A basic summary of SOD2 – cleaning up cellular waste
Superoxide dismutase (SOD2) is an enzyme that rids the body of superoxide, a harmful free radical thought to cause oxidative stress (R). SOD2 processes “bad” superoxide into “better” hydrogen peroxide and diatomic oxygen, both of which are much less harmful to our bodies than is superoxide.
You can think of superoxide as a mitochondrial waste product (R). When mitochondria produce energy, they leave superoxide in their wake, similar to exhaust from a car. Left unchecked, this waste can accumulate in the body and lead to oxidative stress, which causes cellular damage and, over time, heightened risk of disease.
The figure below, from the Biochemical Journal 2009, explains this process (R). “ROS” stands for reactive oxygen species. In the same way that quercetin is a type of antioxidant, superoxide is a type of ROS.
Luckily, our bodies have a solution to the superoxide problem. Rather than letting this superoxide waste stick around in a hazardous form, SOD2 converts cellular waste into forms less damaging to our cells, in effect cleansing our bodies. Put simply, SOD2 is good, and superoxide is bad. When our bodies have decreased ability to produce SOD2, it can leave us more vulnerable to disease as we have a diminished ability to naturally sweep away free radicals (R).
SOD2 A16V is a gene prominently listed on many genetic reports, such as Genetic Genie, StrataGene, and others. It is commonly mentioned in discussions about genetics and nutrition because there is a good bit of clinical data addressing SOD2, and the associated health risks of mutations.
Before I delve into the implications of a SOD2 A16V mutation, I want to start the post by including an email snippet from a good friend, who is much smarter than I am, and who gave an excellent summation on the impact of a SOD2 A16V mutation in a discussion we were having on the subject of genetics and nutrition. My friend, Jennifer, is a research scientist at a prestigious Infectious and Inflammatory Diseases Center in Southern California.
Here is what she had to say about SOD2 A16V.
SOD2: a scientific overview, and antioxidant function
“I want to go over a couple of things about SOD2 and its role in nutrition. I think there’s a slight difference in understanding what the gene does from the everyday perspective, versus the biological mechanism of the gene.
There are three basic mechanisms of antioxidants:
enzymes that degrade free radicals
proteins that can bind to metals, thus making them unable to stimulate the production of free radicals (transferrin)
antioxidants like vitamins C and E that act as free radical scavengers
SOD2 falls into the first category, breaking down free radicals, but not for anything usable. It’s role is simply to break down free radicals to prevent them from causing oxidative stress, which has been shown to be important pathophysiologically in diabetes, breast cancer, chronic kidney disease, and several others. The nutrition part that you’re looking for here isn’t in SOD2 itself and what it metabolizes, but that it has protecting effects against free radicals that can cause oxidative stress.
The mutation in the A16 SNP results from the fact that MnSOD has a substitution at the 16 position from valine to alanine (in scientific community this SNP is actually called MnSOD Ala16Val polymorphism, it’s been shorted by your everyday bloggers). This conformational change decreases the transport efficiency of the enzyme into the mitochondria. It also produces a β-sheet instead of an α-helix structure that reduces MnSOD activity. So the total antioxidant levels in people with this polymorphism would likely be down, along with the total antioxidant capacity (TAC), Lower antioxidants –> higher levels of free radicals –> increase in oxidative stress.
Within this SNP there are a couple of different genotypes:
Ala/Val (or CC or GG in some cases) genotypes have a protective role (maybe, see below).
Ala/Val (CT) genotypes – Val carriers are less resistant to oxidative stress because of the limited antioxidant potential that I talked about in the paragraph above.
Val/Val (TT) genotypes – studies showed that this genotype, in combination with low free radical scavenging from antioxidants from group 3, could lead to glucose intolerance. In patients with diabetes this was the most common genotype. The association between the Val/Val genotype and diabetes is significant.
The big association with these mutations is actually with diabetes. Low TAC levels combined with high blood glucose can increase oxidative stress and activate stress pathways.
MnSOD can be modulated by dietary factors, but again that looks more at the other total levels of the antioxidants. In this case, because the group 1 is not as efficient, you would try to boost group three, by adding in antioxidants that are free radical scavengers.”
Studies linking oxidative stress to disease
Remember, the main issue for SOD2 A16V mutations is oxidative stress caused by a diminished ability to process superoxide into a less toxic form. As Jennifer establishes above, this can mean greater oxidative stress.
Several studies suggest that oxidative stress may play direct and indirect roles in human disease. I’ve included two studies below, but this list is obviously far from exhaustive.
A study done at the Salk Institute in San Diego, CA reported in Cell that Amyloid beta protein (A beta), an amino acid peptide associated with plaques in the brains of Alzheimer’s patients, often results in free radical damage and caused increased levels of H2O2 (hydrogen peroxide) to accumulate in cells. They showed that A beta was cytotoxic to neurons from the free radical damage and that H2O2 degrading enzymes (such as SOD2) protected the cells from A beta toxicity (Hydrogen peroxide mediates amyloid beta protein toxicity Behl C, Davis JB, Lesley R, Schubert D. Cell. 1994 Jun 17;77(6):817-27.)
Another study from the Center for Translational Medicine at Thomas Jefferson University showed that uncontrolled oxidative stress in systemic lupus erythematosus (SLE) can trigger autoimmunity (Oxidative stressand its biomarkers in systemic lupus erythematosus Shah D, Mahajan N, Sah S, Nath SK, Paudyal B. J Biomed Sci. 2014 Mar 17;21:23).
SOD2 A16V – is GG the “risk allele?”
When you pull SOD2 A16V information from Genetic Genie, two copies of the G allele are listed in red, as the risk allele. It would appear that two copies of the G allele would denote a “SOD2 A16V homozygous mutation.” However, running the same 23andme report through Dr. Ben Lynch’s Strata Gene tool, the GG allele is listed in green as the “wild” allele.
Why the discrepancy?
Here is what Dr. Lynch has to say about the issue:
In general, kinetic research on SOD2 A16V (rs4880) is contradictory and in at least two cases, results have failed to be reproduced in similar populations by other investigators. This may be in part be due to how alleles were attributed in the early literature. In some cases, Ala was said to code for cysteine (C), and in others Ala was attributed to code for thymine (T). This confusion muddies the waters for data interpretation. There are also discordant results for kinetics. In vitro rat liver cell results shows the CC variant as being 40% faster, although some researchers doubt the veracity of testing methods. One in vivo human study showed the opposite, TT is faster. After review of studies done from 2015 forward, the rs4880CC (GG in 23andMe) appears to be the riskier allele to inherit, as it appears to have slowed activity in vivo.
Dr. Lynch acknowledges just how confusing genetic research can be due to the lack of uniform naming conventions, even within the scientific community. In this case, the risk allele, GG, has also been called CC in past studies. A reasonable interpretation of Dr. Lynch’s notes would lead one to believe that there is some ambiguity as to the actual riskiest allele to inherit, although it does seem that the consensus is leaning towards GG.
Health and lifestyle implications
There are already numerous websites that list the parade of terrible conditions that have been associated with SOD2 mutations, so I will keep my list here short, especially because SOD2 is only one SNP, our bodies act in concert with the totality of our genetics, as well as with our environment. It’s never a good idea to freak out over one gene.
Mutations in this gene have also been associated with idiopathic cardiomyopathy (IDC), premature aging, sporadic motor neuron disease, and cancer (R). How fun! For more information related to decreased levels of SOD2, this WikiGenes page is a great resource to continue your research.
Are there studies that show any promise with increasing SOD2 levels? SOD supplements are widely available, but without understanding what mutation you have, they might not be effective. People with a mutation in SOD2 who take the currently available SOD supplements won’t necessarily see a difference since these targets the cytosolic SOD1.
Are there supplements, other than SOD, that can be taken to reduce oxidative stress?
For example, this study, performed on mice, showed promising results for curcumin’s ability to reduce oxidative stress. Authors of the study found reduced aortic superoxide production in both young and old treated animals to levels below young control values (R). So essentially, this curcumin study found supplementation turned back the clock on mouse heart health. To quote the study:
Antioxidant expression of MnSOD was reduced in old compared to young control mice, and curcumin supplementation increased MnSOD expression in old mice to levels not significantly different from young control animals.
This study found curcumin as an effective nutrient for reducing oxidative stress in patients taking Cisplatin (R).
For a complete list of nutrients proven to impact function of SOD2, take a look at this SOD2 resource page.
The SOD2 A16V gene is fascinating. It helps regulate our body’s ability to dispose of cellular waste, protecting us from oxidative damage. The scientific implications of the “riskiest” alleles appear to be far from settled, however, there is mounting evidence that the GG allele carries increased risk.
We will continue to update this page over time, please share your stories in the comments section.
John O'Connor is the founder of Gene Food. He is passionate about nutrition, genetics, and wellness and uses this blog to publish self experiments as well as some of the research that the Gene Food team does internally to highlight stories of bio-individuality.