The family of SODs is thought to play a role in aging processes due to their involvement in stress response signaling and their ability to protect cells from ROS (Buettner 2011; Nozik-Grayck et al. 2005). Some studies in model organisms have shown that moderate levels of ROS induce down-regulation of the insulin-like signaling pathway (Brunet et al. 2004; Honda and Honda 1999; Wang et al. 2007). This promotes lifespan extension via the activation of stress resistance, which itself is mediated by an increase in SOD expression (Araujo et al. 2011; Brioukhanov et al. 2006), thereby supporting the hypothesis of hormetic effects (Rattan 2010; Rattan and Demirovic 2009; Ristow and Zarse 2010). In humans, some studies failed to show a correlation between a higher SOD activity and lifespan (Doonan et al. 2008; Yen et al. 2009) and other investigations revealed that SODs enzyme activities are lower in healthy cente- narians compared to nonagenarians (Andersen et al. 1998; Casado et al. 1998; Mecocci et al. 2000). This finding seems counter-intuitive in view of the protec- tive role of enzymes in stress resistance. On the other hand, those results might indicate less oxidative stress in the very old, thus allowing them to live such a long and healthy life. This hypothesis is further supported by studies that have shown a lower extent of oxidative stress in centenarians as compared to nonagenarians (Barbieri et al. 2003; Paolisso et al. 1998). As previous genetic investigations suggested that genetic variation in the SOD genes may influence the proteins’ antiox- idant activity, which could be expected to affect susceptibility to age-related diseases or life span of the individual (Caple et al. 2010; Charniot et al. 2011; Soerensen et al. 2009; Wiener et al. 2007), we investigated whether genetic variation in those genes is associated with longevity in our German study sample.

published findings for rs4880 (Soerensen et al. 2009; Stessman et al. 2005). In order to reduce the number of false-positive results, replication studies in a large independent sample are mandatory. Although no significant association was observed for the tested SNP, the presentation of negative association results provides important and comprehensive information about all obtained findings for the SOD genes. Otherwise, publication bias may occur by selective publishing only positive outcomes. This might lead to over-estimation of the observed effects. For a com- prehensive overview of all obtained research findings both positive and negative results should be published by journals, as already suggested by Dirnagl and Lauritzen (2010) and Ioannidis (2006).

In a case–control study reproducing positive asso- ciation findings represents one of the major challenges. Reasons for replication failures in human longevity research could be the following: Validation of associ- ation results might be hampered by the fact that different sample sizes and age ranges for case and control groups were used. Another reason might be that the associations are population-specific. For example, different findings were observed for rs4880 in several populations. The Jewish sample (Stessman et al. 2005) was much smaller and younger than the German study group and represents a different ethnicity. And even though the German and Danish populations are quite close in sample size, age range and ethnicity, the Danish study was conducted in a prospective manner, which might also explain the different result in our retrospective case–control analysis. Furthermore, varying sets of interacting genetic and environmental factors might induce population-specific effects (Cal- iebe et al. 2010).

Neither in the entire LLI sample nor in the cente- narian subgroup a significant association between the tested SNPs or haplotypes and the longevity phenotype was observed. By tagging an informative subset of common variants and in consideration of haplotype differences, comprehensive information about common SNPs and haplotypes was covered. Additionally, it should be possible to obtain statistical evidence for the effects of rare variants that are captured by one of the common haplotypes (Lin et al. 2004). The possibility that our negative association finding results from population stratification in our sample is unlikely,

For the human longevity phenotype it is well known that most common genetic variants are likely to have only small to moderate effects (Christensen et al. 2006; Deelen et al. 2011; Nebel et al. 2011; Newman

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