et al., 2007), we find a slightly lower frequency of TT individuals. This might indicate an antagonistic pleiotropic effect of the SNP in Danes; TT individuals might have an increased mortality from middle age to very old age (as compared to CC and CT individuals), whereas in very old age TT individuals have a survival advantage. On the other hand, the deviation in TT individuals may simple be a chance observation.

Three studies measuring the GPX1 activity (with respect to the rs1050450 GPX1 SNP) in human erythrocyte extracts have been reported; the activity of CT/TT extracts was found to be 9% lower than the activity of CC extracts (Ravn-Haren et al., 2006) and the activity was 13% lower in TT males as compared to CT/CC males (Bastaki et al., 2006), while Forsberg et al. (2000) detected no 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 life span is probably not as straight forward as low ROS levels (possibly ensured by efficient antioxidant enzymes) equaling increased life span. Finally, a slightly more active GPX1 could lead to increased OH(cid:3) levels due to decreased levels of reduced glutathione. Therefore, it can not 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 difference in MnSOD activity in the matrix and hence to 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 O   accumulation in the matrix, which could 2 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 life span 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 difference in mitochondrial purification, activity measurement procedures and in 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

We observe a difference between genders in the effects of genotypes on mortality; the effects are apparently more pro- nounced 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 appear to be lower than in females; Bastaki et al. (2006) reported it to be 7.7% lower, whereas Blankenbergmeasured a 5%difference (Blankenberget 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., M

ue, 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.

, M

–M

Christensen,K.,Johnson,T.E.,Vaupel,J.W.,

Thequestforgeneticdeterminants of human longevity: challenges and insights. Nat. Rev. Genet.

,

–

Cox, D.G., Tamimi, R.M., Hunter, D.J.,

Gene  een Gene interaction between M

OD and GPX-

and breast cancer risk: a nested case-control study. BMC Cancer

,

De Benedictis, G., Carotenuto, L., Carrieri, G., De, L.M., Falcone, E., Rose, G., Caval- canti, S., Corsonello, F., Feraco, E., Baggio, G., Bertolini, S., Mari, D., Mattace, R., Yashin, A.I., Bonafe, M., Franceschi, C.,

Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD

). Eur. J. Hum. Genet.

,

–

de Haan, J.B., Bladier, C., Griffiths, P., Kelner, M., O’Shea, R.D., Cheung, N.S., Bronson, R.T., Silvestro, M.J., Wild, S., Zheng, S.S., Beart, P.M., Hertzog, P.J., Kola, I.,