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

J Clin Endocrinol Metab. 2003 Jul;88(7):3299-304. doi: 10.1210/jc.2002-021810.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / genetics
  • DNA-Binding Proteins / genetics
  • Evolution, Molecular
  • Female
  • Forkhead Box Protein O1
  • 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


  • DNA-Binding Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Insulin
  • Transcription Factors
  • Insulin-Like Growth Factor I
  • Phosphatidylinositol 3-Kinases
  • Receptor, IGF Type 1