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.
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.
Bonafè
Massimiliano
M
Department of Experimental Pathology, University of Bologna, 40126 Bologna, Italy. giuseppe.paolisso@unina2.it
Barbieri
Michelangela
M
Marchegiani
Francesca
F
Olivieri
Fabiola
F
Ragno
Emilia
E
Giampieri
Claudia
C
Mugianesi
Elena
E
Centurelli
Matteo
M
Franceschi
Claudio
C
Paolisso
Giuseppe
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011110:Polymorphism, Genetic; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1