In analyzing the effects of 5HTT genotype on physical, cognitive, and biological status in centenarians, no significant effects were observed for Barthel Index or MMSE. However, an association was found between the l allele and lower serum albumin concentration, particularly in women.Effect of genotype was observed for serum albumin concentration (F = 4.2, p < 0.05). Further, multiple comparisons indicated that serum albumin concentrations were higher in association with the l/l genotype than with the s/s genotype (p < 0.01). Neither a significant gender main effect nor a gender-genotype interaction was observed. We also conducted the same analysis on serum albumin concentration for our younger control subjects. The distribution of genotype and allele frequency for 5HTT in centenarians and control subjects is presented in Table 3. The genotype distributions matched expectations for Hardy-Weinberg equilibrium in younger control subjects. The l/l genotype was uncommon in both centenarians (8.3%) and control subjects (3.9%). The distribution of genotypes between centenarians and young control was compared, and a statistically significant difference was observed (l/l versus l/s and s/s, x2 = 7.8, p < 0.01). When an analysis was performed according to gender, a significant distribution difference was observed.

Mean and (S.D.) of NEO-FFI, Barthel Index, Mini-Mental State Examination, and serum albumin concentration by 5HTT genotypes in centenarians.

| | Men | Women | Statistics |
| --- | --- | --- | --- |
| NEO-FFI dimensions | | | |
| Neuroticism | 21.5 (6.4) | 15.9 (8.8) | n.s.. |
| Extraversion | 23.0 (5.7) | 26.7 (6.2) | n.s.. |
| Openness | 25.0 (4.2) | 22.2 (6.1) | n.s.. |
| Agreeableness | 30.0 (0.0) | 31.5 (6.4) | n.s.. |
| Conscientiousness | 35.5 (3.5) | 32.3 (9.2) | n.s.. |
| Barthel Index | 73.3 (46.2) | 73.3 (32.7) | Sex p < 0.01 |
| MMSE | 20.3 (5.5) | 16.3 (8.7) | Sex p < 0.05 |
| Albumin (g/dl) | 4.1 (0.2) | 3.7 (0.4) | Genotype p < 0.05 |

However, no significant effect of 5HTT genotype was observed in younger control subjects.

It was suggested that this gender difference could be explained by the biological and lifestyle differences between men and women. Several studies have suggested the existence of gender-genotype interactions in the effects of the serotonergic system. Whole blood serotonin level is higher in men (Weiss et al., 2005). The rate of serotonin synthesis in the central spinal fluid is lower in women than in men (Nishizawa et al., 1997), and it has been reported that the effect of the 5HTT genotype on serotonin turnover differs between the genders (Williams et al., 2003). The effect of treatment with a serotonin reuptake inhibitor on emotional disorders is greater in women throughout the life cycle (Yonkers, 2003). A higher frequency of suicide attempts was reported only in women with the s/s genotype (Baca-Garcia et al., 2002). The higher ratio of the l/l genotype in women theoretically results in increased sensitivity of their serotonergic system.

Discussion

The influence of 5HTT polymorphism on longevity in the Japanese population was investigated. We hypothesized that 5HTT polymorphism could mediate the human affective state, which influences health and longevity. First, we found a significant difference in genotype distribution and allele frequency for 5HTT polymorphism between centenarians and younger control subjects, particularly women. Second, we found a statistically significant but weak association between the 5HTT genotype and serum albumin concentration, which is a biological marker of health status among centenarians.

There is much psychological stress in human life. Centenarians living in Tokyo have experienced catastrophic life events including a catastrophic earthquake, two world wars, and personal life events such as bereavement resulting from the deaths of spouses and children. The negative impact of these life events on the affective state is thought to be greater in individuals with the s allele (Caspi et al., 2003; Grabe et al., 2004). We found that the distribution of both the l/l genotype and the l allele, which is a protective factor against stressful experiences, was higher in centenarians than in young control subjects. Even though we could not examine theProxy, 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 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 all participants in our study was deteriorated, Barthel Index score in visit survey participants (mean = 44.1, S.D. = 34.8) was significantly higher (p < 0.01) than in mail-survey participants (mean = 34.4, S.D. = 32.7). This implies that healthier centenarians were likely to participate in our study. To avoid sampling bias, a non-invasive sampling method (e.g., postal buccal washes) will be needed in future studies. However, concerning exploring the long-lived and healthy aging gene polymorphisms, the purpose of our study, observed results here could be situated as finding a clue of contribution of affect-associated gene to longevity.