Healthy Aging

Glutathione, the Master Antioxidant

Does supplementation really increase glutathione levels?

Scientists have been trying to understand the aging process for, well, ages. One thing we know for sure is that oxidative stress plays a major role in the aging process, and a powerful antioxidant known as glutathione helps fight that oxidative stress.[1],[2]

Oxidative stress is a process that occurs within our cells and tissues similar to the process that causes apples to turn brown or oils to go rancid. Cells produce metabolic byproducts known as reactive oxygen species (ROS). The term “reactive” means that these forms of oxygen can react with (bind to) proteins, lipids, and/or DNA, causing them to become oxidized.  Excessive oxidation can cause permanent damage to cell structure and function, eventually leading to cell death.[3],[4],[5]

When cell death occurs in the brain, it may increase the risk of neurodegenerative diseases, including Alzheimer’s and Parkinson’s.[6],[7],[8],[9] In the heart, cell damage can increase the risk of heart disease.[10],[11],[12] And that’s not all: oxidative stress is also associated with lung disease,[13] non-alcoholic fatty liver disease (NAFLD),[14],[15] high blood pressure,[16] diabetes,[17],[18] glaucoma,[19] macular degeneration,[20] and viral and mycobacterial infections.[21],[22],[23],[24]

A decline in GSH levels contributes to oxidative stress, and it’s abundantly clear that GSH levels decline with age.

This is why glutathione (GSH), the master antioxidant in human cells, is vitally important. The beneficial effects of GSH are a result of its direct ROS scavenger action as well as its ability to support the activity of GSH-peroxidase, a selenium-containing enzyme that defends against peroxides, a form of ROS.[25]

A decline in GSH levels contributes to oxidative stress, and it’s abundantly clear that GSH levels decline with age.[26],[27],[28] Low GSH levels are also associated with vitamin D deficiency,[29] and vitamin D supplementation may not correct vitamin D deficiency unless GSH is first restored.[30] Smoking,[31],[32],[33]  alcohol use,[34] eating an unhealthy diet,[35] exposure to environmental and air pollutants,[36], [37],[38] and use of certain medications also deplete GSH and increase oxidative stress.

For all these reasons, some scientists have suggested that increasing cellular levels of GSH may help preserve health and slow the aging process.[39] The key question then becomes: is it possible to increase the body’s GSH levels?

N-acetylcysteine: a glutathione precursor

GSH is made from the amino acids cysteine, glycine, and glutamine. Low levels of cysteine within cells can thus limit the ability of cells to make their own GSH during times of oxidative stress.[40],[41] A supplement known as N-acetylcysteine (NAC), which is metabolized to cysteine following absorption, can supply the cysteine required for the synthesis of GSH. NAC can thus often correct GSH depletion and reduce oxidative stress.[25]

Clinically, NAC may be used to counteract acetaminophen toxicity. Acetaminophen, a common pain reliever, is metabolized in the liver to a highly toxic substance, abbreviated NAPQI.[42] Detoxification of NAPQI requires high concentrations of GSH, and the resulting depletion of GSH stores can cause permanent liver damage.[42] Acetaminophen-induced liver damage can be prevented by administering NAC.[42]

NAC also has shown clinical benefits in cases of acute kidney, heart, and brain damage, all of which are associated with oxidative stress.[43],[44],[45] GSH has direct effects against mycobacteria, such as tuberculosis (M. tuberculosis), and NAC has thus been suggested as an adjuvant to the standard medical treatments for tuberculosis infections.[46],[47]

Oxidative stress is a major feature of Alzheimer’s disease (AD).[48] A reduction in GSH has been detected selectively in the brain regions affected by AD pathology and correlated with the extent of cognitive impairments.[7] NAC supplementation has been shown to have positive effects in animal models of AD, including improvements in memory.[49],[50],[51] A preliminary study showed that administration of NAC daily (50 mg/kg/day) for 6 months resulted in favorable changes in some cognitive symptoms in individuals with AD.[52]

It’s worth noting that NAC is not a powerful antioxidant in its own right: its strength lies in the replenishment of GSH in deficient cells, and it is thus likely to be ineffective in cells replete in GSH.[25] The efficacy of NAC also depends on the activity of enzymes for the synthesis of GSH. NAC is therefore not effective in all cases.[17],[21],[53]

Does glutathione supplementation work?

The human body produces GSH, but GSH is also present in the diet. Some of the richest food sources of GSH are spinach, avocado, asparagus, and okra.[54] Because the intestines contain an enzyme that degrades GSH, however, some researchers believe that oral intake of GSH does not increase GSH levels in the body.[55] One study published in 1992 stated that a single oral dose of GSH had no impact on plasma GSH levels after 4.5 hours.[55] A 2011 study also reported that GSH supplementation had no effect on red blood cell GSH levels after one month.[56] These negative results, however, may be more indicative of the limitations of the techniques used to assess blood GSH than of the actual GSH concentrations.[57]

Long-term oral administration of glutathione is an effective means of enhancing body stores of glutathione.

In contrast, more recent studies have shown that supplemental GSH can boost GSH levels in the body.[57],[58],[59] GSH has been shown to be absorbed in the intestine and rapidly transferred to red blood cells and the liver.[58] In a randomized, double-blind, placebo-controlled trial, healthy adults were given either 250 mg GSH, 1,000 mg GSH, or placebo daily for six months; both dosages increased blood GSH levels compared to a placebo.[57] In the 1,000 mg GSH group, the level of GSH increased by up to 30-35% in blood and up to 260% in buccal (cheek) cells, a highly significant result. The researchers conclude, “Altogether, these findings are consistent with previous pre-clinical studies and indicate that long-term oral administration of glutathione is an effective means of enhancing body stores of glutathione.”[57]

In animal studies, GSH supplementation was shown to increase blood, heart, and brain levels of GSH;[60],[61],[62] protect the brain against oxidative stress;[62],[63] protect the intestines against fasting-induced stress;[64] and reverse the age-associated decline in immune responsiveness.[65] GSH also was shown to reduce the toxicity of acetaminophen;[66],[67] in fact, one study suggests that GSH may be even more effective than NAC at the same dose.[67]

GSH supplementation in humans also has measurable effects. In one study, participants’ natural killer cell activity was enhanced more than twofold after three months of GSH supplementation (1,000 mg per day).[57] In a pilot study of individuals with NAFLD, GSH supplementation at a dose of 300 mg per day for four months led to a significant decrease in alanine aminotransferase (ALT), a liver enzyme, suggesting a reduction in liver damage.[68] In addition, a liposomal formulation of GSH was shown to boost immune responses against M. tuberculosis and HIV.[69],[70]

A supplemental form of GSH known as S-acetylglutathione has been shown to be more bioavailable than the standard, non-acetylated form of GSH.[71],[72] Just as NAC is a precursor of cysteine, S-acetylglutathione is a precursor of GSH that is well absorbed in the gut and more stable in plasma.[72],[73],[74]

In sum, GSH supplementation can help restore the body’s GSH levels in times of need – including conditions of oxidative stress and aging. Data suggests that the S-acetylglutathione form may be more effective in this regard than non-acetylated glutathione.

What about other antioxidants?

Glutathione may be the “master” antioxidant, but it’s not the only antioxidant! The word “antioxidant” refers to a general common action, but antioxidants are in fact distinct chemical entities with different means of achieving their effects.[75]

Antioxidants can be found in certain botanicals, foods, and beverages.[76],[77] Along with vitamins C and E, examples of natural products with antioxidant (and other) health-benefiting properties include (but are not limited to) silymarin (milk thistle);[78],[79] curcumin (from turmeric);[80],[81] alpha lipoic acid;[82],[83] melatonin;[79],[84] CoQ10;[85],[86] resveratrol;[87],[88] sulforaphane;[89] and berberine.[90]  When considering antioxidant supplementation, it is important to select the substance with the right profile, based on the nutritional and health status of each person and their individual needs.[75]

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