Mechanisms of Ageing and Development 126 (2005) 1178–1184

www.elsevier.com/locate/mechagedev

of an affect-associated gene to human Prevalence of the long-allele genotype of the serotonin transporter-linked gene in Japanese centenarians

a,* b b b Yasuyuki Gondo , Nobuyoshi Hirose , Yasumichi Arai , Ken Yamamura , b b b Ken-ichirou Shimizu , Michiyo Takayama , Yoshinori Ebihara , b a a c Susumu Nakazawa , Hiroki Inagaki , Yukie Masui , Koji Kitagawa

aTokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan bDepartment of Geriatric Medicine, Keio University School of Medicine, Tokyo, Japan cGumma Paz College, Gumma, Japan

Abstract

Negative affect such as depression and anxiety has been reported to be associated with morbidity and mortality, and polymorphisms of the serotonin transporter (5HTT) gene may be associated with such affect disorders. Hypothesizing that 5HTT gene polymorphisms could influence human longevity via negative affect; we compared the polymorphic variation of the 5HTT gene between 265 Japanese centenarians and control subjects. In addition, we evaluated the relationships between the 5HTT genotype and the physical, cognitive, and biologic status of centenarians, as indicated by the Barthel Index, the Mini-Mental State Examination, and serum albumin concentration, respectively. The frequency of the l/l genotype and the l allele was significantly greater in centenarians than in younger control subjects, particularly women. A significant effect of the 5HTT genotype on serum albumin concentration was observed in both sexes. Although, there was sex optionality, the l allele may carry a longevity advantage possibly through behavioral mechanisms. # 2005 Elsevier Ireland Ltd. All rights reserved.

Keywords: Serotonin transporter gene-linked polymorphism region; Longevity; Centenarians; Gender difference; Serum albumin

1. Introduction

between gene polymorphisms and human emotion, affect, or behavior have been reported (Lesch et al., 1996). We describe here an investigation of the contribution of the affect-related serotonin transporter (5-hydroxytryptamine, 5HTT) gene-linked polymorphism region (5HTT-LPR) to longevity in a cohort taken from the Japanese population.

Recent progress in genome studies has indicated that gene polymorphisms contribute to human longevity. These polymorphisms are thought to influence longevity through several potential mechanisms including the immune system (Takata et al., 1987; Bonafe et al., 2001) and the metabolic system (Schachter et al., 1994; Geesaman et al., 2003). Although psychobehavioral systems are also important factors in longevity, little is known about them, and little interest has been paid to polymorphisms of candidate genes that might influence human behavior. Recently, relationships

The adverse impact of negative affect on health has been reported in many papers (Kiecolt-Glaser et al., 2002). Major depression or depressed mood has been associated with increased risk of myocardial infarction (Pratt et al., 1996), decreased physical function (Rantanen et al., 2000), and higher cancer risk (Penninx et al., 1998), as well as mortality (Herrmann et al., 1998). Anxiety has been linked to heart disease, including myocardial infarction (Eaker et al., 1992; Kawachi et al., 1994).

0047-6374/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2005.06.006

Even though the findings regarding the effect of 5HTT gene polymorphism on negative emotion or health in Japanese subjects are equivocal, they do suggest that it would be valuable to explore the influences of 5HTT on human health and mortality. We hypothesized that 5HTT gene polymorphism influences human longevity via a negative impact on the affective state as a result of stressful life experiences. The frequency of the l/l genotype and l allele would therefore be higher among long-lived indivi- duals than in the younger population. We also hypothesized that if a particular gene polymorphism has a positive impact on longevity, the functional status, such as basic activities of daily living (ADL), or cognitive function among people who possess this genotype would be better maintained, even in the final stages of their life. In the study presented here, we compared the distribution of 5HTT polymorphisms in a large number of Japanese centenarians with that in younger control subjects. We also explored the effects of 5HTT polymorphisms on physical, cognitive, and biological function in the centenarians.

The 5HTT-LPR has been linked with negative affect and personality (Lesch et al., 1996). The two most common alleles are a 44-bp insertion (l allele) or deletion (s allele) in its promoter region. The s allele reduces the efficiency of transcription of the gene, resulting in decreased serotonin transporter expression and serotonin uptake by lymphoblasts (Lesch et al., 1996). Possession of the s allele has been associated with higher neuroticism, higher harm avoidance, and depression (Lesch et al., 1996), including geriatric depressive symptoms (Steffens et al., 2002). For healthy adults, the 5HTT showed strongest association to personality trait among personality-associated genes (Munafo et al., 2003).