Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways

Abstract

Recent studies have demonstrated a significant association between mutations in genes involved in the insulin/IGF1 signaling pathway and extension of the life span of model organisms. In this study which compared 122 Japanese semisupercentenarians (older than 105) with 122 healthy younger controls, we examined polymorphic variations of six genes which are involved in insulin/IGF1 signaling. These genes were FOXO1A, INSR, IRS1, PIK3CB, PIK3CG, and PPARGC1A. We investigated the possible association of each gene locus and longevity by haplotype-based association analyses using 18 SNPs from public databases and the published literature. One INSR haplotype, which was comprised of 2 SNPs in linkage disequilibrium, was more frequent in semisupercentenarians than in younger controls.

Introduction

Recent studies using model organisms have demonstrated a significant association between mutations in genes involved in the insulin/insulin-like growth factor 1 (IGF1) signaling pathway and extension of the life span. The first examples of such genes were found in Caenorhabditis elegans (Kenyon et al., 1993). They include daf-2, an ortholog of the insulin/IGF1 receptor gene family, and daf-16, an ortholog of the forkhead transcription factors which regulate insulin/IGF1-induced gene transcription.

Another example is age-1 which is the C. elegans ortholog of the gene encoding the catalytic subunit of phosphoinositide-3-kinase, a protein involved in insulin/IGF1 signal transduction (Morris et al., 1996). A long-lived mutant of the insulin-like receptor gene (InR) was also reported in Drosophila melanogaster (Tatar et al., 2001). At almost the same time, the ablation of the D. melanogaster gene chico, which encodes an insulin receptor substrate, was reported to extend the life span of the fly (Clancy et al., 2001). Regulations of life span by insulin receptor and IGF1 receptor were also reported in mice (Bluher et al., 2003, Holzenberger et al., 2003). Based on these studies, genes involved in the insulin/IGF1 signaling pathway are believed to play a role in longevity throughout evolution. In fact, polymorphic variations of the genes for insulin-like growth factor 1 receptor (IGF1R) and phosphoinositide-3-kinase have been reported to affect human longevity (Bonafe et al., 2003).

In this study, we compared 122 Japanese semisupercentenarians (SSCs) (older than 105) with 122 healthy younger controls. We examined polymorphic variations of the genes for six proteins, forkhead box O1A (FOXO1A), insulin receptor (INSR), insulin receptor substrate 1 (IRS1), phosphoinositide-3-kinase, catalytic, beta polypeptide (PIK3CB), phosphoinositide-3-kinase, catalytic, gamma polypeptide (PIK3CG), and peroxisome proliferative activated receptor, gamma, coactivator 1, alpha (PPARGC1A), all of which are involved in insulin/IGF1 signaling.