The prevailing theory of aging, and of many chronic diseases, has to do with oxidative damage. The idea is that matter likes to be both electrically and magnetically neutral: positive charges balanced with negative charges, and electrons (which are electronegative) like to be paired “spin up” and “spin down,” which cancels out their magnetic potential. All chemical reactions are fundamentally driven by these principles.

Unpaired electrons are called “free radicals.” They will steal another electron from anything nearby, and if they happen to steal it from another electron that previously had a pair, now that electron will scavenge a buddy from anything that happens to be near it… and on the process goes. This process is called oxidative damage, because the substance containing the unpaired electron is “oxidized,” and because the process triggers inflammation. It becomes “reduced” (in electrical charge) once it gets a buddy, and the electrons are paired up again.

The body has a number of different mechanisms by which it “quenches” free radicals like these to prevent unchecked oxidative damage. These are the “redox” (oxidation/reduction) pathways.

How Oxidative Stress Happens

The most common source of free radicals, or oxidative stress, comes from the mitochondria. These little powerhouses take oxygen and the protons from your food, and turn them into water and ATP (the body’s primary energy currency). Healthy mitochondria have very little “leakage” into the surrounding cell, but at least 4-5% of the oxygen that goes in does leak out, turning into free radicals like hydroxyl (OH-), superoxide anion (O2-), hydrogen peroxide (H2O2), hypochlorite (OCI-), and peroxynitrite (ONOO-) free radicals.

With aging, toxicity to the mitochondria, or lifestyle choices such as overeating and lack of exercise, free radical leakage from the mitochondria increases, producing many more endogenous (internally generated) free radicals.

Toxic exposures can also cause exogenous oxidative stress to the rest of the body’s tissues, too, not just to the mitochondria. These include cigarette smoke, medications, pesticides and solvents, and radiation damage.

Enter Glutathione: The Master Antioxidant

Fortunately, the body has a way to deal with oxidative stress when it occurs: glutathione, a peptide of three amino acids (cysteine, glycine, and glutamate). Glutathione can’t do this alone, but it is the star of the redox show—found in most cells at levels comparable to that of glucose, cholesterol, and potassium. This makes it pretty important!

As you probably noticed from the description of oxidative stress, by its very nature, the process is a cycle. Glutathione can only quench one free radical before it needs to be reduced again itself, if it’s to continue to do any good. Two enzymes facilitate this process: glutathione peroxidase (necessary for glutathione to donate its electron to the offender), and then glutathione reductase (necessary to regenerate glutathione so that it can do it all over again).

Healthy cells should have a ratio of reduced to oxidized glutathione at 100:1 or more. Toxic or stressed cells tend to have a ratio closer to 10:1. The body responds to this kind of stress by increasing synthesis of new glutathione to perpetuate the antioxidant process. Elevated levels of the GGT liver enzyme indicate that this is occurring.

Perhaps not surprisingly, since mitochondrial dysfunction and subsequent endogenous oxidative stress is still the primary theory of cellular aging, glutathione levels have been linked to life expectancy.

Glutathione’s Helpers: The Other Antioxidants

When we talk about other antioxidants, we mostly mean the extra compounds that help in the process of glutathione regeneration.

NAC is probably best known for this because it provides cysteine for glutathione synthesis, which is the rate-limiting step in producing more glutathione. Supplementation with it has been shown to drop GGT levels by 25%.

Vitamin E particularly protects lipids from oxidation, like those in the cell membrane, as it is fat soluble. Vitamin C, a water soluble antioxidant, works in concert with Vitamin E, helping to regenerate it once it gets oxidized.

Alpha Lipoic Acid is another water-soluble electron donor, helping to regenerate glutathione as well as Vitamin C, Vitamin E, and CoQ10. CoQ10 might be the most important antioxidant to support mitochondrial function, by the way, since it is the first and rate-limiting step in the chain that ultimately produces ATP. If you’re going to get electron leakage from the mitochondria, most of it happens at this first step.

Selenium is also considered an antioxidant because it is a cofactor for glutathione peroxidase. Several other minerals like zinc and manganese are also important cofactors for the other panoply of peripheral antioxidant enzymes as well.

Interestingly enough, meditation has also been shown to boost glutathione levels by up to 20%! Presumably this is because it gets people out of the sympathetic “fight or flight” mode, which invariably triggers inflammation when prolonged, and into the parasympathetic “rest and digest”.

The Upshot

The bottom line is not so much that the key to anti-aging and reversing chronic disease is antioxidant supplementation—these are systems that the body already has in place as protection against damage both from within and without, and if we’re already healthy, the precursors to keep it going can be found in our food (plus some minimal supplementation, since alas, the soil isn’t what it used to be).

The real key is to keep the mitochondria working as well as possible, which is primarily about avoiding toxic exposures (or detoxing from them after the fact), exercising, and slightly under-eating.

But there are times when the redox systems are already compromised, when supplementation becomes an important part of intervention. Glutathione or NAC are at the top of the list, but glutathione can’t do it alone—make sure that you have all the other major players on board in adequate levels too, testing your levels if necessary.

The Redox (Oxidation / Reduction) Pathways