Glutathione and NAC Play Crucial Roles in Health and Fitness

Sulfur is the third most abundant mineral in your body and plays important roles in a variety of bodily processes, including metabolism and detoxification, and for maintaining the proper shape and structure of proteins and enzymes.

Sulfur-containing amino acids increase your levels of glutathione and N-acetylcysteine (NAC), and these two play important roles in health and fitness.

Glutathione Basics

Glutathione comprises three amino acids: cysteine, glutamate and glycine. It's commonly referred to as "the master antioxidant," as it is your body's most powerful antioxidant, and is found inside every cell in your body.

Antioxidants combat free radicals — highly reactive particles that bounce around the cell, damaging everything they touch. Most originate during the process of metabolism but they can also arise during exercise, and from exposure to toxins, irradiation and toxic metals.

Because free radicals are so destructive, cells have a network of defenses designed to neutralize them. This antioxidant network is composed of numerous components that include vitamins, minerals and special chemicals called thiols (glutathione and alpha-lipoic acid).

Glutathione differs from other antioxidants in that it is intracellular, and has the unique ability of maximizing the activity of all the other antioxidants, including (but not limited to) vitamins C and E, CoQ10 and alpha lipoic acid. It also removes toxins from your cells and protects you from the damaging effects of radiation, chemicals and environmental pollutants.

NAC Basics

NAC is a precursor to and rate-limiting nutrient for the formation of glutathione. Glutathione is poorly absorbed so, in many cases, it's easier to raise your glutathione by taking NAC instead.

In emergency medicine, NAC is used as an antidote for acetaminophen toxicity resulting from an overdose. Mortality due to acetaminophen toxicity has been shown to be virtually eliminated when NAC is promptly administered.

It is believed the liver damage acetaminophen causes is largely due to the fact that it can deplete glutathione, which is secreted by your liver in response to toxic exposure.

On a side note, NAC supplementation can also help "pre-tox" your body when taken before alcohol, thereby minimizing the damage associated with alcohol consumption.

Taking NAC (at least 200 milligrams) 30 minutes before you drink can help lessen the alcohol's toxic effects. Vitamin B6 may also help to lessen hangover symptoms.

While the most common use of NAC is for liver support, it's also showing promise as a neuroprotectant. Scientists are currently investigating it as a treatment for Parkinson's disease, which has been linked to glutathione deficiency in the substantia nigra, a region that houses dopamine neurons.

Research looking at autopsied brains suggests Parkinson's patients have barely detectable levels of glutathione in this brain region. Subsequent studies have found glutathione deficiency in the substantia nigra is common in a number of other neurodegenerative conditions as well, including Alzheimer's disease.

Another area where NAC shows particular promise is in the treatment of mental health disorders, including post-traumatic stress disorder, depression and substance use disorders. Dozens of additional health benefits are also reviewed in a November 29, 2019, SelfHacked article.

Glutathione Helps Regulate Epigenetic Disease Mechanisms

One factor that can help explain the wide-ranging benefits of NAC and glutathione is glutathione's role in the regulation of epigenetic disease mechanisms. As noted in a November 2017 paper in Free Radical Biology and Medicine:

"Epigenetics is a rapidly growing field that studies gene expression modifications not involving changes in the DNA sequence.

Histone H3, one of the basic proteins in the nucleosomes that make up chromatin, is S-glutathionylated in mammalian cells and tissues, making Gamma-L-glutamyl-L-cysteinylglycine, glutathione (GSH), a physiological antioxidant and second messenger in cells, a new post-translational modifier of the histone code that alters the structure of the nucleosome.

However, the role of GSH in the epigenetic mechanisms likely goes beyond a mere structural function. Evidence supports the hypothesis that there is a link between GSH metabolism and the control of epigenetic mechanisms at different levels (i.e., substrate availability, enzymatic activity for DNA methylation, changes in the expression of microRNAs, and participation in the histone code)."

The following graphic illustrates how glutathione influences pathological changes in gene expression.

NAC Improves Cardiovascular and Mitochondrial Function

According to a 2018 study, NAC supplementation may be useful for the prevention of cardiovascular problems in older people. As you might expect, oxidative stress can over time induce metabolic and functional changes that speed cardiovascular aging and dysfunction, and your glutathione levels declines with age, putting you at greater risk.

In this study, aging mice received either NAC or a combination of NAC and glycine. After seven weeks, their cardiac function was assessed, showing those receiving NAC plus glycine had improved several parameters of their cardiovascular function, including:

• Improved diastolic function
• Increased peak early filling velocity
• Reduced relaxation time
• Reduced left atrial volume
• Reduced left ventricle end diastolic pressure

NAC alone did not impart these cardiovascular benefits, although both groups had decreased levels of inflammatory mediators. The NAC and glycine combination also improved mitochondrial function and upregulated mitochondrial genes in the heart that are normally downregulated with age.

According to the authors, "Our data indicate that NAC+Gly supplementation can improve diastolic function in the old mouse and may have potential to prevent important morbidities for older people."

Glutathione Deficiency Lowers Vitamin D Levels in the Obese

Other recent research published in Scientific Reports shows that glutathione deficiency can induce epigenetic changes in genes that regulate vitamin D metabolism in the liver. Emerging evidence also suggests glutathione metabolism plays a role in the epigenetic regulation of oxidation-reduction (redox) reactions, the authors note.

According to this paper, obesity has been correlated with low levels of glutathione and 25-hydroxyvitamin D3 — especially in Type 2 diabetics and the obese — and when obese mice were fed a glutathione-deficient diet, it downregulated vitamin D metabolism genes and vitamin D receptors in the liver. As a result, oxidative stress increased.

According to the authors, their findings suggest glutathione supplementation could help reduce the risk of vitamin D deficiency in obese individuals. Supplementation with L-cysteine, a rate-limiting precursor to glutathione, has also been shown to increase vitamin D levels and reduce oxidative stress, the paper notes, which supports the link between glutathione and vitamin D.

Glutathione and NAC Ameliorate Exercise-Induced Stress

As mentioned earlier, exercise is one of the ways through which free radical production increases and, with it, oxidative stress. Provided you get enough rest between bouts, this oxidative stress is actually part of what makes exercise so beneficial.

That said, as noted in a 2005 paper, "Effective regulation of the cellular balance between oxidation and antioxidation is important when considering cellular function and DNA integrity as well as the signal transduction of gene expression." In other words, excessive exercise can cause more harm than good. As explained by the authors:

"Exercise enthusiasts and researchers have become interested in recent years to identify any means to help minimize the detrimental effects of oxidative stress that are commonly associated with intense and unaccustomed exercise. It is possible that a decrease in the amount of oxidative stress a cell is exposed to could increase health and performance...

To protect against the deleterious effects of ROS [reactive oxygen species], our bodies have a complex system of endogenous antioxidant protection in the form of enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Under normal, resting conditions reactive oxygen species are removed from the cell preventing any subsequent damage.

However, under more extreme conditions such as: 1) inadequate intake of foodstuffs containing the antioxidants, 2) excessive intake of pro-oxidants, 3) exposure to noxious chemicals or ultraviolet light, 4) injury/wounds, and/or 5) intense exercise, especially eccentric exercise, the body's endogenous antioxidant system is not able to effectively remove excessive ROS production.

In situations such as the ones listed above in which the production of pro-oxidant molecules increase to a point where the antioxidant system cannot effectively remove them is when oxidative stress is known to occur.

Oxidative stress has been implicated in a number of diseases which include atherosclerosis, pulmonary fibrosis, cancer, Parkinson's disease, multiple sclerosis, and aging. Research on oxidative stress during exercise has begun to indicate that regular training enhances the ability of these mechanisms to effective respond to the increase of oxidative product."

Exercise Boosts Your Glutathione Level

The 2005 paper above goes on to explain how exercise affects your glutathione level, and thus your health, fitness and risk of disease. In short, when you engage in intense exercise, your blood level of glutathione significantly decreases while circulating levels of oxidized glutathione increases, indicating that it's been used inside the muscle to quench free radicals produced during the exertion.

Considering the importance of glutathione to counteract free radicals, effective regulation of glutathione levels when exercising is a significant concern. The good news is that the more you exercise, the higher your base levels of glutathione get.

This adaptation allows your body to effectively deal with the increase in free radicals that the exercise brings about. While exercise itself will boost your glutathione level over time, raising glutathione through supplementation is an oft-used strategy among athletes.

As mentioned, glutathione supplementation is ineffective due to its poor absorption, so NAC is generally considered a much better choice. According to the authors of the 2005 paper cited above:

"In addition to the role glutathione and other thiols have on maintaining the cellular redox state, many studies have begun to explore if NAC supplementation can actually improve performance due to its ability to promote a more favorable cellular environment to achieve higher levels of performance …

One of the first studies to utilize NAC to determine its role in improving muscle performance was conducted by Reid and colleagues. They pretreated subjects with n-acetyl-cysteine infusion (150 mg/kg) or a 5% dextrose placebo while undergoing an extended fatiguing bout of electrical stimulation of the ankle dorsiflexors.

N-acetyl-cysteine was found to have no impact over the nonfatigued muscle, but a significantly increased force output of approximately 15% was found after 3 minutes of repetitive contractions which persisted throughout the 30-minute protocol. The authors concluded that NAC resulted in improved performance suggestive of oxidative stress having a causal role in the fatigue process."

Other studies have also confirmed that NAC supplementation helps delay muscle fatigue during exercise, thereby improving endurance. In one study, NAC infusion increased the time to exhaustion by 26.3%.

NAC's ability to reduce fatigue and improve cellular redox (oxidation reduction) also hints at its potential benefit for those struggling with chronic fatigue syndrome (CFS).

The Glutathione Depletion Theory of CFS

As explained by the U.S. Centers for Disease Control and Prevention, CFS, also known as myalgic encephalomyelitis or ME, is characterized by "overwhelming fatigue that is not improved by rest." The fatigue is frequently such that it challenges your ability to perform even the most common of daily life tasks, such as showering or preparing a meal.

The role of glutathione in this condition is addressed in "A Simple Explanation of the Glutathione/Methylation Depletion Theory of ME/CFS" by the late Rich Van Konynenburg, Ph.D., developer of the methylation protocol used by many in the CFS community.

According to Van Konynenburg, oxidative stress "is probably the best-proven biochemical aspect of chronic fatigue syndrome," and in order for your oxidative stress to overwhelm your system, something must be placing excessive demands on your glutathione supply.

Several examples were already listed above, such as inadequate antioxidant and/or excessive pro-oxidant intake, toxic exposures and physical injuries. Long-term emotional stress can also be a factor. As noted in Van Konynenburg's article:

"All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed.

However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low...

One of the jobs that glutathione normally does is to protect your supply of vitamin B12 from reacting with toxins... When your glutathione level goes too low, your B12 becomes naked and vulnerable, and is hijacked by toxins.