The Glutathione Theory of Aging

Over 100,000 scientific studies have been published regarding the biological effects of glutathione. It is a multi-tasking compound that is made in every cell. Its primary functions include regulation of antioxidant activity, detoxification, and regulation of the body’s immune function. Consequently, glutathione is an important regulator of the health of every cell in the body.

Many people have depleted levels of glutathione and most chronic degenerative diseases are associated with low glutathione levels.^1,2 Low glutathione result in increased production of free radicals, increased levels of inflammation, an increased accumulation of toxins in the body, which all contribute to accelerated biological aging.

The primary goals of this article are to discuss glutathione’s wide-ranging functions in the body, to discuss the history and discovery of Lactobacillus fermentum ME-3, which is a unique strain of probiotic bacteria that synthesizes glutathione, and to explain why boosting glutathione levels is one of the most important proactive step people can take to slow down biological aging, thereby increasing their health span and their life span.

Glutathione is referred to as the Master Antioxidant because it is made in every cell, and consequently, it is one of the most prevalent antioxidants the human body.³ One of glutathione’s primary “jobs” is to protect all the components inside every cell in your body against oxidative stress and free radical damage. Glutathione is also a required cofactor for glutathione peroxidases, which are enzymes that provide additional antioxidant protection throughout the body.⁴
In addition to neutralizing free radicals, glutathione also increases the effectiveness of other antioxidants because it can recycle, or regenerate oxidized or “used up” antioxidants like vitamin C and vitamin E back to their active/reduced form.⁵

Glutathione plays a critical role in many detoxification processes, and it helps detoxify every cell in the body. Tissue levels of glutathione are highest in the liver, which is the body’s primary organ for detoxification. Glutathione protects the body from a wide range of environmental toxins as well as toxins that are produced within the body, such as the hydroxyl radical, superoxide, hydrogen peroxide and hydroperoxides.^6,7,8

Glutathione is a cofactor for a superfamily of detoxification enzymes named glutathione S-transferases, which are responsible for detoxifying a wide range of carcinogens and environmental toxins.⁹ Glutathione also independently binds with heavy metal toxins such as mercury, lead, cadmium, and arsenic to eliminate them from the body.¹⁰

Glutathione is essential for the function and activity of white blood cells, and it has been reported that even a partial depletion of glutathione results in a profound inhibition of immune function.¹¹

White blood cells (WBCs) are a critical part of your immune system. Using a military metaphor, white blood cells function like scouts or an early warning surveillance team. They circulate throughout your body, constantly on the lookout for bacteria, viruses, and other foreign invaders. Hence, WBCs are our first line of defense against infections. A sub-category of white blood cell, called natural killer or NK cells, are involved in the identification of cancer cells and the control of tumor growth and metastasis.¹²

White blood cells, which account for about 1% of your blood, are made in the bone marrow and released into the bloodstream. When a foreign invader is identified, the bone marrow releases a massive number of WBCs into circulation, which travel to the site of the infection to fight the invader. Most people have experienced getting a cut that becomes red, swollen, inflamed and painful. These effects are due to the ‘army’ of WBCs that have traveled to the site of the injury to fight and kill the invading pathogen.

Since COVID, an increasing number of studies have been published reporting on glutathione’s anti-viral activity. Studies have reported that glutathione helps to protect against viral infections and that boosting/replenishing glutathione levels can be therapeutically useful in the treatment of various viral infections.¹³

Glutathione levels have been found to be low in people with viral infections such as HIV, hepatitis C, Epstein-Barr, West Nile, herpes, and COVID-19. The title of a paper published in the early stages of the COVID-19 pandemic stated that glutathione deficiency is the most likely cause of serious manifestations and death in COVID-19 patients.¹⁴

Every time a molecule of glutathione neutralizes a free radical, the body’s supple of glutathione is depleted. Similarly, when a molecule of glutathione binds to a toxin, the resulting glutathione-toxin compound gets eliminated from the body, which also depletes glutathione. Consequently, glutathione levels are constantly being depleted and the health of most people will improve if steps are taken to boost glutathione levels.

Some of the major factors that cause glutathione depletion are environmental toxins, poor diets, alcohol, smoking, nutritional deficiencies, and protein malnutrition, especially in the elderly. Also, the following classes of drugs deplete glutathione: acid blockers, antacids, antibiotics, anti-viral medications, tricyclic antidepressants, oral contraceptives, and acetaminophen, which is an ingredient in many OTC and prescription pain medications.

Acetaminophen deserves special attention because it is the most widely used pain medication in the United States and it is the also the leading cause of acute liver failure. Acetaminophen is safe when taken as directed in small doses. However, it depletes glutathione rapidly when taken in high doses or when taken continuously over extended periods of time. Many people who take acetaminophen-containing pain medications also consume alcohol. This greatly increases the risk of liver damage because both substances are metabolized in the liver. In the U.S., acetaminophen toxicity is responsible for over 50% of cases of acute liver failure and about 20% of liver transplant cases.¹⁵

Depleted glutathione levels result in a greater body burden of toxins, increased free radical damage and accelerated aging. Thus, keeping glutathione at optimal levels is critical for healthy aging. Also, studies have shown that the body’s ability to synthesize glutathione declines with age and this could be a major contributing factor to health problems accelerate as people age.¹⁶

Glutathione is a compound consisting of three amino acids, which are glycine, cysteine, and glutamic acid. Glutathione exists in two forms. Reduced glutathione (GSH) is the active form. Oxidized glutathione (GSSG) is the inactive from, which occurs when two molecules of glutathione are joined together.

The ratio of GSH to GSSG (reduced to oxidized, or active to inactive) is an important determinant of cellular health. Healthy cells have a GSH/GSSG ratio of over 100, which indicates a high level of antioxidant protective ability. When cells are exposed to high levels of free radicals or other forms of oxidant stress, the GSH/GSSG ratio often drops to below 10. Thus, the glutathione GSH/GSSG ratio is an important indicator of cellular health, and the overall health of an organism, or a human.

Three important classes of glutathione-dependent enzymes also regulate important aspects of heath. Glutathione peroxidases are antioxidants, the glutathione S-transferases are detoxification enzymes that neutralize and eliminate a wide range of toxins, and glutathione reductase converts inactive GSSG back to the active GSH form.

Most common chronic degenerative diseases, which are also referred to as age-related diseases, have been found to be associated with low glutathione levels. This includes cancer, cardiovascular, inflammatory, immune, metabolic, and neurodegenerative diseases.^17,18

Loss of cognitive function is one of the greatest fears people have about aging. Glutathione levels are known to be low the brain of people with Parkinson’s disease, Alzheimer’s disease, schizophrenia, bipolar disorder, depression, ADHD, and other brain disorders.^19,20,21

Telomeres are repeating segments of DNA (often described as protective “caps”) on the ends of chromosomes that protect our genes from damage. In 2009, three scientists were awarded the Nobel Prize for their discoveries on how telomeres and the enzyme telomerase protect our chromosomes and our genes from damage.

Telomeres become shorter each time a cell divides. Telomere length and the rate of telomere shortening is recognized as one of the best biomarkers of aging.²² Glutathione has been found to play a role in the preservation of telomere function. This explains one of the ways glutathione slows down the process of biological aging.²³

In the 1980s, Drs. John Richie and Calvin Lang began researching how glutathione affects health and aging. In a landmark study, they added a glutathione precursor to the drinking water of adult mosquitoes and measured their glutathione levels and their life span. The outcome was quite surprising. Glutathione levels increase from 50-100%, which resulted in increased lifespans of 30-38%. Consequently, Drs. Richie and Lang proposed the glutathione deficiency hypothesis, which suggests that a low level of glutathione is a primary biochemical cause of biological aging.²⁴

Studies have shown that centenarians have higher glutathione levels compared to people between 60-79 years of age selected as controls. The authors proposed that the higher glutathione levels in the centenarians was a key factor in their longevity.²⁵

Because many factors previously discussed contribute to glutathione depletion, it can be assumed that most people have low levels of glutathione. It is also well established that low glutathione levels are associated with increased risks of a wide range of health problems. On the other hand, scientific evidence in animals and in humans consistently show that increasing glutathione levels slows the process of biological aging. Consequently, boosting glutathione levels is one of the most important, proactive steps people can take to create and maintain good health and achieve healthy longevity.

In 1995, Professor Marika Mikelsaar at the University of Tartu in Estonia isolated a strain of bacteria named Lactobacillus fermentum ME-3 (often referred to as ME-3) from the intestinal tract of a healthy 1-year child. Testing revealed that ME-3 exhibited extremely high antioxidant activity. Follow-up research reported that ME-3’s high antioxidant activity is due to its ability to synthesize glutathione.

Because Lactobacillus fermentum ME-3 synthesizes glutathione, it has attracted a great deal of scientific attention. Studies in animal models and in human clinical trials report that taking ME-3 orally provides a wide range of health benefits that parallel the health benefits of glutathione.

ME-3 has been shown to increase glutathione by three different mechanisms which are:

1. ME-3 synthesizes glutathione.
2. ME-3 accumulates glutathione from the environment.
3. ME-3 recycles oxidized (inactive) glutathione back to its reduced (active) state.

Lactobacillus fermentum ME-3 is the only organism or substance known at this time that is able to increase glutathione by three independent mechanisms. Consequently, ME-3 is often referred to as a “complete glutathione system.”

Supports cardiovascular health: Lactobacillus fermentum ME-3 has been shown to have a positive effect on several cardiovascular risk factors. Results from a 2-week double-blind, placebo-controlled human clinical revealed that subjects taking ME-3 had reductions in oxidized LDL-cholesterol and triglycerides, and an increase in HDL-cholesterol.²⁶ During this same time period, the values of these same markers got slightly worse for the placebo control subjects.

ME-3 Synthesizes Manganese Superoxide Dismutase: Lactobacillus fermentum ME-3 also produces the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD).²⁷ Mitochondria consume over 90 percent of the oxygen used by cells, which makes them especially vulnerable to oxidative free radical damage.²⁸ Because MnSOD plays a critical role in protecting mitochondria and preserving energy production, it has been called the guardian of the powerhouse.²⁹

Reduces Inflammation: Lactobacillus fermentum ME-3 has been shown to significantly inhibit levels of several key inflammatory markers including glycated hemoglobin (HbA1c), high sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6), and it is also capable of stimulating production of the anti-inflammatory and anti-diabetic peptide adiponectin.³⁰

Detoxifies Organophosphate Pesticides: Organophosphates are one of the most widely used pesticides worldwide. These highly toxic compounds are sprayed on agricultural food crops, and they are commonly used on residential lawns and gardens. Lactobacillus fermentum ME-3 s increases the activity of paraoxonase enzymes (called PON1), which helps detoxify organophosphates.³¹

Interest in glutathione is growing fast because people are becoming more aware of glutathione’s many health benefits and the role it plays in the prevention and treatment of age-related chronic degenerative diseases.

The is some confusion and controversy regarding which method of boosting glutathione levels achieves the best health outcomes and is most cost effective. There are several commonly methods of boosting glutathione and the pros and cons of each method will be discussed.

1. Ingesting glutathione orally
2. Taking glutathione precursors
3. Intravenous (IV) glutathione
4. Taking Lactobacillus fermentum ME-3 orally

Oral glutathione supplements are not well absorbed because an intestinal enzyme named gamma-glutamyl transpeptidase or GGT break it down before it can be absorbed.³² Most studies on oral glutathione report little or no increase in plasma glutathione levels.³³ Although taking glutathione orally is the most convenient way to take glutathione, its poor absorption explains why this form is seldom used in scientific studies.

The nutritional supplement N-acetyl cysteine (NAC) is the most commonly used nutritional agent used to boost glutathione levels. However, studies report that NAC is very poorly absorbed with only 10% being available after oral ingestion. After ingestion, intestinal enzymes convert about 90% of the NAC into the amino acid cysteine, which is unstable and quickly gets oxidized to cystine. Cystine has very low solubility; it is the least soluble of the naturally occurring amino acids.^34,35 Thus, N-acetyl cysteine is not an effective method of boosting glutathione levels.

Many complimentary and functional medicine physicians and/or clinics are offering IV glutathione therapy. Some of the key benefits include reducing inflammation, boosting immune function, improving mental clarity and cognitive function, increasing energy, and slowing the aging process. However, glutathione gets oxidized very quickly, its half-life is only about 10 minutes.³⁶ Thus, people getting IV glutathione often get infusions 2 or 3 times a week. Thus, IV glutathione infusions can be time consuming and somewhat expensive (average price $200-$350/treatment).

Human clinical trials reveal that oral ingestion of Lactobacillus fermentum ME-3 results in substantial and consistent increases in glutathione levels. In addition to boosting glutathione levels, tests in animals and humans report oral ingestion of ME-3 provides a wide range of health benefits. The scientific evidence indicates that taking Lactobacillus fermentum ME-3 orally is the best method to boost glutathione levels.

Here is a summary of the scientific studies that document and explain the benefits of taking Lactobacillus fermentum ME-3 orally.

1. Reduced cardiovascular risk: The first column shows that individuals taking ME-3 had a 16% reduction in the levels of oxidized LDL-cholesterol compared to placebo controls.³⁷
2. Reduced 8-Isoprostanes: The second column reports that people taking ME-3 had a 20% reduction in levels of 8-isoprostanes, which indicates reduced amounts of free radical damage due to ME-3’s antioxidant activity.³⁸
3. Elevated Glutathione: The study reported in the third column shows that people taking ME-3 daily for three weeks (6 billion CFU/day) had a remarkable 49% increase in the ratio of reduced to oxidized glutathione.³⁹ No other product has ever come close to increasing glutathione levels this effectively.
4. Reducing Oxidative Stress & Inflammation⁴⁰ The fourth column reports the increase in Total Antioxidant Activity (TAA) gained by the individuals taking Lactobacillus fermentum ME-3. (data for this comes from the following 2 studies)

Many patients with atopic dermatitis have genetic polymorphisms in glutathione-dependent enzymes, which results in increased oxidative stress, inflammation and impaired skin membrane barrier function.⁴¹ Individuals taking ME-3 experienced significant reduction in inflammation with accompanying improvements in skin condition, blood markers and in self-assessment rating scores.⁴²

Stroke patients consuming ME-3 exhibited significant improvements in both the Scandinavian Stroke Scale (from 33 up to 42) and the Functional Independence Measure inventory (from 21 up to 40). Stroke patients also experienced impressive improvements in the following blood markers: oxidized LDL-cholesterol, glutathione levels and ratio of reduced to oxidized glutathione, total antioxidant capacity, paraoxonase enzyme activity as well as reductions in markers of inflammation and free radical damage.⁴³

In a human clinical trial, it was shown that ME-3 is capable of surviving transit through the harsh acid environment in the stomach and when it arrives in the small intestines, it adheres to the intestinal lining and begins producing glutathione. After 21 days, there was a doubling of the concentration of live ME-3 bacteria in these test subjects.⁴⁴

Bacterial imbalance in the intestinal tract causes inflammation. This results in intestinal permeability or leaky gut, which is associated with chronic inflammation and the acceleration of biological aging. A study with Lactobacillus fermentum ME-3 revealed that ME-3 helps prevent intestinal permeability.⁴⁵

Diabetes and obesity are epidemics with enormous health consequences. Also, elevated blood sugar causes glycation, which is a significant risk factor for cardiovascular disease. A study was conducted with strain of mice bread to spontaneously develop type 2 diabetes and become obese. The mice treated with ME-3 had improved glucose tolerance, less glycation and gained much less weight compared to the control mice. Thus, treatment with ME-3 was shown to have therapeutic potential to reduce glycation and the incidence of common diabetes-related health complications.⁴⁶

In 2020 there was an official nomenclature change for many species of Lactobacillus bacteria. Among the changes, the species formerly referred to as Lactobacillus fermentum ME-3 is now named Limosilactobacillus fermentum ME-3. The new name will appear in scientific publications, but the older traditional name will continue to be used in general communication.⁴⁷

With its wide range of documented benefits due to synthesizing glutathione, Lactobacillus fermentum ME-3 is one of strongest multi-function probiotics ever discovered.

The University of Tartu owns the patent on the method to produce Lactobacillus fermentum ME-3. Commercial products containing ME-3 are available in many countries, including the U.S. under the brand name Reg’Activ. Products containing Lactobacillus fermentum ME-3 are easily available by doing an internet search for Reg’Activ or Lactobacillus fermentum ME-3.

Taking a product that contains Lactobacillus fermentum ME-3 is the most effective method of increasing glutathione levels. In boosting glutathione levels, Lactobacillus fermentum ME-3 provides support for antioxidant protection, immune and anti-viral activity and detoxification which will likely improve health, increasing lifespan and healthspan.

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