However, no association was found between the 5HTT genotype and anxiety-related personality traits among the centenarians. Our previous report indicated that centenar- ians are more neurotic than young controls (Masui et al., 2002). This higher degree of neuroticism contributes to increased health-seeking behavior, such as frequently consulting a doctor (Jerram and Coleman, 1999), which is assumed to be a helpful coping mechanism for survival. Such a confounding factor might influence the null effect of 5HTT polymorphism on the behavioral aspect of centenar- ians. In addition, a recent functional neuroimaging study has shown that activation of the right amygdala, which processes angry and fearful facial expressions, was stronger in the s-allele-positive group than in the s-allele-negative group, even though there was no difference in anxiety-related personality traits between these groups (Hariri et al., 2002). According to this finding, we might hypothesize that even if we could find no difference in personality phenotype among the different genotypes, the biological response, is functioning and may contribute to survival.

We were able to analyze the data from 25.2% of all recruited centenarians. This might have resulted in a selection bias such that those centenarians with low anxiety levels who possess the l allele and high ADL healthier centenarians tended to participate in this study. With regard to the anxiety level, because of the prevalence of dementia among our sample of centenarians (65% of all participants), in the majority of cases agreement to participate was obtained from a family member or by proxy, rather than from the centenarians themselves. Thus, it is unlikely that the anxiety level of the centenarians influenced the decision to participate. We also compared the NEO-FFI score between those mail-survey participants (n = 209) who did not agree to be visited by our research members and those

The frequency of the l/l genotype and l allele was prominent only for female centenarians. We hypothesize

investigate these associations using a lager sample and different design, as well as to confirm the associations in different ethnic groups and genders.

who did; no significant difference between the two groups was observed for any of the personality dimensions. Thus, we believe that the gene-related anxiety level did not influence participation in the study.

On the other hand, though the ADL level of whole participants of our study was deteriorated, Barthel Index score in visit survey participants (mean = 44.1, S.D. = 34.8) were significantly higher ( p < 0.01) than in mail-survey participants (mean = 34.4, S.D. = 32.7). This implies that the healthier centenarians were likely to participate in our study. To avoid the sampling bias, non-invasive sampling method (e.g. postal buccal washes) will be need in future study. However, in terms of exploring the long live and healthy aging gene polymorphisms, the purpose of our study, observed result here could be situated as to find a clue of contribution of affect-associated gene to the longevity.

Acknowledgments

We greatly appreciate the time and assistance provided by the centenarians and their family members. We could not have carried out this study without their kind cooperation.

This study was partly supported by a grant from the Japanese Ministry of Health and Welfare for the Scientific Research Project on Longevity, a grant for studying the sociomedical background of centenarians (Principal Inves- tigator, Nobuyoshi Hirose), a grant from the Japanese Ministry of Education, Science and Culture (No. 15730346, Yasuyuki Gondo), and aid for research from the Keio Health Consulting Center.

In terms of sampling bias, we also have to mention the young control data. Because of the low frequency of l/l genotype, and not population based standardized value, we used pooled values as control. This method has advantage to stabilized the scattered genotype distribution among small sample studies. However, we could not avoid the publication bias, that not all conducted data were published and difficult to control the participants back ground. Standardized distribution of 5HTT polymorphism in various age groups with representative sample must be compared to conform and replicate this finding.

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