Glutathione: A key molecule from biochemistry to anti-aging

As more and more people start to pay attention to topics such as "antioxidation", "improving sleep" and "anti-aging", one name frequently comes up: Glutathione (GSH).

Glutathione is one of the most important low-molecular-weight thiol substances in the body and is regarded as a core molecule for maintaining cell health and delaying aging.

In 2023, a review article published in Ageing Research Reviews systematically summarized the mechanism of action of glutathione and its dependent enzymes from biochemistry to geriatrics.

Provide a clear and comprehensive introduction to the structure, function, metabolic pathways, changes in aging, and feasible strategies for increasing glutathione levels of glutathione.

What is glutathione?

Glutathione is a tripeptide composed of glutamic acid, cysteine and glycine. It has a simple structure but plays a crucial role in the redox homeostasis within cells.

In the vast majority of aerobic organisms, glutathione exists in two forms:

Reduced glutathione (accounting for 98-99%

Oxidized glutathione (a disulfide bond is formed between two GSH)

In the body, the reduced state is usually dominant, which ensures that glutathione has a strong electron donor capacity, can neutralize oxides, participate in various metabolic reactions and signal regulation.

Glutathione has the highest concentration in liver cells, reaching up to 10 mM. It is approximately 1 to 2 mM in most cells.

main functions of glutathione

Far more than just "antioxidation"

The literature system has summarized the multiple functions of glutathione in the human body, which can be classified into the following three categories:

Antioxidation and maintenance of REDOX homeostasis

Glutathione itself can eliminate free radicals, but the vast majority of its antioxidant effects come from the synergy with various enzymes, including:

Glutathione peroxidase (GPxs) : Eliminates H₂O₂, lipid peroxides, etc

Peroxy-reduced proteins (Prdxs) : Regulate oxidation signaling and protein folding

Glutathione reductase: Regenerates GSSG into GSH

They jointly maintain the REDOX balance of cells, enabling oxidation signals to be conducted normally without developing into damage.

Detoxification function

Glutathione eliminates harmful substances through two pathways:

Binding with glutathione transferase (GSTs) : Eliminating drug metabolites, environmental toxins and lipid peroxidation products (such as 4-HNE)

Participate in the detoxification of methylglyoxal (MG) and formaldehyde: through the glucose oxidase system and ADH5 enzyme

This means that Glutathione has an undeniable impact on abnormal glucose metabolism, inflammation, cardiovascular health, etc.

Other critical life activities

Glutathione participates in or influences:

• DNA synthesis, gene expression
• The steady state of iron and metal ions
• Protein folding and modification (such as S-glutathiylation)
• Cell proliferation, differentiation and death patterns (including apoptosis, ferroptosis, etc.)
• Immune regulation (such as the functions of lymphocytes and neutrophils)
• Nervous System signal transduction and neuroprotection
• The generation of substances such as hormones, prostaglandins, and leukotrienes
• Regulation of vitamin D status

It can be said that glutathione is almost involved in every key node of cellular life activities.

How is glutathione synthesized and circulated in body?

The metabolism of glutathione is mainly accomplished through the γ -glutamyl cycle.

1. Synthesis: Two steps, consuming ATP

Step 1: Glutamic acid + cysteine → γ -glutamylcysteine (catalyzed by GCL enzyme, it is the rate-limiting step)

Step 2: γ -glutamylcysteine + glycine → glutathione

Among them, cysteine is the most crucial. The activity of GCL enzyme significantly decreases with age.

2. Distribution and Transport

Glutathione can enter organelles (such as mitochondria and endoplasmic reticulum), and also be exported outside the cell.

Subsequently, it is decomposed by γ-GT and others, and then absorbed and utilized by adjacent cells.

3. Regeneration

The oxidized Glutathione is reconverted into GSH through glutathione reductase.

The synthesis, decomposition, output and regeneration processes of glutathione jointly ensure its homeostasis in the body.

Glutathione and Aging: Declining or Rising?

Most studies show that glutathione decreases with age

Studies on experimental animals and human tissues have shown that as people age:

• The levels of glutathione in all tissues generally decreased
• The activity of GCL (a key synthase) has decreased
• Excessive oxidation load consumes glutathione
• Decreased Nrf2 activity (regulating the expression of antioxidant enzymes)

This decline is closely related to cellular dysfunction during the aging process. For instance, a reduction in glutathione in the lens is associated with cataract formation.

glutathione level is actually higher in healthy elderly people

Literature indicates that research has found:

Elderly people in excellent physical and cognitive conditions actually have higher levels of glutathione

This might be related to the adaptive mechanisms associated with longevity

Glutathione levels are both a result of aging and may also affect the rate of aging.

What are ways to increase glutathione levels?

The literature summarizes a variety of potential methods for enhancing glutathione, including nutritional supplementation, lifestyle and functional substances.

1. Provide synthetic raw materials

• Cysteine supplementation: The common form is N-acetylcysteine (NAC)
• Glycine supplementation: It may be one of the limiting factors and can be combined with NAC
• Glutamine: It is converted into glutamic acid to participate in synthesis

Directly supplement glutathione itself

There was once controversy over whether oral GSH is effective, but research shows that:

Certain specific forms (such as S-acetylated glutathione) can increase GSH in blood and red blood cells

Oral GSH has also been observed to be absorbed by tissues in animals

Activate the glutathione-related enzyme system

By enhancing the Nrf2 pathway, the expression of enzymes such as GCL can be increased, for example:

Moderate exercise

Some plant polyphenols and nutrients (such as alpha-lipoic acid)

Nutrients that enhance energy metabolism (such as pantothenic acid promoting ATP production)

influence of lifestyle on glutathione

Regular exercise can enhance the activity of the glutathione system

Certain diseases, chronic inflammation, smoking and pollution exposure can reduce GSH

Antioxidant diets (rich in sulfur-rich amino acids, vitamins, etc.) support GSH homeostasis

Glutathione and "Successful Aging"

The literature regards glutathione as an indispensable part of "successful aging".

• GSH affects healthy lifespan by controlling oxidative stress, lipid peroxidation, inflammation and apoptosis
• Detoxification function is particularly important for long-lived individuals
• The expression levels of enzymes such as GST are positively correlated with the extension of lifespan
• Maintaining a high level of GSH may be an important characteristic of long-lived people

Glutathione is not only an antioxidant but also likely a "hub molecule" that regulates the aging process.

Summary

Glutathione is the most important reducing agent within cells and plays a core role in antioxidation, detoxification, signal transduction, immune regulation, and metabolic homeostasis.

Aging is closely related to the decline in GSH levels, but elderly people in excellent health tend to maintain high GSH levels.

Based on current research, strategies to increase GSH in the body include:

• Supplement the precursor amino acids: NAC + glycine
• Activate the synthase system (such as the Nrf2 pathway)
• Reasonable exercise
• Supplement glutathione appropriately
• A healthy lifestyle and diet

For people who want to improve sleep, enhance energy status, support immunity and reduce oxidative stress, maintaining a good level of glutathione may be of great significance.