Previously, three cross sectional studies have been published on the role of the rs4880 MnSOD SNP in human survival or longevity. Taufer et al. (2005) did not find an association with survival from newborn (N = 65), to age 21–79 years (N = 296) or to age 80–105 years (N = 75) in individuals of mixed European Caucasian and native South American origin. De Benedictis et al. (1998) did not find an association with longevity in 167 centenarians and 186 controls (age 10–85 years) of Italian origin. However, based on their geographical origin (northern or southern Italy) the centenarians and controls in the latter study were divided in two groups (62 + 80 individuals and 105 + 106 individuals, respectively) and in the former study the sample size of the 80– 105 age group was 75 individuals. Hence, these observations may simply be due to lack of power to detect a moderate effect on longevity (as observed in our study) as a result of the relatively small sample sizes. Furthermore, the study groups in Taufer et al.’s study were of mixed European Caucasian and native South American origin, which could give rise to population stratification. However, Taufer et al. do argue that this is not the case, since

3.4. Synergetic effect of the MnSOD and GPX1 SNPs

Since the MnSOD and GPX1 proteins are involved in the same biological pathway we wanted to investigate a possible synergetic effect of the two SNPs. Hence, the association of the combinations of the rs4880 MnSOD and rs1050450 GPX1 SNP genotypes with survival was investigated. Individuals holding at least one minor allele in both SNPs had a significantly decreased mortality as compared to individuals being homozygous for both the major alleles. The HR was 0.76 (P = 0.001, 95%CI: [0.647–0.894], N = 1613), indicating that there might be a more than additive effect of holding both the ‘‘best survival’’ alleles as compared to holding both the ‘‘worst survival’’ alleles.

simply be due to difference in genetic background of the study populations. In any case does the study by Bastaki et al. show the opposite as Sutton et al. However, Sutton et al. did use a cellular system only differing in the rs4880 MnSOD SNP, excluding influence from difference in genetic background. Yet, the in vivo data obtained by Sutton et al. remains to be confirmed in a separate study.

mitochondrial DNA lineage studies previously showed homo- geneous miscegenation (Parra et al., 2003). Finally, since the two studies are cross sectional, it cannot be excluded that cohort specific variation in environment may introduce bias.

from age 22 (N = 441) to age 75 (N = 224) (Stessman et al., 2005). An increase in T allele frequency (from 33% to 51%) and an increase of TT homozygotes (from 25% to 45.5%) were here observed in an Israeli (Ashkenazi) population. These results are somehow contra- dictory to our results, yet there are several possible explanations for this inconsistency. Firstly, an association of the rs4880 MnSOD SNP with survival may differ between populations (Israeli versus Danes), secondly the role of rs4880 MnSOD genotype (and hence possibly activity (see below)) may be of different importance at different ages (22–75 years versus 92–100+) and finally, the difference in study design (cross sectional versus longitudinal) may be of importance.

We report for the first time an association of the rs1050450 GPX1 SNP with longevity. The rs1050450 GPX1 SNP genotype frequencies in the 1905 cohort deviate from the once expected from the observed allele frequencies. However, as previously mentioned, such deviations have been reported before for SNP genotype frequencies in populations of the oldest old (Bathum et al., 1998; Geesaman et al., 2003). A deviation might indicate that there is a selection with respect to the rs1050450 GPX1 SNP genotypes up untilold age (the 1905 cohortmembers were age 92– 93 when they entered the survey, an age at which individuals can be said to be cases of extreme survival). Furthermore, the survival estimates obtained here have the same effect size and indicate a survival advantage of CT and TT individuals in old age, although not significant for the TT genotype.

When looking at the possible functional basis of the observed association of the rs4880 MnSOD SNP genotype with longevity, several experiments support such an association. The SNP is located in the mitochondrial targeting signal leading to disruption of its helical structure in the 16Valine(T) variant protein (Shimoda- Matsubayashi et al., 1996). By using purified rat liver mitochon- dria, Sutton et al. (2003) showed that this disruption hampers the transport of the protein into the mitochondrial matrix; about 35% of (recombinant) 16Valine(T) proteins are arrested in the inner mitochondrial membrane, as compared to only 8% of the 16Alanine(C) proteins. In the matrix the mitochondrial targeting signal is cleaved off generating the active protein (Matsuda et al., 1990). This processing is hampered for the 16Valine(T) variant, since it generates 29% less processed protein than the 16Alanine(C) variant and the activity of the 16Valine(T) variant is 23% less than the 16Alanine(C) variant (Sutton et al., 2003). A hampered processing of the 16Valine(T) variant has also been found by Hiroi et al. (1999). Sutton et al. later confirmed their data in a human in vivo system (hepatoma cells transfected with construct carrying either genotype); in 16Alanine(C) variant cells the levels of processed protein and the activity was four fold higher than in 16Valine(T) variant cells. Also, the O   level in 16Alanine(C) cells 2 was 60% lower than in 16Valine(T) cells (Sutton et al., 2005).