A Link Between Antioxidant Enzymes and Aging (GPX1)

Glutathione peroxidase 1 (GPx) is one of the body’s antioxidant enzymes. After the superoxide dismutase (SOD) enzymes convert superoxide into hydrogen peroxide and oxygen, GPx converts hydrogen peroxide and glutathione into glutathione disulfide and water [R].

This entire process gradually converts superoxide (one of the strongest reactive oxygen species) to less and less harmful compounds. GPx is responsible for the final step [R].

Oxidative stress is broadly implicated in aging and age-related diseases, with many researchers outright attributing aging to a deterioration of the body’s antioxidant defenses. This is a controversial and contested topic in the study of longevity, but it’s fairly clear that oxidative stress plays some kind of role in aging [R].

As such, researchers are very interested in the genes that code for antioxidant enzymes, including GPX1.

How Does Oxidative Stress Make Us Age?

According to some research, oxidative stress accumulates and worsens as we age, possibly because of a deterioration of our natural antioxidant defenses (including GPx). Increased oxidative stress opens the door for DNA damage and cell death, which in turn can lead to tissue damage and diseases from cancer to Alzheimer’s [R, R, R].

Some researchers have suggested that this process is enough to account for aging and age-related disease. At the very least, oxidative stress appears to accelerate the process of aging.

Oxidative stress may contribute to DNA damage, cell death, and age-related disease. Glutathione peroxidase (GPx) is one of our most important antioxidant enzymes.

Glutathione is sometimes called the “mother of all antioxidants” because of how essential it is for the body’s antioxidant defenses. It is made of three amino acids — glutamic acid, cysteine, and glycine — and it plays a central role in the function of glutathione peroxidase, which uses it to convert hydrogen peroxide to water [R, R].

Glutathione levels decrease in the human body as we age, and low glutathione levels have been linked to cognitive decline, age-related disease, and general mortality among the elderly [R, R].

Glutathione Peroxidase & Longevity

One study found a direct link between a common GPX1 variant and human longevity. According to a cohort of elderly Danish people born in 1905, the heterozygous genotype ‘AG’ at rs1050450 was significantly more common in the very elderly than in the general population. The authors of the study suggested there could be some kind of survival benefit for the ‘AG’ genotype, but they did not speculate as to why the heterozygote might have an advantage over ‘AA’ and ‘GG’ [R].

That said, other studies and other researchers have strongly suggested that the ‘G’ allele at rs1050450 confers higher GPx activity than the ‘A’ allele, and that higher GPx activity is associated with better health outcomes [R, R].

The heterozygous genotype ‘AG’ at rs1050450 is more common in very elderly Danish people than in the general population, suggesting a possible survival advantage. Generally, the ‘G’ allele produces a more efficient enzyme.

GPX1 Variants & Disease

Multiple GPX1 variants have been associated with various diseases that can significantly shorten a person’s life. 

Three GPX1 (rs1050450, rs3448, and rs1800668) have been linked to cancer so far. People with the ‘A’ alleles of rs1050450 and rs1800668 developed prostate cancer and brain tumors at higher rates than those with the ‘G’ alleles, according to multiple studies. These two SNPs are closely linked, and if you have the ‘A’ allele at one, you very likely also have the ‘A’ at the other. Meanwhile, the ‘CC’ genotype at rs3448 was associated with prostate cancer in another study [R, R, R, R].

Three SNPs, rs1050450 (the ‘A’ allele), rs1800668 (the ‘A’ allele) and rs3811699 (the ‘C’ allele), have also been associated with Kashin-Beck disease (KBD), a bone disease that causes arthritis-like joint pain, enlarged joints, and decreased range of motion. People with KBD tend to have significantly higher oxidative stress and significantly lower selenium than average, suggesting that the disease could be caused (at least in part) by poor GPx activity [R, R].

The ‘A’ allele of rs1800668 was also associated with rheumatoid arthritis in Pakistani people [R].

Finally, the ‘A’ allele of rs1050450 was associated with cardiovascular disease in a meta-analysis of eight studies in East Asian populations. The influence of the ‘A’ allele was considered small, but significant, especially in light of the potential lethality of cardiovascular disease [R].

Multiple GPX1 SNPs have been associated with age- and oxidative stress-related diseases like cancer, Kashin-Beck disease, rheumatoid arthritis, and cardiovascular disease.

The following SNPs have been linked either directly to longevity or to life-threatening diseases, but current research is limited, and the data is incomplete. Future research may produce opposite findings, and the effect of any particular SNP may be limited to a single ethnic group. Use caution when interpreting your results.

SNP Summary and Table

GPX1 rs1050450

• ‘A’ = Associated with cardiovascular disease, Kashin-Beck disease, some cancers, and lower GPx activity
• ‘G’ = Associated with higher GPx activity (AG higher than GG)
• The heterozygous ‘AG’ genotype is more common in exceptionally long-lived Danish people

GPX1 rs3448

• ‘C’ = Associated with prostate cancer (CC genotype)
• ‘T’ = Not associated with prostate cancer

GPX1 rs180068

• ‘A’ = Associated with increased rates of prostate cancer & brain tumors
• ‘G’ = Not associated with cancer

GPX1 rs3811699

• ‘C’ = Associated with Kashin-Beck disease and increased oxidative stress
• ‘T’ = Associated with lower oxidative stress

GPX1 rs8179164

• ‘A’ = Associated with higher GPX1 activity
• ‘T’ = Associated with average GPX1 activity
• Only 1.5% of people in the world have a copy of the ‘A’ allele, which is slightly more common (5.4%) among Europeans and almost nonexistent in Africans and Asians.