Functionally significant insulin-like growth factor I receptor mutations in centenarians

Abstract

Rather than being a passive, haphazard process of wear and tear, lifespan can be modulated actively by components of the insulin/ insulin-like growth factor I (IGFI) pathway in laboratory animals. Complete or partial loss-of-function mutations in genes encoding components of the insulin/IGFI pathway result in extension of life span in yeasts, worms, flies, and mice. This remarkable conservation throughout evolution suggests that altered signaling in this pathway may also influence human lifespan. On the other hand, evolutionary tradeoffs predict that the laboratory findings may not be relevant to human populations, because of the high fitness cost during early life. Here, we studied the biochemical, phenotypic, and genetic variations in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls and demonstrated a gender-specific increase in serum IGFI associated with a smaller stature in female offspring of centenarians. Sequence analysis of the IGF1 and IGF1 receptor (IGF1R) genes of female centenarians showed overrepresentation of heterozygous mutations in the IGF1R gene among centenarians relative to controls that are associated with high serum IGFI levels and reduced activity of the IGFIR as measured in transformed lymphocytes. Thus, genetic alterations in the human IGF1R that result in altered IGF signaling pathway confer an increase in susceptibility to human longevity, suggesting a role of this pathway in modulation of human lifespan.IGF1 receptor ͉ human longevity ͉ genetic variation

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

“…The SNP in the known longevity gene FOXO3 has not only been previously associated with reduced fasting insulin and HOMA‐IR (Willcox et al ., 2008), but here it was found to produce lower circulating IGF‐I levels. Multiple genetic determinants for circulating IGF‐I in normal and IGF1R resistance states might partially explain the U‐shaped association of circulating IGF‐I concentration with mortality (Suh et al ., 2008; Burgers et al ., 2011). …”

VCAM‐1 upregulation accompanies muscle remodeling following resistance‐type exercise in Snell dwarf (Pit1dw/dw) mice

“…Individuals with IGF1 variants associated with high IGF‐1 blood levels gain more strength following resistance training (Hand et al, 2007; Kostek et al, 2005). Yet, genetic polymorphisms in the gene for IGF‐1 receptor, which result in decreased IGF‐1 plasma levels, associate with longevity (Bonafe et al, 2003; Suh et al, 2008). Although the responsiveness to resistance‐type exercise training may be muted, absolute performance gains may still be possible as evident by research regarding growth hormone deficient adults (Werlang Coelho et al, 2002).…”

A/ASP/VAL allele combination of IGF1R, IRS2, and UCP2 genes is associated with better metabolic profile, preserved energy expenditure parameters, and low mortality rate in longevity

“…To this regard, we have previously demonstrated that the G to A transition in exon 16 of IGF1R gene is associated with longevity in an Italian population ) and more recently an overrepresentation of heterozygotes for mutation in IGF1R gene has been found among Jewish female centenarians (Suh et al 2008). Recently, we have also found that subjects with one or two IRS2 Asp alleles displayed a greater chance of living between 96 and 104 years of age (Barbieri et al 2010).…”