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Polymorphic Variants of Insulin-Like Growth Factor I (IGF-I) Receptor and Phosphoinositide 3-Kinase Genes Affect IGF-I Plasma Levels and Human Longevity: Cues for an Evolutionarily Conserved Mechanism of Life Span Control

Department of Experimental Pathology, University of Bologna, 40126 Bologna, Italy; Department of Geriatric Medicine and Metabolic Diseases II, University of Naples (B.M., R.E., P.G.), 80138 Naples, Italy; and Italian National Research Centers on Aging (M.F., O.F., G.C., M.E., C.M.), 60100 Ancona, Italy

Address all correspondence and requests for reprints to: Giuseppe Paolisso, M.D., Department of Geriatric Medicine and Metabolic Diseases, IV Divisione di Medicina Interna, Piazza Miraglia 2, I-80138 Naples, Italy. E-mail: giuseppe.paolisso{at}unina2.it.

Current literature indicates that abrogation of the IGF-I response pathway affects longevity in Caenorhabditis elegans, and that the down-regulation of IGF-I gene expression is associated with an extension of the life span in mice. In this paper we tested the hypothesis that polymorphic variants of IGF-I response pathway genes, namely IGF-IR (IGF-I receptor; G/A, codon 1013), PI3KCB (phosphoinositol 3-kinase; T/C, -359 bp; A/G, -303 bp), IRS-1 (insulin receptor substrate-1; G/A, codon 972), and FOXO1A (T/C, +97347 bp), play a role in systemic IGF-I regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF-IR have low levels of free plasma IGF-I and are more represented among long-lived people. Moreover, genotype combinations at IGF-IR and PI3KCB genes affect free IGF-I plasma levels and longevity. These findings represent the first indication that free IGF-I plasma levels and human longevity are coregulated by an overlapping set of genes, contributing to the hypothesis that the impact of the IGF-I/insulin pathway on longevity is a property that has been evolutionarily conserved throughout the animal kingdom.

The EU Projects (PROTAGE, FUNCTIONAGE, and ECHA) and AIRC, MIUR ex 40% and ex 60% Unibo, are acknowledged.

Abbreviations: BMI, Body mass index; HOMA, homeostatic model assessment; IGF-IR, IGF-I receptor; IR, insulin resistance; IRS-1, insulin receptor substrate-1; PI3KCB, phosphoinositol 3-kinase.

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