Epigallocatechin gallate (EGCG)

Epigallocatechin gallate (epigallocatechin gallate), EGCG

Epigallocatechin gallate, abbreviated EGCG, is one of the substances found mainly in green tea. It is one of the best-studied substances with epigenetic effects and is characterised by its strong broad-spectrum positive effects on the whole body.

Description and occurrence

EGCG is an ester of epigallocatechin, a natural substance found in the highest concentration in green tea. Chemically, it belongs to the polyphenols. However, its content varies considerably according to the type and quality – it is highest in high quality, loose green teas with large, uncrushed leaves. Lower-quality, crushed green teas in sachets have a significantly lower content of active substances (up to 100 times) and highly processed teas, such as instant or iced ones, are practically free of EGCG. In addition, other catechins are found in good quality green tea. (40)

High-quality white teas are also a relatively rich source of EGCG and other catechins; black teas and oolong teas are considerably worse off, as catechins are significantly lost during the fermentation process.

EGCG is also found in smaller amounts in some fruits (strawberries, blueberries, cranberries, kiwi, avocados, apples, pears, cherries and peaches) and nuts such as hazelnuts, pecans and pistachios (40).

EGCG is also taken in the form of a dietary supplement – green tea extract. Its main advantage is that EGCG and other types of catechins are found here in many times higher concentrations than in the drink. In addition, some types of extracts do not contain caffeine.

History

The oldest herbarium containing records of tea dates back to China and was written 1500 years ago. However, the tradition of drinking tea is probably several thousand years older – according to archaeological findings, it would have been consumed as early as 5,000 years ago. And equally, its medicinal benefits have been exploited for much longer.

TheKissa Yojoki, or Book of Tea, from 1191 describes the positive effects of drinking green tea, for example, on the heart, digestion, preventing fatigue, supporting brain and urinary function. In recent years, the so-called Asian paradox has often been mentioned by experts – although cigarette smoking is widespread in this part of the world, the death rate from cancer and cardiovascular disease is relatively low, which is attributed to the abundant drinking of green tea.

Tea came to Europe in the 17th century. Today, it is the second most commonly consumed beverage – after plain water.

Healing effects

EGCG is known primarily for its powerful antioxidant action, but it is also one of the substances that is capable of very strong epigenetic effects.

Epigenetics is a relatively young field of science, thanks to which we know that who we are and what diseases afflict us do not depend only on genetic information. In fact, there are mechanisms that can “turn off” or “turn on” certain genes – chemically, for example, gene methylation or histone acetylation. These changes can be so pronounced that two individuals with the same genetic information can be completely different, as in the case of a queen bee and a worker bee.

EGCG is one of the most powerful natural preparations that are able to influence the body in terms of epigenetics. It has a vital role in the prevention and treatment of cancer and cardiovascular disease, promotes weight loss, and may even influence the course of Alzheimer’s disease and the degree of disability in Down syndrome. It is also effective in promoting endurance performance in athletes and providing relief from joint disease. It is also a powerful antioxidant and a substance that has the ability to influence cell regeneration processes.

Weight Loss

Many overweight people like to claim that they have “fat in their genes”. Research shows that they are essentially right, but it is still within their power to influence the condition – because the key role in the development of obesity is not played by “hard heredity”, but rather by epigenetic processes such as gene methylation or histone acetylation. The epigenetic changes that our parents had at the time of conception can be inherited from them, and many others originate in the pregnancies of obese mothers (15).

Fortunately, the process is not irreversible, and one of the substances that can influence the development and treatment of obesity is EGCG. While the balance between energy intake and expenditure will always be the most important factor in weight loss, there are other factors at play: the proliferation (i.e. rapid multiplication) of the cells that give rise to adipose tissue, the rate of fat production from the energy received (called lipogenesis), and the body’s willingness to use fat stores as an energy source (a process called “lipogenesis”). (16) For example, research has shown that obese people have different rates of epigenetic changes in DNA and histones (proteins that make up the spatial structure of DNA) compared to people of normal weight (17-19).

Green tea has been popular for years as a “fat burner”, but for a long time its effects were mainly attributed to its caffeine content. However, research has shown that more important is the presence of EGCG, which can influence weight loss through a number of processes: it increases energy expenditure, the rate of fat oxidation (i.e. burning), reduces glucose and fat absorption, inhibits fat cell differentiation and lipase enzyme activity, and affects appetite. (16)

Another important factor is the reduction of inflammatory processes in the body. Obesity brings with it mild inflammation throughout the body, which not only worsens overall health but also complicates weight loss efforts. Reducing inflammation therefore also means facilitating weight loss (45).

Another factor is the effect of EGCG on the composition of the gut microbiome. It turns out that the microbiome of obese people generally has a lower species diversity and different species are represented in different proportions – in particular, a lower proportion of Bacteroidetes and a higher proportion of Firmicutes. There is also an increase in the number of genes that are responsible for the absorption of carbohydrates from food – in other words, because of the different composition of the gut microbiome, obese people are able to extract more energy from the same food than lean people and therefore gain more weight after an identical diet. EGCG can also positively influence this problem (45-49).

EGCG is particularly effective in conjunction with physical activity – taking it with regular exercise has been shown to lead to greater weight loss than exercise alone. Not only is there fat loss, including the medically problematic fat in the abdominal area, but the risk of active muscle mass loss is reduced – even in conjunction with weight training, it grows better with EGCG than without it. Aerobic exercise, in turn, improves the body’s ability to use fat as an energy source and increases overall energy expenditure. The volunteers also had higher metabolic rates after exercise, so their bodies burned more energy at rest (56, 57).

Importantly, EGCG also facilitates weight maintenance after dietary restrictions have ended (44).

Consequences of unhealthy eating

Interestingly, EGCG may also help to alleviate the effects of some dietary irregularities. For example, when scientists fed experimental mice a high-fat diet, they experienced negative changes in gene methylation, as well as a decrease in the ratio of important gut bacteria(Firmicutes/Bacteroidetes) and an overall increase in inflammatory processes in the body. When EGCG was then administered to the animals, all of these negative processes were reversed (43).

Anticancer action

EGCG helps prevent cancer in several ways. The first is its powerful antioxidant action, which limits damage to cellular DNA. This phenomenon is well studied, for example in the case of breast cancer (1).

But equally important is the epigenetic action. Simply put, EGCG is able to switch on and off certain genes that are responsible for the development of cancer (9). This effect has been demonstrated, for example, in colon cancer (2-3, 8), but it is also very pronounced in those cancers in which hormonal balance plays an important role, in particular breast (4) or prostate (7, 12) cancer and others. The ability of EGCE to inhibit tumor spread by metastasis is also of epigenetic nature – this has been well studied, for example, again in breast cancer (5-6).

However, EGCG is even capable of directly causing cancer cell death. This is because the body’s cells have the so-called ability to undergo apoptosis, or programmed cell death. When such a cell receives the signal that it is multiplying too quickly, it starts the process of self-destruction. Cancer cells, however, lose this ability, which is the cause of their uncontrolled multiplication. EGCG is then one of the nutrients that, through epigenetic action, can restore this ability and thus stop tumour growth (1).

An important role in the anticancer action of EGCG is played by its ability to influence the so-called NF-kappaB transcription factors. These are substances that enter the cell nuclei, where they directly influence the transcription of certain genes. NF-kappaB, for example, is involved in the production of antibodies, so it affects our immunity, but it also regulates the process of apoptosis, or cell death. Interestingly, EGCG affects the apoptosis of cancer cells but not normal cells – it leaves them unaffected.

In addition, EGCG forms very effective combinations with some anti-cancer drugs, where they enhance each other’s effectiveness. This is the case, for example, with tamoxifen, sulindac or selective cyclooxygenase-2 inhibitors (66).

Cardiovascular disease

Until recently, the antioxidant effects of green tea polyphenols have been emphasized in this field, but recent research suggests that the epigenetic action of EGCG may play an important role here as well – it appears that the development of some cardiovascular diseases, especially atherosclerosis, is linked to the process of cytosine methylation, which is one of the main epigenetic mechanisms.

For example, a Japanese study is often cited, which is unique in its scope – the authors followed more than 40 000 people for 11 years. They found that those who drank at least 5 cups of green tea a day had a 16% lower risk of premature death and a 26% lower incidence of cardiovascular disease. (10) EGCG has also been shown to have a significant effect on lowering LDL cholesterol and blood pressure (11).

Moreover, even in the area of cardiovascular problems, EGCG is known to support each other’s effectiveness with certain drugs – for example, verapamil, which is used for high blood pressure (66).

Anti-inflammatory activity

The principle of anti-inflammatory action of natural substances and chemical drugs is the inhibition or suppression of the mediator of inflammation – prostaglandins. A key role in their formation is played by enzymes called cyclooxygenases (COX), which are involved in the formation of prostaglandins from arachidonic acid. It was not until 1991 that it was discovered that cyclooxygenase is not just one compound, but exists in two forms – COX1 and COX2. COX1 is present in constant amounts in all cells, whereas COX2 is produced only at the site of inflammation. Therefore, if we want to suppress inflammation, it is important to inhibit primarily COX2, but not COX1, because the latter has a number of important functions in the body, such as protecting the gastric mucosa. This is also why some anti-inflammatory drugs that inhibit the production of both types of COX can cause stomach upset (aspirin is a typical example).

EGCG is one of the substances that can effectively inhibit COX2, but without affecting COX1.(30) In addition, it suppresses the production of pro-inflammatory cytokines and other inflammation-promoting substances. As a result, they may influence the development and treatment of certain cancers that have an inflammatory basis, cardiovascular disease, (32) diabetes, obesity, arthritis, (31) but also, for example, accelerate recovery after strenuous physical activity.

The aging process

Ageing is inevitable, but we can influence its speed quite significantly. The key is again epigenetics. The processes that are its essence (gene methylation, histone acetylation) influence whether a gene will be “read”, i.e. whether or not proteins will be synthesized according to it. This then affects not only the aging process itself, specifically, for example, the ability of cells to repair damaged DNA, but also a number of age-related degenerative diseases (14, 20).

EGCG positively influences both the overall rate of gene methylation and other epigenetic responses, but also some specific genes that are associated with ageing. For example, studies focusing on the effect of EGCG on the so-called Methuselah gene look promising. This is a gene named after the biblical Methuselah, who is said to have lived to be 960 years old, whose function is to rid the body of damaged cells. When scientists tried to manipulate this gene in octopi, they found that they lived a third longer than their normal counterparts. (34)

However, EGCG also positively influences other ageing-related processes. After just 12 weeks of use, for example, one study found an increase in the production of the enzyme telomerase, which slows the shortening of telomeres during cell division. Telomeres are the ends of chromosomes that shorten with each cell division, and when their length reaches a certain critical value, cells lose their ability to divide. At that point, they can enter what is known as senescence, a condition sometimes called ‘cellular zombie’. It is the accumulation of senescent cells that then impairs the function of individual tissues, increases the rate of inflammation in the body and accelerates the ageing process. Thus, by promoting the production of telomerase, EGCG not only prolongs the life of individual cells in the body, but also suppresses the formation of senescent cells. At the same time, it prevents the excessive production of this enzyme, which could result in an increased risk of cancer. (34, 35, 90, 91)

Another important group of enzymes that EGCG positively affects are the sirtuins. These enzymes are essential for the formation and proper functioning of mitochondria, the cellular organelles in which nutrients are converted into energy. If the mitochondria in a tissue are dysfunctional or few in number, the tissue in question suffers from a lack of energy, its function deteriorates and the ageing process is accelerated (92, 93).

EGCG can also affect the visible signs of aging, such as the condition of our skin. It activates the skin cells called keratinocytes in the top layer of the skin, influencing their ability to divide and thus reducing the formation of wrinkles. At the same time, it can also improve the condition of certain skin diseases (such as psoriasis), have a positive effect on wound healing and reduce scarring.

Fattening of the liver

Administration of EGCG has been very successful in experiments on mice in fatty liver of non-alcoholic origin. Here, EGCG significantly suppressed fat deposition and triglyceride accumulation in the liver. The reason for this is probably the positive effect on the gut microbiome (50).

Alzheimer’s and Parkinson’s disease

Scientists have identified a total of 28 regions in the human genome that may be responsible for the development of Alzheimer’s disease. It turns out that epigenetics plays an important role in this process – for example, high levels of methylation of certain regions of genes have also been found in people who were found to have high levels of amyloid plaques in their brains after death (one of the manifestations of Alzheimer’s disease). (23-25) EGCG can effectively inhibit the process of gene methylation and may therefore play a significant role in the prevention and treatment of the disease.

Positive effects have also been shown in other neurodegenerative diseases, such as Parkinson’s disease. Research shows that two cups of green tea a day can significantly reduce the risk of this disease and also have a positive effect on cognitive abilities.(21, 22) In addition, taking EGCG increases the effectiveness of treatment for Parkinson’s disease. This is because it involves the use of a drug containing a substance called levodopa (L-dopa), from which dopamine is synthesised in the brain (dopamine itself does not cross the barrier between the bloodstream and the brain, and so its use is pointless). ECCG reduces the methylation of L-dopa, in which it is converted into an ineffective form.

Mental performance and stress levels

EGCG also directly affects mental performance in healthy people, not only with regular use but also immediately. For example, when volunteers in one study were given 300 g of EGCG, they experienced a significant increase in brain activity, which was also recorded by EEG. Interestingly, although the subjects showed an improvement in attention and brain activity, they also experienced an overall calming and reduction in stress levels. (53) The anti-stress effects of green tea have also been confirmed by other studies.

Positive effects on mental performance have even been reported in children suffering from fetal alcohol syndrome, a set of physical and mental disabilities resulting from drinking alcohol during pregnancy (83).

Depression

Both green tea and EGCG extract have positive mood and anti-depressant effects. It combines several mechanisms of action, such as a strong anti-inflammatory effect or regulation of the activity of the pituitary-hypothalamus-adrenal axis. As far as green tea is concerned, consuming three cups a day reduces the risk of depression by an average of 37 % (54).

Down syndrome

The basis of this disease, which manifests itself in a number of physical and mental symptoms, is purely genetic – affected persons have not twice but three times chromosome 21 in their cells. However, it turns out that the degree to which the disorder manifests itself can be influenced to a large extent – in particular, the degree of impairment in learning and memory is influenced epigenetically, for example through DNA methylation and histone modification, and these changes are even reversible (28, 29).

Research has shown that the presynaptic protein alpha-synuclein is significantly reduced in people with Down syndrome. Experiments in mice have confirmed that EGCG can positively influence the production of this substance.(26) In addition, it can regulate the production of the enzyme Dyrk1A, which is essential for brain development. Its excessive activity is considered a pathogenic factor in Down syndrome. (27)

Administration of EGCG to people with Down syndrome also slows mental decline over the course of life, helping to improve memory and behavioural problems (83).

Arthrosis

In vitro studies have confirmed that EGCG has the potential to protect articular cartilage from degradation. An important mechanism here is the suppression of the production of pro-inflammatory interleukins (one of the substances that induce inflammation), which have a destructive effect on cartilage cells. EGCG-treated cartilage cells have also shown in studies to be more viable and resistant to free radicals, and they also had a higher content of proteoglycans, which are water-binding substances that increase the flexibility of articular cartilage and its resistance to pressure (34, 55).

Autoimmune diseases

The combination of the strong anti-inflammatory effect of EGCG and epigenetic action makes it a very suitable remedy for a number of autoimmune diseases:

Rheumatoid arthritis

The ability of EGCG to increase cartilage resistance and promote proteoglycan formation is not only used in arthritis, but also in an inflammatory autoimmune joint disease called rheumatoid arthritis. Perhaps even more important, however, is its ability to modify the balance of two types of immune T-cells referred to as Th-17 and Treg. Indeed, it is the high ratio of Th-17 to Treg that is typical of rheumatoid arthritis (35, 82).

EGCG also suppresses the excessive growth of cells called synovial fibroblasts and their ability to produce inflammatory substances, a process typical of rheumatoid arthritis, and generally reduces the level of inflammation in affected joints (35).

Crohn’s disease and ulcerative colitis

In a healthy intestine, the number of epithelial cells is regulated so that they precisely cover the surface of the so-called villi, or protrusions, of the intestinal mucosa. Therefore, when new cells arise, the original ones succumb to apoptosis (i.e. cell death). If the process of apoptosis is disturbed, the barrier function of the intestinal wall is disrupted, the immune system reacts inappropriately and inflammatory substances are produced. These are the main manifestations of the two most common intestinal diseases, Crohn’s disease and ulcerative colitis.

In studies, EGCG administration has been shown to reduce intestinal inflammation, the production of inflammatory substances (especially cytokines), and disease activity to a similar level as the most commonly used conventional drug sulfasalazine, which has a number of adverse effects (51, 52, 82).

Multiple sclerosis

This autoimmune disease attacks the nervous system, causing demyelination (i.e., the disappearance of myelin sheaths on nerve fibers that are essential for conducting nerve impulses), and damaging the nerve cell processes.

EGCG not only has anti-inflammatory effects, but also its antioxidant action and ability to protect nerve cells from damage. It also helps to restore the balance between the different T-cell groups and reduces the so-called leukocyte infiltration. (82)

Even better results than with EGCG alone were achieved here when it was combined with coconut oil (600 mg EGCG + 60 ml coconut oil (81).

Sjogren’s syndrome

This lesser-known but still relatively common autoimmune disease is characterized by the fact that the body’s own immune cells attack the so-called exocrine glands, especially the salivary and lacrimal glands, causing their chronic inflammation and destruction. It can occur alone or accompany other autoimmune diseases. EGCG not only reduces the level of inflammation in the glands concerned, but also protects their cells from apoptosis or cell death and improves their overall function (82).

Sports performance

In the context of weight loss, we have already mentioned that EGCG supports the body’s ability to use fat as fuel during aerobic exercise. However, this effect is also very important for endurance athletes, especially those whose performance in a race exceeds 90 minutes in duration (by which time the body usually makes do with carbohydrate stores).

For example, when researchers in one study gave normal-weight volunteers 890 g of green tea catechins, 366 g of which were EGCG, before physical activity (30 minutes of exercise at 60% VO2max), they experienced a whopping 17% increase in whole-body fat oxidation during exercise! In another study, volunteers underwent 10 weeks of endurance training (3 times a week for 60 minutes at 60% VO2max) while taking 573 g of tea catechins daily (of which about 100 g was EGCG), and after this time, during a 90-minute control exercise, the researchers observed an increased ability to use fat as an energy source, at the expense of carbohydrate burn. Meanwhile, there was no significant change in the ratio of sugars and fats burned in the group that took a placebo during the same workout. This is a very important effect because when an athlete is able to burn more fat at the same intensity of exercise, he or she conserves the polysaccharide glycogen stores in the muscles and is therefore able to maintain the appropriate pace for a significantly longer period of time. In experiments on mice that underwent 10 weeks of endurance training along with EGCG use, there was even a significant increase in performance in the constant speed to exhaustion test afterwards – the experimental mice could run an average of 30% longer (57)!

In other studies, volunteers in endurance training associated with higher doses of EGCG (up to 1,000 mg per day) also experienced an increase in VO2max, a value that reflects the maximum amount of oxygen the muscles are able to use during exercise. VO2max is considered an important indicator of endurance performance. In addition, EGCG significantly reduces oxidative stress associated with physical exercise, which, together with its anti-inflammatory effects, leads to accelerated recovery (57).

Immunity and antiviral action

EGCG acts as an immunostimulant, improving the immune system’s response to infection as well as a wide range of other immune functions. EGCG has also been shown to be directly effective against certain viruses, both DNA viruses and RNA viruses. This is also true, for example, for the COVID-19 virus, where it prevents its replication and reduces the risk of cytokine storm (a severe inflammatory condition) and lung damage. Its antifibrotic effect is also applied here, which reduces the formation of blood clots that are common in covid infection. EGCG also shows activity against herpes simplex viruses causing cold sores, influenza viruses, zika and dengue viruses, and even HIV (79, 83).

Eyes

The antioxidant, epigenetic and anti-inflammatory effects of EGCG are also exerted within the eyes. For example, long-term consumption of a single cup of high quality green tea per day reduces the risk of glaucoma by 74%! For glaucoma that has already developed, EGCG can then significantly slow down the progression of the disease. It is also effective in preventing and supporting the treatment of cataracts and has a protective effect on retinal cells and is also suitable for macular degeneration. In one study, for example, administration of 200 mg of EGCG for three months was able to significantly improve retinal function (84, 88, 89).

Diabetes

EGCG along with other catechins from green tea alleviate diabetes 2. Type 2, they promote glucose uptake and the formation of storage polysaccharide glycogen in muscles, reduce oxidative stress that promotes insulin resistance, improve the formation of mitochondria, where glucose is converted into energy, and improve insulin production. (85)

EGCG also counteracts some of the complications of diabetes, such as diabetic nephropathy and retinopathy. (83)

Pulmonary fibrosis

EGCG, as well as other catechins from green tea, have an antifibrotic effect, which is also seen in pulmonary fibrosis (83).

Hair fall

Epigallocatechin gallate is useful for male pattern baldness because it suppresses the conversion of testosterone to DHT, a substance that causes hair loss, among other things. In addition, it stimulates overall hair growth, is anti-inflammatory, and has a wide range of other positive effects, and therefore may be beneficial for other causes of excessive hair loss (86).

Use and contraindications

EGCG is usually taken at 100-200 mg per day for prevention, but higher doses, usually 400-1000 mg per day, are used for therapeutic purposes. However, high doses should not be consumed over the long term. Indeed, elevated levels of transaminase, a substance that signals liver damage, have been found in people taking more than 800 mg of EGCG per day (41). A dose not exceeding 338 g is considered safe for daily use (42). To be effective, a minimum of a two-month course is recommended.

EGCG and the other catechins in green tea are best absorbed when consumed in the morning on an empty stomach – when volunteers’ blood levels of catechins were measured to be 3.5 times higher than when taken at other times of the day or with food. For example, when a dietary supplement with EGCG was taken with breakfast, there was a 30% reduction in bioavailability in women, and absorption was even virtually inhibited in men. Moreover, EGCG is unstable in high temperature environments – which is why it is not advisable to pour boiling water over green tea. The stability is also reduced by the alkaline pH, so it may be advantageous to administer it together with vitamin C. The bioavailability of EGCG is also increased by the presence of caffeine, which is why it is worth, for example, washing it down with tea (but not hot tea). Its absorption is also enhanced by taking it together with curcumin, piperine, rutin or genistein – the latter combination is particularly suitable for menopausal women, as genistein is a very potent phytoestrogen (64-68).

EGCG is not suitable for reduced thyroid function and also for liver disease (except for fatty liver, where it has a significantly positive effect). Contraindications may include the use of heart rhythm stabilizers, benzodiazepines (for anxiety), beta-blockers, ephedrine, some antidepressants, and may even interfere with the effectiveness of antibiotics.

Suitable combinations

In addition to the above combinations that increase the bioavailability of EGCG, many other combinations with dietary supplements are also beneficial:

Slowing aging: EGCG + quercetin (58), EGCG + ginkgo biloba (77)

Cancer prevention and treatment: EGCG + quercetin (59), EGCG + curcumin (67), EGCG + genistein (70), EGCG + resveratrol (71, 73), EGCG + OPC (72), EGCG + selenium (75)

Immunity and antimicrobial action: EGCG + quercetin (60), EGCG + OPC (72), EGCG + zinc (76)

Sports performance: EGCG + quercetin (61), EGCG + OPC (72)

Heart and blood vessels: EGCG + quercetin (62), EGCG + curcumin (69), EGCG + resveratrol (74), EGCG + lycopene (80)

Mental performance: EGCG + OPC (72), EGCG + Ginkgo biloba (78)

Anti-inflammatory and antioxidant action: EGCG + + quercetin (63)