Image by Devon Breen from Pixabay

I wrote here on the concept of oxidative stress, and its relevance to aging and chronic disease. But it’s also important to note that oxidative stress occurs as an unavoidable part of normal life—not just toxic exposures, but also the act of converting food and oxygen into energy (via your mitochondria). 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.

When this happens, the main molecule already on the scene to clean up the damage is glutathione. It’s in nearly every cell of your body, in high concentrations. 

Or at least it should be. 

Glutathione Levels Decline Over Time

Newton’s Second Law of Thermodynamics states that everything proceeds from order to chaos over time, a process also known as entropy. Unfortunately, this applies to every one of our bodily processes too, including our glutathione concentrations. There is a marked decline of glutathione in our bodies with age—though whether this is due to fewer precursors to make it, slower enzymes to produce it, slower enzymes to regenerate it, higher demand due to increased exposure to oxidative stress, less efficient mitochondria, or a combination of all of the above is unclear. (My money is on all of the above!) 

Anything else that might increase demand for glutathione besides the ordinary process of being on the planet longer can do it too, though. Inflammation is a big one. 

Inflammation —> Oxidative Stress —> Depleted Glutathione 

I’ve often heard inflammation blamed as the root cause of all illness. I don’t think that’s quite true (more on this here), but it certainly is the case that chronic inflammation is a major driver of disease. Part of this is because the inflammatory process is inherently pro-oxidative: that is, it produces free radicals on purpose, in an effort to kill off foreign invaders. In its place, this is great—very much like fire. You want it in your fireplace. You don’t want it burning down your house. 

An example of “good” oxidative stress is exercise. It’s contained, and because it ultimately helps to maintain the balance in the mitochondria between energy coming in and energy output, the net effect is definitely a win. 

“Bad” inflammation and oxidative stress would certainly be autoimmunity, such as Rheumatoid Arthritis. This study shows that subjects with RA had 50% less glutathione than healthy controls. The same is true for other autoimmune conditions, and inflammatory conditions generally.

Toxic exposures are also certainly in the bad category too (and they can potentially lead to diagnosable conditions, of course). Electromagnetic Fields (EMF) are a modern toxin clearly associated with oxidative stress and thus, glutathione depletion, though there are many, many others as well. 

We live in a toxic world. (I wonder how much faster glutathione levels are depleted today, compared to decades past.)

The Brain and the Liver: Especially High Demand

Speaking of toxicity, the highest cellular concentration of glutathione is found in the liver, as it is a critical component of the body’s detoxification strategy. Glutathione neutralizes toxins, rendering them harmless for purposes of elimination. 

The second highest concentration of glutathione is in the brain. This is because even though the brain only comprises 2% of your body weight, it consumes 20% of your oxygen. Oxygen gets turned into ATP via the mitochondria. This means that even if those mitochondria are perfectly healthy, since some 4-5% of it still leaks out, lots of free radicals are produced too. And that means a very high demand for glutathione. 

This increased demand in the brain is no doubt the reason why so much glutathione research has centered on various neurodegenerative diseases, such as Parkinson’s, Alzheimer’s, ALS, and autism. All of them are associated with significantly decreased levels of glutathione.

Undermethylation and Glutathione 

And speaking of autism, many children on the spectrum also suffer from methylation defects. This likely only compounds the problem of oxidative stress, since the methylation pathway also produces glutathione. 

Glutathione Repletion 

There’s some debate over the best way to boost glutathione levels. As mentioned earlier, there’s a number of possible reasons why it might be low. One indirect approach might be to simply support the other antioxidants that help to regenerate glutathione. This can be done with diet, increasing especially colorful fruits and veggies. (A good rule of thumb for produce is, the more intense the colors, the higher the antioxidant content!) A good multivitamin is also advisable. 

Another approach is to supplement with the precursors to glutathione. Glutathione is a tripeptide comprised of the amino acids glycine, cysteine, and glutamate. Of these, the least abundant is cysteine, so N-Acetyl Cysteine (NAC) is often preferred as a precursor supplement. In my experience, in many cases, NAC is effective in increasing glutathione levels (and not terribly expensive). This study also shows that supplementation with dietary precursors cysteine and glycine is helpful. 

Oral supplementation with glutathione itself is controversial, because it’s not absorbed very well. Part of this is because it’s a highly reactive molecule. Also, if you take it orally, once it gets to your gut, it will be broken down into its constituents, and then your body gets to decide what it wants to assemble with them. It may reassemble glutathione, or it might make something else entirely. (The same is true of the precursors themselves too, of course, but they have the benefit of being much cheaper.) That said, reduced glutathione oral supplements do show efficacy too—I just wonder if it’s any better than just taking the individual precursors. 

Some try to get around the problem of glutathione delivery by encapsulating it in a liposomal form. This too appears to boost glutathione levels at least to some degree. Liposomal glutathione is particularly utilized as a skin delivery method; however, in my interview with Dr Nayan Patel, he argued that lipid absorption through the skin is “slow and sticky,” and not terribly efficient. His preference is a water-based topical glutathione approach, which use the “highways” of the pores for more rapid absorption.

Another approach is sublingual, often preferred to oral supplementation for many things, as it bypasses the gut and thus allows more rapid and less encumbered absorption. This study compared sublingual glutathione to oral or precursor supplementation, and found a significant improvement in absorption.

IV glutathione of course also bypasses the gut, delivering the whole molecule intact to the bloodstream—but the body can only use so much glutathione at any given moment. Thus, while the initial effects may be very impressive, they’ll typically only last a few hours, and you’ll pee out whatever you don’t use. These can be quite pricey, if you do them often.

The Upshot

We’re surrounded by toxic insults, and oxidative stress, even if we’re healthy. While I believe that the foundation of any healthy lifestyle is a whole foods-based (unprocessed) diet full of lots of produce in a wide range of colors, it certainly makes sense to add in some additional antioxidant support.