longevity. In humans, a number of poly- morphisms have been identified in the IRS2 gene, including Gly1057Asp variant that occurs with an allelic frequency of 34% (6). Some, but not all, studies have indicated a role for such variant in the pathogenesis of obesity and obesity- associated insulin resistance (6–12). Furthermore, in some but not all populations, obesity and IRS2Asp have been found associated with infertility, reduced pancreatic b-cell function, and increased type 2 diabetes susceptibility (6–12).

In humans, insulin resistance ordinarily develops with age and is an important risk factor for various metabolic disorders—hypertension, atherosclerosis, obesity, and type 2 diabetes—strongly affecting morbidity, disability, and mortality among the elderly participant (13). 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 (14). Because the metabolic profile of long-lived participants resembles that of IRS2+/− mice, we investigated whether the IRS2Asp variant is associated with human longevity.

Materials and Methods

Interestingly, IRS2 knockout mice display similar charac- teristics, including infertility, reduced b-cell mass and insulin secretion, and an increased peripheral insulin resistance that predisposes to diabetes (5). By contrast, a hemizygous IRS2

Participants

Six hundred seventy-seven Caucasians (388 females and 289 males; mean age: 62.76 ± 26.01 years) from northern, central, or southern Italy volunteered for the study. In order

Statistical Analysis

to assess the impact of the IRS2 gene polymorphism on longevity, on the basis of literature data (15), 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.”