A recent report has also indicated that gene-environment interactions exist in relation to the 5HTT gene polymorph- ism and an individual’s emotional state. Decreased serotonergic function, which is associated with impulsive- ness, aggressive behavior, and low sociality, is observed in rhesus monkeys with the s allele if they are not reared by their mothers (Bennett et al., 2002). In addition, in humans the susceptibility to becoming depressed after experiencing negative life events is higher in individuals with s alleles than in those with l alleles (Caspi et al., 2003). In women, carriers of the s allele tend to complain of psychological and somatic symptoms if they are not employed or have a chronic disease (Grabe et al., 2004). In a recent functional neuroimaging study it was reported that activation of the right amygdala in response to angry and fearful facial expressions was stronger in subjects with, than in those without the s alleles (Hariri et al., 2002).

2. Materials and methods

2.1. Subjects

2.1.1. Centenarian group

women) living in the 23 wards of metropolitan Tokyo participated in a survey in which they were visited by Tokyo Centenarian Study staff between July 2000 and May 2002. We randomly chose centenarians from the residential list and sent a letter inviting participation to 1194 centenarians, accounting for 66.9% of an estimated 1785 centenarians living in this area in the study period. Five hundred thirteen (43.0%) agreed to participation. Three hundred four represented 25.5% of the letter recipients, participated in the visit survey. Women outnumbered men in our sample by 1:3.5, which was not significantly different from the ratio for the total centenarian population in this area (1:3.9). Among our participants, 206 were living at home and 98 were institutionalized; eight of those living at home were living alone. A medical doctor, a psychologist, and a nurse conducted the survey in a visit to the centenarians’ residences. After a medical checkup and blood sampling, the psychologist conducted cognitive assessment and psychological testing. The ADL were evaluated using the Barthel Index (Collin et al., 1988). Psychologists assessed cognitive function using the Mini-Mental State Examination (MMSE; Folstein et al., 1975) at the time of the visit. Anxiety-related personality traits were evaluated by NEO- FFI (Costa and McCrae, 1985) Japanese version (Shimonaka et al., 1997) answered by proxy who knows participants well. The Barthel Index and the MMSE are used commonly in centenarian studies to evaluate physical function and cognitive status, respectively. Serum albumin concentration

The frequency of occurrence of the l/l genotype and l allele is far less common in Japanese people than in Caucasians (Nakamura et al., 1997; Arinami et al., 1999; Ishiguro et al., 1999; Ishikawa et al., 1999; Katsuragi et al., 1999; Kumakiri et al., 1999; Murakami et al., 1999; Kunugi et al., 2000; Umekage et al., 2003). The reported effects of 5HTT polymorphism on negative affect have not been consistent. While no relationship has been observed between this polymorphism and either bipolar affective disorder (Kunugi et al., 1997) or anxiety-related personality (Umekage et al., 2003), Murakami et al. (1999) and Katsuragi et al. (1999) reported an association with anxiety-related personality. Another study has also revealed an association with anxiety- related personality trait, but this finding could not be confirmed statistically because of the low number of l/l

Negative influences of the l allele on health in Japanese people have also been reported. Possession of the l allele was correlated with the early onset of alcohol dependence (Ishiguro et al., 1999), habitual smoking (Ishikawa et al., 1999), and coronary heart disease among smokers (Arinami et al., 1999). However, these reports included either only men or only few women as participants. These inconstant results may be attributable not only to ethnic differences, but also to gender differences and to the small sample sizes used in these previous Japanese studies.

Development 126 (2005) 1178–1184 2elbaT snairanetnec-nonnworuodnastcejbusesenapaJfoseidutssuoiverpnimsihpromylop)TTH5(retropsnartninotoresfonoitubirtsiD scitsiretcarahcstnapicitraPdenibmoCnemoWneMsrohtuA egnaR).D.S(eganaeMelpmaSs/ss/ll/ls/ss/ll/ls/ss/ll/l 77–74)4.7(1.55tneitappukcehclacideM–––––––––––)%7.66(841)%8.82(46)%5.4(01.lateimanirA –)2.8(7.15sreetnulovyhtlaeH)%3.96(102)%9.72(18)%8.2(8–––––––––––.lateorugihsI 56–6495–73)(cid:2)(8.64ApuorGpukcehclacideM––––––––––––)%3.96(862)%9.62(401)%9.3(51.lateawakihsI )(cid:2)(6.25Bpuorgtneitap –)6.3(0.52sffutslacideM)%3.56(66)%7.03(13)%0.4(4––––––––––––.lateigarustaK 26–02neewteberew441*sffutslacideM)%8.26(021)%4.13(06)%8.5(11–––––––––––.lateirikamuK 53dna02 18–91)4.01(9.74sreetnulovyhtlaeH)%1.56(623)%7.13(951)%0.4(61–––––––––––.lateimakaruM –)41(23ffatSsffutslacideM)%6.56(412)%8.92(79)%6.4(51–––––––––––.lateigunuK )8(75stneitapstneitapdna –)2.2(6.91stnedutsegalloC––––––)%8.86(821)%6.92(55)%6.1(3––––––.latearumakaN –)9.11(7.73sffutslacideM)%0.66(161)%7.82(07)%3.5(31)%3.56(421)%9.82(55)%8.5(11)%5.86(73)%8.72(51)%7.3(2.lateegakemU 76–91)5.11(9.73stnedutsytisrevinU)%2.66(941)%7.03(96)%1.3(7)%6.56(68)%8.92(93)%6.4(6)%0.76(36)%9.13(03)%1.1(1elpmasruO lacidem-oc .krelcknablanosrep)%9.56(7321)%2.03(765)%9.3(47)%7.66(833)%4.92(941)%9.3(02)%2.86(615)%1.82(312)%7.3(82llarevO

was measured as a biologic indicator of health status that has been linked to physical and cognitive function as well as the mortality risk of centenarians (Shimizu et al., 2001). Of the 304 participants, 265 (men 59, women 206) blood samples were suitable for analysis of DNA polymorphism. Table 1 details the characteristics of the centenarians studied.

2.1.2. Younger control subjects