A polymorphic variant of the insulin-like growth factor 1 (IGF-1) receptor correlates with male longevity in the Italian population: a genetic study and evaluation of circulating IGF-1 from the "Treviso Longeva (TRELONG)" study

Abstract

Background: An attenuation of the insulin-like growth factor 1 (IGF-1) signaling has been associated with elongation of the lifespan in simple metazoan organisms and in rodents. In humans, IGF-1 level has an age-related modulation with a lower concentration in the elderly, depending on hormonal and genetic factors affecting the IGF-1 receptor gene (IGF-1R).

Methods: In an elderly population from North-eastern Italy (n = 668 subjects, age range 70-106 years) we investigated the IGF-1R polymorphism G3174A (rs2229765) and the plasma concentration of free IGF-1. Frequency distributions were compared using chi2-test "Goodness of Fit" test, and means were compared by one-way analysis of variance (ANOVA); multiple regression analysis was performed using JMP7 for SAS software (SAS Institute, USA). The limit of significance for genetic and biochemical comparison was set at alpha = 0.05.

Results: Males showed an age-related increase in the A-allele of rs2229765 and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level. We found no clear correlation between rs2229765 genotype and IGF-1 in the females.

Conclusion: These findings confirm the importance of the rs2229765 minor allele as a genetic predisposing factor for longevity in Italy where a sex-specific pattern for IGF-1 attenuation with ageing was found.

Figure 1

Age-related reduction of circulating IGF-1. Scatter-plot showing individual plasma IGF-1 levels measured by a dedicated ELISA kit, described in Methods. The superimposed line indicates the simple linear interpolation, whose equation and statistical significance are shown in the box on the graph. r: correlation coefficient.

Figure 2

Effect of sex and rs2229765 A-allele on IGF-1 circulating level. (A) The sample was divided into two groups, older and younger than 85 years of age, then each group was divided according to sex. The distribution of IGF-1 concentrations in each group was stratified according to the rs2229765 genotype. The vertical bars represent the mean ± standard deviation (SD); *: p < 0.05, Tukey's post-hoc test vs. M 85+ G/G group; M: men, F: women (B) Scatter plot showing male rs2229765 genotype-specific linear regressions according to age. All males have been included. Regression slopes are reported next to each regression line.