G/A-IGF1R and Pro/Ala IRS2 variants in human longevity and allele combination analysis firstly demonstrate a combined effect of IGF1R, IRS2, and UCP2 genes on longevity being AAV allele combi- nation overrepresented among long-lived subjects. Although test for the univariate association between this UCP2-55T polymorphism and longevity was not statistically significant, however, allele combination analysis indicated that allele combination possessing allele Val of UCP2 is associated with an increased probability to reach extreme old age. Such results support the hypothesis that interaction with a different

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longevity is due to a general effect rather than to a specific diseases process.

Further studies will be necessary for replicating our finding in an independent larger population group with sufficient power to investigate gene– gene and – gene environment interaction. Interaction with a different genetic and/or environmental background may, in fact, differently modulate the effect of a given

In conclusion, our study demonstrates that A- IGF1R/Asp-IRS2/Val-UCP2 allele combination is associated with a decreased all-cause mortality risk and with an increased chance of longevity. Such an effect is probably due to the combined effect of IGF1R, IRS2, and UCP2 genes on energy metabolism and on the age-related metabolic remodeling capacity. Collectively, these data support the hypothesis that those subjects, identified as successfully aged people (free of major age-related diseases and preserved from the metabolic derangement normally occurring with aging) may be genetically advantaged for longevity.

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