Experimental Gerontology 39 (2004) 1595–1598

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

a,* a,b a c c Toshio Kojima , Hidehiko Kamei , Tomoyuki Aizu , Yasumichi Arai , Michiyo Takayama , c c d d d Susumu Nakazawa , Yoshinori Ebihara , Hiroki Inagaki , Yukie Masui , Yasuyuki Gondo , a c Yoshiyuki Sakaki , Nobuyoshi Hirose

aHuman Genome Research Group, Genomic Sciences Center, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan bDepartment of Periodontology, School of Dentistry, Aichi-gakuin University, Nagoya, Japan cDepartment of Geriatric Medicine, Keio University School of Medicine, Tokyo, Japan dDementia Intervention Group, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

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. q 2004 Elsevier Inc. All rights reserved.

Keywords: Aging; Centenarian; Gene polymorphism; Insulin/IGF1 signaling; Longevity

1. Introduction

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). Regulationsoflifespanbyinsulinreceptorand IGF1receptor 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 vari- ations 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).

Recent studies using model organisms have demon- strated 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

Another example is age-1 which is the C. elegans ortholog of the gene encoding the catalytic subunit of phosphoinosi- tide-3-kinase, a protein involved in insulin/IGF1 signal

In this study, we compared 122 Japanese semisupercen- tenarians (SSCs) (older than 105) with 122 healthy younger controls. We examined polymorphic variations of the genes for six proteins, forkhead box O1A (FOXO1A), insulin

* Corresponding author. Tel.: C81 45 503 9174; fax: C81 45 503 9170. E-mail address: tkojima@gsc.riken.jp (T. Kojima).

0531-5565/$ - see front matter q 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2004.05.007

present for this study (Table 1). Forty-six SSCs were living at home and 76 were institutionalized. None were in an acute care situation and none were receiving tube feeding. The gender matched control subjects comprised 122 healthy volunteers (105 female, 17 male, mean age 33.3G11.4 years, range 19–63) recruited from hospital and institutional workers, medical and nursing school students, and bank clerks. The control subjects were free from diseases such as coronary artery disease, stroke, diabetes, and cancer. Smoking and alcohol consumption was moderate to nil. All subjects enrolled in this study were Japanese. Twenty milliliters of non-fasting venous blood was collected from all subjects, and genomic DNA was prepared from peripheral leukocytes according to standard protocols. Written informed consent was obtained from all participants directly, or by proxy. This study was approved by the ethics committees of the medical school of Keio University and RIKEN Yokohama Institute.

Group Number Mean ageGSD (male/female) SSC 122 (15/107) 106.8G1.0 Control 122 (17/105) 33.3G11.4

SSC, semisupercentenarian.

receptor (INSR), insulin receptor substrate 1 (IRS1), phosphoinositide-3-kinase, catalytic, beta polypeptide (PIK3CB), phosphoinositide-3-kinase, catalytic, gamma polypeptide (PIK3CG), and peroxisome proliferative acti- vated receptor, gamma, coactivator 1, alpha (PPARGC1A), all of which are involved in insulin/IGF1 signaling.

2.1. Subjects

2.2. Single nucleotide polymorphisms (SNPs) typing

Twelve SNPs in the FOXO1A, INSR, IRS1, PIK3CB and PIK3CG gene loci (3, 6, 1, 1, and 1 SNPs, respectively) were

A total of 122 Japanese SSCs (107 female, 15 male, mean age 106.8G1.0 years) were recruited from 2002 to

Polymorphisms in six genes and association study of SSCs and controls using allelic frequencies