Polymorphisms in the superoxide dismutase gene reveal no association with human longevity in Germans: a case-control association study. Liljana Gentschew, Friederike Flachsbart, Rabea Kleindorp, Nandini Badarinarayan, Stefan Schreiber, and Almut Nebel tested 19 SNPs in their collection of 1,612 long-lived individuals (centenarians and nonagenarians) and 1,104 younger controls. They also intended to replicate the previous association of the SOD2 SNP rs4880 with longevity observed in a Danish cohort. In their study, no association was detected between the tested SNPs and the longevity phenotype, neither in the entire long-lived sample set nor in the centenarian subgroup analysis. Their results suggest that sequence variation in the SOD genes does not considerably influence human longevity in Germans. The role of SODs in aging and oxidative stress regulation has been widely studied. There is growing evidence that imbalances in these processes influence lifespan in several species.

In humans, genetic polymorphisms in SOD genes may play an important role in the development of age-related diseases. Genetic variation in SOD2 is thought to be associated with longevity. These observations prompted Gentschew et al. to perform a case-control association study using a comprehensive haplotype tagging approach for the three SOD genes (SOD1, SOD2, SOD3) by testing a total of 19 SNPs in their extensive German longevity sample. In addition, they tested the finding for the SOD2 SNP rs4880 in their extended sample set because of the previously observed inconsistent association results with old age.

The accumulation of reactive oxygen species (ROS) causes the alteration of physical or cognitive functions with aging. To date, most of the research on longevity supports this hypothesis. However, some studies have shown that a moderate level of oxidative stress might have positive effects on lifespan as put forward by the hormesis hypothesis. High levels of ROS are responsible for the onset of various common diseases that are associated with a decreased lifespan including hypertension, atherosclerosis, type 2 diabetes, cancer, and Alzheimer's disease. It is possible that long-lived individuals carry beneficial genetic variants in longevity-assurance genes that are involved in stress response signaling or help to protect against oxidative damage caused by free radicals.

Superoxide dismutases (SODs) are one class of molecules with antioxidant properties that remove superoxide from organisms by catalyzing the dismutation of the superoxide radical to hydrogen peroxide. They are a central player in the redox biology of cells and tissues and represent an important endogenous antioxidant defense and signaling system that protects cells from free radicals.

In mammalian cells, three SOD genes have been identified that all have specific functions and cellular distributions: the cytoplasmic copper-zinc SOD1 (CuZnSOD), the mitochondrial SOD2 (MnSOD) and extracellular SOD3 (EC SOD). An overexpression of SOD2 in adult Drosophila melanogaster resulted in an increased lifespan that is proportional to the increased expression of the enzyme. Similar effects were observed in mice overexpressing SOD2 or SOD1, whereas mice with conditional SOD2 deficiency in fibroblasts showed a reduced lifespan and premature onset of age-related phenotypes such as weight loss, skin atrophy, osteoporosis, and muscle degeneration. Mice deficient in SOD3 also displayed a shorter life.

In humans, genetic polymorphisms in the three SOD genes may play an important role in the development of age-related diseases and longevity. The most widely studied SOD single nucleotide polymorphism (SNP) rs4880 is located in the SOD2 gene and results in a T [ C substitution causing an amino acid substitution from valine to alanine. The association results for that SNP are inconsistent. It was found that individuals carrying the T allele have an increased risk for cardiomyopathy, atherosclerosis, coronary heart disease, diabetes mellitus, and lung cancer. Other studies have shown that the C allele is more common in patients with breast cancer, Parkinson's disease, Alzheimer's disease, gastric cancer, and prostate cancer. However, Soerensen et al. indicated that the C allele of rs4880 is significantly associated with decreased mortality in a longitudinal study of 1,650 LLI (age at intake: 92-93 years) from the Danish 1905 cohort. A previous study showed an increased frequency of the T allele in older Ashkenazi male subjects (75 years) compared to younger controls (22 years). Other case-control studies did not show an association between rs4880 and longevity.