Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles

Abstract

SummaryDampening of insulin ⁄ insulin-like growth factor-1 (IGF1) signaling results in the extension of lifespan in invertebrate as well as murine models. The impact of this evolutionarily conserved pathway on the modulation of human lifespan remains unclear. We previously identified two IGF1R mutations (Ala-37-Thr and Arg-407-His) that are enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with the reduced activity of the IGF1 receptor as measured in immortalized lymphocytes. To determine whether these human longevity-associated IGF1R mutations affect IGF1 signaling, we engineered mouse embryonic fibroblasts (MEFs) expressing the different human IGF1R variants in a mouse Igf1r null background. The results indicate that MEFs expressing the human longevity-associated IGF1R mutations attenuated IGF1 signaling, as demonstrated by significant reduction in phosphorylation of both IGF1R and AKT after IGF1 treatment, in comparison with MEFs expressing the wild-type IGF1R. The impaired IGF1 signaling caused by the IGF1R mutations resulted in the reduced induction of the major IGF1-activated genes in MEFs, including EGR1, mCSF, IL3Ra, and TDAG51. Furthermore, the IGF1R mutations caused a delay in cell cycle progression after IGF1 treatment, indicating a dysfunctional physiological response to a cell proliferation signal. These results demonstrate that the human longevity-associated IGF1R variants are reduced-function mutations, implying that dampening of IGF1 signaling may be a longevity mechanism in humans. Key words: human longevity; insulin ⁄ insulin-like growth factor-1 signaling; genetic variation; gene expression. We previously identified two functionally significant IGF1R mutations (A37T and R407H) that are rare but enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with the reduced activity of the insulin-like growth factor-1 (IGF1) receptor as measured in immortalized lymphocytes (Suh et al., 2008). As we do not have complete genotype information of the IGF1R mutation carriers, functional information obtained from immortalized lymphocytes from these subjects is correlational and cannot establish cause-effect relationship between the mutations and the associated phenotypes, e.g., longevity. Indeed, it is formally possible that the association of these IGF1R mutants and centenarian status might reflect variations of linked alleles, in this or another locus, that were not evaluated in our study.To determine whether these human longevity-associated IGF1R mutations affect IGF1 signaling, we engineered mouse embryonic fibroblasts (MEFs) expressing the different human IGF1R variants in a mouse Igf1r null background (S1). After lentiviral transfection of Igf1r ) ⁄ ) MEFs (Sell et al., 1994), we tested the differences in IGF1 signaling. The results show that, compared to MEFs expressing the wild-type (WT) IGF1R, MEFs expressing the human longevity-associated IGF1R variants, A37T (M1) and R407H (M2), showed attenuation of IGF1 signaling, a...

Genetic landscape of APOE in human longevity revealed by high-throughput sequencing

“…Using this population, we have successfully identified longevity associated-phenotypes, -genotypes, and their association with health outcomes (Atzmon et al, 2006; Barzilai et al, 2006; Barzilai et al, 2003). In particular, we identified two rare missense variants in the IGF-1 receptor gene (IGF1R) that were enriched in Ashkenazi Jewish centenarians as compared to younger elderly and we further showed that they were true reduced-function variants (Suh et al, 2008; Tazearslan et al, 2011). These results highlight the value of resequencing candidate genes in our Ashkenazi Jewish centenarian cohort to identify clinically relevant targets in humans.…”

The GH/IGF-1 axis in ageing and longevity

“…71 These mutations have been shown to suppress IGF-1 signalling and decrease transcription of target genes. 71 Female carriers of these mutations have high IGF-1 levels and slightly short stature, which implies that they are IGF-1-resistant. 72 These studies provide evidence that reduced IGF-1 signalling can positively affect human lifespan.…”

The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research

“…Nonagenarian female carriers of genetic polymorphisms that attenuate the action of the GH/IGF-1 pathway exhibit longer survival (van Heemst et al, 2005). Likewise, individuals with exceptional longevity are enriched with functional mutations in the IGF1R gene, which confer partial IGF-1 resistance (Suh et al, 2008; Tazearslan et al, 2011). Variants in AKT1 and FOXO3A genes, which are elements of the GH/IGF-1 signaling pathway, have been identified in long-lived individuals from several different cohorts of diverse ethnic backgrounds, although their functional role has not yet been defined (He et al, 2014; Pawlikowska et al, 2009).…”