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 l/l l/s s/s l/l l/s s/s NEO-FFI dimensions Neuroticism 21.5 (6.4) 15.9 (8.8) 17.4 (5.8) 22.2 (6.4) 19.3 (6.2) 19.4 (5.8) n.s.. Extravesion 23.0 (5.7) 26.7 (6.2) 25.8 (5.7) 27.9 (7.9) 27.0 (6.9) 26.0 (6.4) n.s.. Openness 25.0 (4.2) 22.2 (6.1) 23.2 (6.0) 21.9 (4.4) 22.4 (5.0) 22.4 (4.8) n.s.. Agreeableness 30.0 (0.0) 31.5 (6.4) 31.5 (8.1) 30.4 (7.8) 30.8 (7.8) 31.3 (7.8) n.s.. Conscientiousness 35.5 (3.5) 32.3 (9.2) 33.9 (7.7) 31.7 (6.6) 31.4 (7.2) 31.8 (5.8) n.s.. Barthel Index 73.3 (46.2) 73.3 (32.7) 73.3 (34.1) 48.7 (37.7) 44.9 (32.9) 39.5 (33.1) Sex p < 0.01 MMSE 20.3 (5.5) 16.3 (8.7) 17.1 (8.4) 13.9 (8.5) 13.2 (7.7) 12.3 (8.1) Sex p < 0.05. Albumin (g/dl) 4.1 (0.2) 3.7 (0.4) 3.6 (0.4) 3.8 (0.4) 3.6 (0.4) 3.6 (0.4) Genotype p < 0.05

younger control subjects. However, no significant effect of 5HTT genotype was observed (data not shown).

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 seroto- nergic 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 serotoninergic system.

4. 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 for5HTT polymorphism betweencentenarians 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 etal., 2004).Wefoundthatthedistributionofboththel/ 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 the actual responses to the stressful situations of centenarians during their long lives, this finding suggests that this affect- related gene polymorphism may have a positive impact upon human longevity. The mechanism is unknown but perhaps acts through immune (Takata et al., 1987; Bonafe et al., 2001) or metabolic pathways (Schachter et al., 1994; Geesaman et al., 2003) that are also linked to longevity.

Lifestyle differences may also influence gender differ- ences in genotype distribution. Several papers have reported adverse effects of the l allele on longevity. Relationships have been found in Japanese men between possession of the l allele and a smoking habit (Ishikawa et al., 1999), earlier onset of alcoholism (Ishiguro et al., 1999), and a higher prevalence of coronary heart disease among smokers (Arinami et al., 1999). Both alcohol drinking and smoking habits are more prevalent in men than in women in the Japanese population. The positive effect on survival of possessing the l allele might thus be obscured in men because of a lifestyle-genotype interaction.

A gender difference in the gene effect has been reported in several centenarian studies. Among Italian centenarians, an interferon-g allele polymorphism difference was observed only in women (Lio et al., 2002a), while a (cid:2)1082G homozygosity difference was observed only in men (Lio et al., 2002b). The G allele at the (cid:2)174C/G locus, which influences plasma interleukin (IL)-6 concentration, was decreased only in male centenarians (Bonafe et al., 2001). These authors explained the gender difference in terms of hormonal regulation. With regard to the gender difference in the effect of 5HTT polymorphism, it was considered that this might be influenced by the difference of lifestyle and/or hormonal status, between men and women.