What is glutathione?

Glutathione is often referred to as the body's master antioxidant. It is a tripeptide, i.e. a very small protein composed of three amino acids - cysteine, glycine, and glutamate.

Glutathione can be found in almost every cell of the human body, the highest concentration being in the liver, and is vital in the body's detoxification process. 

Glutathione is also an essential part of the body's natural defence system. Bacteria, viruses, radiation, heavy metal toxicity, certain medications, and even the normal ageing process can all cause free radical damage to healthy cells and deplete glutathione levels. When the accumulation of free radicals exceeds the body's ability to neutralise and eliminate them, oxidative stress occurs. A primary function of the master antioxidant is to alleviate this oxidative stress and protect our cells, mitochondria and other organs from further damage.

Glutathione also boosts the utilisation and recycling of other antioxidants inside the cell, such as vitamins C and E, alpha lipoic acid and CoQ10.

There are two different forms of glutathione:

1. Reduced glutathione (GSH, or L-glutathione), which is the active form

2. Oxidised glutathione (GSSG), the inactive form

When GSH protects the cellular environment and donates its electrons to help neutralise oxidative stress, it becomes oxidised and inactive, turning into GSSG.

Inactive GSSG can then be recycled back into active GSH, through an enzyme called glutathione reductase. This is known as the homeostatic glutathione redox cycle. If this enzyme becomes overwhelmed and too much oxidised GSSG accumulates (compared to the active GSH), cells become susceptible to damage.

GSH is under tight homeostatic control both inside and outside the body’s cells. A balance is maintained between GSH synthesis, its recycling from GSSG (oxidised glutathione), and its utilisation. This balance is vital for stabilising and facilitating cellular performance and survival.

Why is glutathione important?

Glutathione's role as an antioxidant

Antioxidants are our body’s natural protectors against free radical damage and oxidative stress. Oxidation occurs naturally within our body as our cells process the oxygen we breathe and convert it into energy. In most cases, the process of oxidation causes damage or destruction.

Oxidation also creates free radicals, which are highly reactive molecules that are missing an electron. These free radicals can be produced by factors such as smoking, pollution, chemicals and UV light exposure, as well as from normal physiological processes in the body like metabolism. These unstable molecules seek out to steal an electron from other molecules to ‘neutralise’ them, while causing damage to other healthy cells. Antioxidants, like glutathione, work to counteract the damage caused by free radicals.

As the body’s master antioxidant, glutathione is a strong electron donor and works by directly binding to these oxidative molecules that damage cell membranes, DNA, energy production, etc., and neutralising them (1).

Glutathione's role in detoxification

As humans, we have a built-in natural detoxification system that works on a deep cellular level. This is the glutathione system (2). By strengthening the glutathione system, we support all three phases of detoxification, but in particular phases II and III:

Detoxification has three phases, mostly occurring in the liver.

1. Phase 1: During this phase, toxins, smoke, alcohol, caffeine, dioxin, drugs, radiation, heavy metals, pesticides, and other carcinogens are partially processed by particular proteins inside the mitochondria of the liver. These partially processed toxins, aka ‘intermediates’, are even more dangerous free radicals than when they were in their original form, so need to be further processed by phases II and III before they cause further damage. They are not only damaging, but they can also deplete glutathione, creating an imbalance between phase 1 and phase 2 activity.

2. Phase 2: During phase 2, various enzymes work directly on the toxic intermediates produced in phase 1, such as heavy metals and other toxins, by binding them with protective compounds. This helps to neutralise and inactivate the toxins, making them more water-soluble and ready for elimination. This binding is called ‘conjugation’ and glutathione is the main player.

3. Phase 3: Once the toxins have been conjugated, they are ready to be eliminated from the body, mainly via the kidneys (urine) and liver (bile).

Glutathione's role in energy production

Energy production occurs within all cells in the body (except red blood cells) inside mitochondria. Mitochondria are the ‘powerhouses’ of each cell, converting food into ATP to be used for all of our cells’ energy needs.

Glutathione is involved in protecting mitochondria from oxidative stress (3). If mitochondria are damaged by oxidative molecules, they slow down their production of ATP, resulting in less energy production and causing the rest of the cell to under-function and become sluggish.

When mitochondria get damaged, they also create more free radicals. As a result, these free radicals cause further mitochondrial damage and create a vicious cycle of less energy and more damage.

Stress also plays a role in energy production. The higher our energy needs (higher metabolism, exercise, stress, etc.), the harder the mitochondria have to work and the more free radicals they produce.

GSH binds these free radicals and neutralises them, reducing oxidative stress on both the mitochondria and the rest of the cell. If this process is overwhelmed and the ratio of GSH/GSSG becomes out of balance, symptoms such as fatigue, lack of mental focus, brain fog, muscle fatigue, and aches and pains can manifest.

Restoring active glutathione levels and the ratio of active reduced to inactive ‘oxidised’ can correct some, if not all, of the energy depletion.

Glutathione and age defence

As we age, the production of glutathione naturally declines in our body. When low levels of glutathione are detected in the body, it can cause our cells to become damaged, breakdown and even die.

As the master antioxidant plays a critical role in cellular and mitochondrial health, it has an impact on our overall health and longevity, helping us to look and feel younger. Its antioxidant properties protect cells from damage, and its role in detoxing prevents a build-up of toxins that would have contributed to oxidative stress and damage to our body.

Many of the common signs of ageing and chronic conditions including heart disease, Alzheimer’s disease, and diabetes are associated with decreased levels of glutathione (4).

Therefore, the more glutathione we have in the body, the healthier our cells and mitochondria are, and the less likely we are to have cellular breakdown, increased risk of disease, and cellular death.

Glutathione benefits 

Glutathione and brain health

As we age, neurons in our brain become damaged or even die, leading to neurodegeneration. Certain disorders that have accelerated neurodegeneration, such as Alzheimer's and Parkinson's Disease, are shown to have high levels of oxidative stress and low levels of glutathione (5). One of the many benefits of glutathione, thanks to its antioxidant action, is that it  can help to slow down the degeneration process and damage to the brain tissue. 

Glutathione and immunity

Glutathione supports the strength of our immune system and protects against invaders and infections.

It has been shown that active glutathione (GSH) primes our white blood cells (lymphocytes) (6) that are responsible for our body’s first line of defence (Natural killer and T cells), and enables T cells to produce more substances that fight infections, helping to control both bacterial and viral infections.

GSH also works to modulate the behaviour of many cells in the immune system, helping to strengthen the innate and adaptive immunity as well as protecting against microbial, viral and parasitic infections (7).

Glutathione and inflammation

Environmental toxins, diet, stress, infections, and other lifestyle factors can cause an imbalance within the body, resulting in chronic, systemic inflammation. When this happens, the body needs extra protection.

Glutathione has been shown to control the increase and decrease of inflammation by instructing and influencing our immune cells (7). Autoimmune diseases have also been associated with imbalanced glutathione levels. Rebalancing glutathione levels can restore immune system function and bring chronic inflammation under better control.

Glutathione and the cardiovascular system

Glutathione can play a role in preventing heart attacks and stroke due to its ability to neutralise the ‘lipid oxidation’ process (8). LDL cholesterol in the blood can become ‘lipid oxidised’ and form plaque (atherosclerosis) which can build up on the walls of the blood vessels, causing damage to the lining. If these plaques become ruptured and break off, they can inhibit blood flow and cause heart attacks or strokes.

The enzyme glutathione peroxidase can help glutathione to deactivate the compounds and free radicals that cause this lipid oxidation, helping to prevent damage and lower the risk of heart attacks.

Glutathione and athletic performance

It appears that glutathione can boost athletic performance when used before workouts, helping to improve performance, reduce fatigue, and lower blood lactic acid levels (9). This is important as increased lactic acid in the body can result in fatigue, low blood pressure, muscle aches, a drop in body temperature, and respiratory problems.

Glutathione and skin

Sun, wind, UV rays and exposure to toxins in the environment can cause damage to skin overtime, resulting in dry, wrinkled skin and age spots. Glutathione plays a role in supporting cells in healing and regenerating themselves, helping to reduce the appearance of wrinkles and improve elasticity of skin. One study found that glutathione worked in achieving the skin lightening effect, which appears to be very gradual and will take weeks to develop (10).

Some studies have shown that glutathione can decrease the melanin (pigmentation) of skin. Glutathione works on skin pigment production mainly by inhibiting the enzyme that is involved in the process of making melanin, tyrosinase (11).

Glutathione deficiency & depletion 

Causes of glutathione deficiency

The natural ageing process is one of the main factors when it comes to reduced glutathione levels in the body, as our production decreases with age.

Other factors that can deplete glutathione levels include:

• Poor diet
• Chronic exposure to chemicals, pollution and toxins
• Alcohol and smoking
• Impaired immune system and infections
• Lack of exercise
• Stress
• Certain medications
• UV radiation exposure

Certain illnesses are also known to decrease glutathione levels. Some of the more common low glutathione-related diseases are:

• AIDS/HIV
• Parkinson’s disease
• Alzheimer’s disease
• Diabetes
• Heart disease
• Hepatitis
• Cancer
• COPD
• Liver disease
• Macular degeneration
• Stroke
• Infertility

Effects of glutathione deficiency 

Low levels of glutathione can contribute to a variety of negative health effects.

Glutathione deficiency and depletion can make us vulnerable to oxidative stress and inflammation, both of which can lead to chronic illness and accelerated ageing. If we don’t have enough glutathione then we can’t protect our cells’ mitochondria from damage, which can result in feeling fatigued as mitochondria are less efficient when they get oxidised.

Oxidative stress also triggers  the immune system to clean up the damage, resulting in inflammation. Depleted levels of glutathione have been associated with lower immune function and increased susceptibility to infection due to the liver's reduced ability to detoxify.

These symptoms are also a result of ‘mitochondrial dysfunction,’ which happens when mitochondria lose protection from glutathione. This allows damaging free radicals to attack the mitochondria, causing  cellular energy to decrease. Mitochondrial dysfunction has been linked to some autoimmune conditions like multiple sclerosis, Crohn’s disease, rheumatoid arthritis, diabetes, Lyme disease, heavy metal load, and others.

Signs of Glutathione deficiency & depletion

Low levels of glutathione can manifest as:

• Fatigue
• Lack of energy
• Lack of mental focus
• Muscle fatigue
• Aches and pains
• Brain fog
• Low Immunity
• Poor sleep

Glutathione sources 

Diet is always the best place to start. Make sure you are eating a well balanced diet containing a combination of glutathione-rich foods, as well as other foods that provide the building blocks you need to boost your glutathione levels naturally. Lifestyle factors such as physical activity, reducing or eliminating alcohol, reducing stress, hydration and getting enough sleep are also important for supporting glutathione production.

Glutathione-rich foods

Glutathione is naturally found in foods like asparagus, avocado, cabbage, brussels sprouts, spinach, broccoli, garlic, chives, tomatoes, cucumber, almonds, and walnuts. However, factors such as cooking and storing can affect the levels of glutathione. In some cases, such as cooking, glutathione content can be reduced by 30 to 60 percent.

Other ways of getting enough glutathione in your diet is by eating foods that contain the precursors to it , namely cysteine, sulphur-containing foods and selenium.

Whey protein: (High in cysteine, a building block for making glutathione): Eating a good quality grass-fed milk source of whey can make it easier to make glutathione.

Cruciferous foods: Broccoli, cabbage, cauliflower, kale, Brussels sprouts, bokchoy, rocket, watercress and radishes.

Sulphur-containing foods: Garlic, onion, chives, shallots and leeks.

Alpha lipoic acid-rich foods: (Antioxidant that helps to regenerate glutathione levels): Organ meats, beef, brewer’s yeast, broccoli, spinach, Brussels sprouts, peas, tomatoes

Selenium-rich foods: (Part of the building blocks that make up the enzyme that produces glutathione, glutathione peroxidase): Seafood, oysters, Brazil nuts, eggs, mushrooms, whole grains, organ meats and dairy products.

Supplementing with glutathione can also be a good way to boost your body’s natural antioxidant production.

Glutathione supplements 

One of the most direct ways to increase glutathione levels is by taking glutathione supplements.

Glutathione can be taken orally in its powdered form, but as it is an extremely fragile molecule it is easily broken down into its three amino acids, cysteine, glycine and glutamate. This results in very little, if any, of the original glutathione molecule making it into blood circulation intact.

Lipid-encapsulated glutathione supplements - in which the glutathione is wrapped in natural lipids that mimic your cells -  ensure that the glutathione bypasses the digestive system and reaches the bloodstream intact. In fact, lipid-encapsulated glutathione has been demonstrated to be 100 times more effective for increasing intracellular levels of glutathione than non lipid-encapsulated glutathione supplements.

Another benefit of glutathione being delivered in lipid bubbles is that detoxification is enhanced even further. This ensures the proper function for the absorption of nutrients and the excretion of cellular waste products and toxins.

Vitamin C and glutathione

Studies show that vitamin C supplementation can support glutathione in a number of ways. Through vitamin C’s antioxidant activities, it works to directly attack and neutralise free radicals first, sparing glutathione levels in the body. Vitamin C is also involved in the process of converting ‘oxidised’ glutathione back into its active form, GSH (11). Lastly, vitamin C has been shown to increase glutathione levels in both red and white blood cells (12).

All of these studies were done through supplementation of vitamin C, so it is not known whether glutathione levels can be increased through vitamin C rich foods, so supplementing with lipid-encapsulated vitamin C may be one way to help provide your body the building blocks needed to support natural glutathione levels in the body. 

Milk thistle and glutathione

Milk thistle has been shown to both increase glutathione levels and decrease its depletion due to its antioxidant and anti-inflammatory properties (13). Curcumin has also been shown to not only increase glutathione levels, but may also improve the activity of glutathione.

Summary

Boosting our glutathione levels has a long list of health benefits and is key for health and longevity. It is important to support all systems of the body that are involved in our body’s own internal production of glutathione, as well as reducing our exposure to environmental toxins, to reduce the burden of free radicals in the body and increased needs for glutathione. Focus on consuming glutathione on a daily basis, reducing alcohol, stress and exposure to environmental pollution, getting regular exercise, adequate sleep and proper hydration.

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2696075/
2. https://pubmed.ncbi.nlm.nih.gov/24752591/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821140/
4. https://pubmed.ncbi.nlm.nih.gov/26467067/ 
5. https://pubmed.ncbi.nlm.nih.gov/12751781/
6. https://www.sciencedirect.com/science/article/pii/S1074761317301292 
7. https://www.frontiersin.org/articles/10.3389/fimmu.2017.01239/full
8. https://link.springer.com/chapter/10.1007/978-1-4684-5730-8_15
9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328900/ 
10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413479/
11. https://pubmed.ncbi.nlm.nih.gov/12499341/ 
12. https://pubmed.ncbi.nlm.nih.gov/8317379/
13. https://pubmed.ncbi.nlm.nih.gov/20600218/