In this paper, we show associations of the rs4880 MnSOD SNP and of the rs1050450 GPX1 SNP with longevity, indicating that variation in the genes encoding MnSOD and GPX1 may influence the variation in human lifespan. Due to minimal immigration into the Danish 1905 cohort, population stratification is minimized; hence, the cohort must be considered to be genetically homogeneous. When looking at males and females separately, it was observed that the effect of the advantageous rs4880 MnSOD and of the rs1050450 GPX1 SNP genotypes on mortality seemed to be most pronounced for males (data not shown). Fig. 2 shows an example of this difference in survival: the Kaplan-Meier survival estimates for the rs4880 MnSOD SNP CC/CT and TT genotypes for females (Fig. 2A) and males (Fig. 2B) separately. When calculating the HR for the CC/CT genotype,Difference. Hence, it might be that the rs1050450 GPX1 SNP genotypes (CT and TT) we find to be associated with decreased mortality in the oldest old may be the variant holding slightly lower activity. This seems somehow contradictory to the idea that efficient antioxidant enzyme activity contributes to reduced mortality. However, oxidative stress is believed also to have beneficial effects; moderate levels of ROS or a temporary increase in ROS levels have positive effects on cellular homeostasis (Droge, 2002; Radak et al., 2008). Hence, there is probably a delicate balance between the advantageous and disadvantageous effects of ROS, and the relation between ROS and lifespan is probably not as straightforward as low ROS levels (possibly ensured by efficient antioxidant enzymes) equaling increased lifespan. Finally, a slightly more active GPX1 could lead to increased OH levels due to decreased levels of reduced glutathione. Therefore, it cannot be excluded that a slight decrease in GPX1 activity (in the TT and CT rs1050450 GPX1 SNP genotypes) could have a positive effect on longevity. These results indicate that the genetic variation in the rs4880 MnSOD SNP might lead to a difference in MnSOD activity in the matrix and hence to a difference in oxidant-antioxidant balance. CC (alanine-alanine) and CT (alanine-valine) individuals would likely hold a higher MnSOD activity (than TT (valine-valine) individuals) and hence have less O2 accumulation in the matrix, which could lead to lower damage levels (as compared to TT (valine-valine) individuals). Such a difference in antioxidant activity and damage level could (according to the free radical theory of aging) be expected to affect the lifespan of the individual. This is indeed what we observe: the CC (alanine-alanine)/CT (alanine-valine) individuals hold reduced mortality as compared to TT (valine-valine) individuals. However, there are a few studies which have not been able to find support for the correlation between genotype and activity as observed by Sutton et al. Two studies measuring the MnSOD activity in mitochondrial extracts of erythrocytes have been reported: Bastaki et al. (2006) observed a 33% reduced activity in CC extracts as compared to CT/TT extracts, while Elsakka et al. (2007) detected no difference. The difference between these two studies might be explained by a difference in mitochondrial purification, activity measurement procedures, and sample sizes (Bastaki et al.: 102 males and 129 females and Elsakka et al.: 20 individuals). Moreover, when measuring the MnSOD activity in mitochondrial extracts, the genetic background of the individuals can influence the activity; hence the difference in results may be due to genetic variation. We observe a difference between genders in the effects of genotypes on mortality; the effects are apparently more pronounced in males. Bastaki et al. (2006) observed a 16% decreased MnSOD activity in males as compared to females. Since the proposed hampering of the T variant is only partial and if women, in general, hold a slightly higher MnSOD activity, it can be speculated that the MnSOD activity in female TT individuals could reach a threshold of activity enabling them to overcome (at least in part) the oxidative stress, perhaps resulting in a less severe effect of the increased mortality in TT genotype individuals observed in our study. For GPX1, the activity in males also appears to be lower than in females; Bastaki et al. (2006) reported it to be 7.7% lower, whereas Blankenberg measured a 5% difference (Blankenberg et al., Development ( ) glutathione peroxidase and catalase in humans. Pharmacogenet. Genomics, Bathum, L., Andersen-Ranberg, K., Boldsen, J., Brosen, K., Jeune, B., Genotypes for the cytochrome P enzymes CYP D and CYP C in human longevity. Role of CYP D and CYP C in longevity. Eur. J. Clin. Pharmacol., Blankenberg, S., Rupprecht, H.J., Bickel, C., Torzewski, M., Hafner, G., Tiret, L., Smieja, M., Cambien, F., Meyer, J., Lackner, K.J., Glutathione peroxidase activity and cardiovascular events in patients with coronary artery disease. N. Engl. J. Med., Christensen, K., MuE, M., Yashin, A., Iachine, I., Holm, N.V., Vaupel, J.W., Genetic and environmental influences on functional abilities in Danish twins aged years and older. J. Gerontol. A Biol. Sci. Med. Sci.,Methods Enzymol., "Glutathione peroxidase 1" and catalase in humans. Pharmacogenet. Genomics, "Glutathione peroxidase" and catalase in humans. Pharmacogenet. Genomics, Bathum, L., Andersen-Ranberg, K., Boldsen, J., Brosen, K., Jeune, B., Genotypes for the cytochrome P enzymes CYP D and CYP C in human longevity. Role of CYP D and CYP C in longevity. Eur. J. Clin. Pharmacol., Blankenberg, S., Rupprecht, H.J., Bickel, C., Torzewski, M., Hafner, G., Tiret, L., Smieja, M., Cambien, F., Meyer, J., Lackner, K.J., "Glutathione peroxidase" activity and cardiovascular events in patients with coronary artery disease. N. Engl. J. Med., Christensen, K., Mue, M., Yashin, A., Iachine, I., Holm, N.V., Vaupel, J.W., Genetic and environmental influences on functional abilities in Danish twins aged years and older.