Authors: Bonafè M; Barbieri M; Marchegiani F; Olivieri F; Ragno E; Giampieri C; Mugianesi E; Centurelli M; Franceschi C; Paolisso G
Abstract: 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.Keywords: Adolescent; Adult; Aged; Aged, 80 and over; Aging/genetics; DNA-Binding Proteins/genetics; Evolution, Molecular; Female; Forkhead Transcription Factors; Gene Frequency; Genotype; Humans; Insulin/metabolism; Insulin-Like Growth Factor I/*metabolism; Longevity/*genetics; Male; Middle Aged; Phosphatidylinositol 3-Kinases/*genetics; *Polymorphism, Genetic; Receptor, IGF Type 1/*genetics; Transcription Factors/genetics
Journal: The Journal of clinical endocrinology and metabolism
Date: July 5, 2003
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Bonafè M, Barbieri M, Marchegiani F, Olivieri F, Ragno E, Giampieri C, Mugianesi E, Centurelli M, Franceschi C, Paolisso G (2003) 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. The Journal of clinical endocrinology and metabolism 88: 3299-304.