How is this Antioxidant Gene Connected to Longevity? (SOD3)

SOD3 codes for an enzyme called extracellular superoxide dismutase. It is a member of the superoxide dismutase (SOD) family, whose job is to take molecules of superoxide (a strong oxidant) and transform them into hydrogen peroxide and oxygen (weaker oxidants). This process is part of the body’s natural antioxidant defenses [R].

On the whole, the SOD family of enzymes differ primarily in their location. SOD1 is located in the cytoplasm, or the cellular fluid, SOD2 is located in the mitochondria, and SOD3 is located outside of the cell — hence the name “extracellular superoxide dismutase.” Another major difference is that SOD2 requires manganese to function, while SOD1 and SOD3 depend on copper and zinc [R, R].

For now, much of the research on longevity and SOD3 is limited to a single human study and a series of mouse studies. Furthermore, the mouse studies found contradictory evidence; some found that inserting human rs1799895-C SOD3 into the mouse genome protected against airway inflammation, while others found that the same procedure accelerated aging and decreased lifespan [R, R].

The only association study to find a link between SOD3 and human lifespan discovered that rs2536512 predicted age at death in a group of just over 1000 participants. In this study, people with the ‘GG’ genotype lived slightly longer than those with the ‘AG’ genotype, and those with the ‘AG’ genotype lived slightly longer than those with the ‘AA’ genotype. The total difference in age at death between ‘GG’ and ‘AA’ was about a year and a half (88.9 vs. 87.4) [R].

A single human study found that people with the ‘GG’ genotype at rs1799895 lived about a year and a half longer than those with the ‘AA’ genotype.

A Weak Link?

The connection between SOD3 and longevity is broadly speculative at this point. Researchers have found an association between variants at this gene and longevity in mice, but the search for a human connection hasn’t borne much fruit so far. In fact, at least one study of known SOD3 variants found no correlation at all with longevity in German volunteers [R].

That said, there’s a reason why researchers keep looking. While studies on variants in the human SOD3 gene haven’t yet turned up a direct correlation with lifespan, such variants do appear to influence:

• Risk of dying from COPD [R]
• Lung injury and mortality [R]
• Stroke in women [R]

Furthermore, low SOD3 levels have been associated with polyneuropathy in people with diabetes [R].

These are all potentially life-threatening conditions. Thus, the search goes on for a more direct link between SOD3 and lifespan.

Evidence of direct links between SOD3 and longevity is sparse, but variants in SOD3 have been linked with mortality rates from COPD and lung injury as well as cerebral infarction, a type of stroke.

It’s important to note that certain genotypes being associated with longevity doesn’t necessarily mean that everyone with that genotype will live an exceptionally long life! Many different factors, including other genetic and environmental factors, are believed to influence longevity.

SNP Summary and Table

Primary SNP:

SOD3 rs2536512

• ‘A’ = Associated with slightly younger age at death
• ‘G’ = Associated with slightly older age at death
• About 40% of all people have the ‘GG’ genotype associated with oldest age at death

Other SNPs under investigation:

SOD3 rs1799895

• ‘C’ = Associated with stroke (cerebral infarction) in women
• ‘G’ = Not associated with stroke (cerebral infarction)
• Only about 5% of the global population has a copy of the apparently protective ‘G’ allele
• C-C-C haplotype at rs1799895, rs13306703, rs699473 most strongly associated with stroke in women
• Other studies have found that ‘G’ was linked with heart disease; effects appear to be mixed.

SOD3 rs13306703*

• ‘C’ = Associated with stroke (cerebral infarction) in women
• ‘T’ = Not associated with stroke (cerebral infarction)
• About 76% of all people have at least one copy of the ‘C’ allele
• C-C-C haplotype at rs1799895, rs13306703, rs699473 most strongly associated with stroke in women

SOD3 rs699473

• ‘C’ = Associated with stroke (cerebral infarction) in women
• ‘T’ = Not associated with stroke (cerebral infarction)
• About 78% of all people have at least one copy of the ‘C’ allele
• C-C-C haplotype at rs1799895, rs13306703, rs699473 most strongly associated with stroke in women

SOD3 rs8192287

• ‘G’ = Not associated with lung disease
• ‘T’ = Associated with COPD, acute lung injury, and mortality
• Only about 14% of all people have at least one copy of the detrimental ‘T’ allele

SOD3 rs8192288

• ‘G’ = Not associated with lung disease
• ‘T’ = Associated with COPD, acute lung injury, and mortality
• Only about 14% of all people have at least one copy of the detrimental ‘T’ allele