Reduced insulin/IGF‐1 signalling and human longevity

Abstract

SummaryEvidence is accumulating that aging is hormonally regulated by an evolutionarily conserved insulin/IGF-1 signalling (IIS) pathway. Mutations in IIS components affect lifespan in Caenorhabditis elegans, Drosophila melanogaster and mice. Most long-lived IIS mutants also show increased resistance to oxidative stress. In D. melanogaster and mice, the longlived phenotype of several IIS mutants is restricted to females. Here, we analysed the relationship between IIS signalling, body height and longevity in humans in a prospective follow-up study. Based on the expected effects (increased or decreased signalling) of the selected variants in IIS pathway components ( GHRHR, GH1, IGF1, INS, IRS1 ), we calculated composite IIS scores to estimate IIS pathway activity. In addition, we analysed the relative impact on lifespan and body size of the separate variants in multivariate models. In women, lower IIS scores are significantly associated with lower body height and improved old age survival. Multivariate analyses showed that these results were most pronounced for the GH1 SNP, IGF1 CA repeat and IRS1 SNP. In females, for variant allele carriers of the GH1 SNP, body height was 2 cm lower ( P = 0.007) and mortality 0.80-fold reduced ( P = 0.019) when compared with wild-type allele carriers. Thus, in females, genetic variation causing reduced IIS activation is beneficial for old age survival. This effect was stronger for the GH1 SNP than for variation in the conserved IIS genes that were found to affect longevity in model organisms.

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

“…We also found that SNPs associated with reduced IGF‐I levels tended to be associated with longer survival defined as death after 90 years (Broer et al ., 2015). This is consistent with an observation from prior analysis of candidate genes associated with the insulin and IGF signaling axis (van Heemst et al ., 2005). In addition, rs934073, an eQTL for additional sex comb‐like 2 ( ASXL2 ), was a genomewide significant SNP associated with lower IGF‐I level which also has enriched frequency in adults older than 90 years of age (Broer et al ., 2015).…”

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

“…Furthermore, a very recent study has demonstrated that the absence of UCP2 shortens life span in wild-type mice, and the level of UCP2 positively correlates with the postnatal survival of superoxide dismutase 2 mutant animals (Andrews and Horvath 2009). Indeed, no difference in relative mortality risk among UCP2 gene variant was observed in a Dutch cohort (van Heemst et al 2005) In our study, univariate analysis confirm the role of G/A-IGF1R and Pro/Ala IRS2 variants in human longevity and allele combination analysis firstly demonstrate a combined effect of IGF1R, IRS2, and UCP2 genes on longevity being AAV allele combination overrepresented among long-lived subjects. Although test for the univariate association between this UCP2-55T polymorphism and longevity was not statistically significant, however, allele combination analysis indicated that allele combination possessing allele Val of UCP2 is associated with an increased probability to reach extreme old age.…”

“…It is likely that variants of UCP2 gene might help to explain such peculiar phenotype found in the long-lived subject. Indeed, although no difference in relative mortality risk among UCP2 gene variant was observed in a Dutch cohort (van Heemst et al 2005), the possibility that UCP2 gene has an influence on human physiology and life span, directly or through the interaction with other genes could not be ruled out. Interaction with a different genetic and/or environmental background may, in fact, differently modulate the effect of a given gene in different populations.…”

“…Several experimental evidences suggest that caloric restriction exerts its beneficial effects on longevity through the modulation of the insulin IGF1 signaling pathway (Fontana et al 2010;Heilbronn and Ravussin 2003;Taguchi and White 2008) and recent association studies on long-lived people have demonstrated that a large array of gene involved in human longevity are in relationship with insulin/IGF1 pathway (van Heemst et al 2005;Bonafè and Olivieri 2009;Pawlikowska et al 2009). 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).…”

Chemical changes in aging Drosophila melanogaster

“…Insulin-IGF signalling appears to be an evolutionarily conserved pathway influencing healthy lifespan (Broughton and Partridge 2009;van Heemst et al 2005;Selman et al 2008). Thus, understanding the mechanism by which it operates is of special interest when attempting to formulate a hypothesis with broad explanatory power for organismal aging.…”