Can Antioxidant Defenses Increase Lifespan? (SOD2)

SOD2 (also called MnSOD) is one of the superoxide dismutase enzymes, alongside SOD1 and SOD3. SOD2 is unique in that it requires manganese (Mn) to work, where the other two need copper and zinc [R].

The superoxide dismutase enzyme family transforms superoxide, a powerful oxidative agent, into hydrogen peroxide and oxygen, which are significantly less reactive oxygen species. SOD2 performs this role inside the mitochondria; hydrogen peroxide can then diffuse out of the mitochondria, where it will be further transformed by the cell’s antioxidant machinery [R].

Thus, SOD2 is a central and essential part of the antioxidant defense mechanisms of the body. Reduced SOD2 activity is associated with increased oxidative stress and degenerative disease [R].

SOD2 is a member of the superoxide dismutase enzyme family. It transforms superoxide into hydrogen peroxide and oxygen in the mitochondria.

SOD2, Disease, and Mortality

SOD2, and the rs4880 variant, in particular, has been implicated in an impressive number of diseases and medical complications. However, the relationship isn’t straightforward; the ‘A’ allele is more common in people with cardiomyopathy, atherosclerosis, and lung cancer, while the ‘G’ allele is more common in people with breast, prostate, and colorectal cancers, hypertension, sporadic motor neuron disease, Parkinson’s disease, and Alzheimer’s disease [R].

One would think that the relationship should be simple: increased SOD2 activity means lower oxidative stress, which should in turn protect against disease. Researchers disagree about why this apparent contradiction exists; some studies have found that temporary increases in oxidative stress have beneficial effects on health. Thus, some researchers have suggested that somewhat reduced SOD2 activity might actually be good in some cases. Research is ongoing [R, R]

The rs4880 variant of SOD2 has been linked to many conditions and diseases. The relationship is complex, with each allele associated with different diseases.

Aging & Neurodegeneration

Researchers are fairly confident that SOD2 plays an essential role in maintaining the function of neurons both in the brain and in nerves in the rest of the body. In fact, SOD2 seems to be disproportionately important for neurons compared to other types of cells [R].

Over the course of our lives, our bodies’ antioxidant mechanisms decline in efficiency, leading to a gradual decrease in neuron function. Higher SOD2 activity appears to maintain neuron function for longer; some researchers contend that higher SOD2 activity therefore delays neurodegenerative disease [R].

Amyotrophic lateral sclerosis (ALS) has a median survival time of 2-3 years, while people with Huntington’s disease typically survive another 25 years after diagnosis; however, neurodegenerative diseases are generally fatal, given that the human body cannot survive the destruction of its nervous system [R].

SOD2 protects against neurodegenerative disease, and researchers believe that more SOD2 is better for this purpose.

Two variants in the SOD2 gene have been directly associated with longevity so far. The rs4880 variant has been studied the most intensively, but the results have been complex and somewhat contradictory.

One study of Danish people born in the year 1905 found that the ‘G’ allele was more common in the very elderly. However, another study found that the ‘A’ allele was much more common in very elderly Ashkenazi Jewish men [R, R].

Some researchers have suggested that one allele or the other may be more beneficial depending on other genetic and environmental factors [R].

Contradictory Results?

Such a complex relationship with longevity also makes sense in the context of other apparently contradictory research on rs4880 and measurements of SOD2 activity and oxidative stress. Some cell studies have found that rs4880-G SOD2 crosses the mitochondrial membrane more easily, leading to higher enzyme activity in the mitochondria. However, a study in humans found that people with rs4880-A had higher SOD2 activity and better protection from oxidative stress [R].

Given all of this apparently contradictory evidence, it’s helpful to look at the SOD2 variants’ relationships with dangerous conditions. The ‘G’ allele has been associated with more and worse diseases, including cancers, hypertension, and neurodegenerative disorders [R].

The ‘G’ allele has also been linked with noise-induced hearing loss, ear toxicity from cisplatin treatment, infertility, and worse lung damage after phthalate exposure [R, R, R, R].

These relationships further support the growing consensus that the ‘G’ allele confers less protection from oxidative stress than the ‘A’ allele.

Despite some contradictory evidence and with some exceptions, the growing consensus is that ‘G’ is the risk allele of rs4880.

A Second SNP

While rs4880 gets most of the spotlight in SOD2 research, a second SNP, rs2758331, has also been associated with lifespan. In one study of exceptionally long-lived people in New England, the ‘C’ allele of rs2758331 was significantly more common in the oldest old than in the general population [R].

This SNP is nowhere near as well-studied as rs4880, and only a single study has investigated its effect on lifespan so far. Furthermore, while the ‘A’ allele of rs2758331 has been associated with prostate cancer (thereby supporting the idea of a beneficial ‘C’ allele), the ‘C’ allele has been associated with liver damage after bisphenol A (BPA) exposure [R, R].

Additional research is required to fully untangle the effect of rs2758331 on SOD2 activity and lifespan.

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. 

Furthermore, keep in mind the complex relationship between SOD2, longevity, and disease in different ethnic groups. If you are not descended from the groups discussed in these studies, the results may not apply to you!

SNP Summary and Table

SOD2 rs4880

• ‘G’ = More common in very elderly Danish people, but less common in very elderly Ashkenazi Jewish men. Decreased SOD2 activity & increased oxidative stress.
• ‘A’ = Less common in very elderly Danish people, but more common in very elderly Ashkenazi Jewish men. Increased SOD2 activity & decreased oxidative stress.
• The growing consensus identifies ‘G’ as the risk allele, despite the Danish cohort
• About 20% of all people have the ‘GG’ genotype

SOD2 rs2758331

• ‘C’ = More common in exceptionally long-lived people
• ‘A’ = Less common in exceptionally long-lived people
• About 14% of all people have the ‘AA’ genotype
• rs4880-G is disproportionately inherited with rs2758331-A, further supporting the hypothesis that rs4880-G is detrimental.