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Health Benefits of Ergothioneine: A Pathway to Longevity

James Odell, OMD, ND, LAc


Mushroon collage

Naturally Synthesized by Microbes


Ergothioneine (EGT) is a naturally occurring amino acid that has potent antioxidant activities and is associated with health and longevity. It is synthesized by a variety of microbes, especially fungi (including in mushroom fruiting bodies), mycobacteria, and cyanobacteria. It is not synthesized by plants and animals who acquire it from the soil and their diet. Since its discovery, ergothioneine has intrigued researchers for its many health benefits. In 1909, Charles Tanret, whilst investigating the ergot fungus, Claviceps purpurea, which devastated rye grain, isolated a unique crystalline sulfur-containing compound, later identified as trimethylbetaine of 2-thiol-l-histidine (now simply known as ergothioneine or EGT).1


Ergothioneine Found in Mushrooms


EGT is a stable antioxidant molecule and does not degrade at high temperatures or high pH. It is not synthesized by plants and animals, including humans. Therefore, EGT is obtained through dietary sources, mainly from edible mushrooms such as Agaricus bisporus (portobello)Lentinula edodes (shiitake)Grifola frondosa (maitake), Pleurotus ostreatus (oyster mushroom), Trametes versicolor (turkey tail), Inonotus obliquus (chaga), Hericium erinaceus (lion’s mane) and numerous others. These mushroom species have been reported to have a high EGT content. EGT is considered a molecule for longevity and is often referred to as a “longevity vitamin”. This article will discuss some benefits of EGT and sources for its food supplementation.


Biochemistry and Benefits


molecular structure of Ergothioneine

In humans, EGT has been shown to accumulate in various cells and tissues at high concentrations. It is most abundant in erythrocytes (red blood cells), bone marrow, liver, kidney, seminal fluid, and the lens and cornea of eyes, and particularly the brain.2, 3, 4, 5 The presence of ergothioneine in the brain was observed as early as the sixties and was initially believed to be a neurotransmitter and identified as the cerebellar factor.6, 7 Later, it was shown that EGT did not affect neurotransmission, but that it exhibited distinct transport properties that enhanced cognition.8, 9 It is not surprising that EGT is enriched in the cerebellum as its transporter is abundant in this tissue.10 Additionally, EGT is concentrated in mammalian mitochondria, suggesting a functional role in protecting it from oxidative damage due to the generation of mitochondrial superoxide.


EGT is also present in other brain regions, such as the cortex. The basal concentration of EGT in the cortex11, striatum, medulla and pons, midbrain, hippocampus, hypothalamus, and the concentration correlates with the expression of its transporter, indicating its ability to cross the blood-brain barrier.12, 13


A Critical Biological Antioxidant


Although no one specific role has yet to be identified, EGT can play a significant function in improving human health due to its presence as a dedicated molecular transporter and antioxidant in many tissues. EGT is water soluble and exerts antioxidant properties through multiple mechanisms, one of which is its powerful ability to scavenge free radicals. It has been proposed that EGT serves as a critical biological antioxidant based on its ability to act with other antioxidants, particularly glutathione, thus protecting against oxidative stress in the mitochondria. Numerous studies have shown EGT possesses antioxidant and cell protective effects, including free radical scavenger activity.14, 15, 16, 17, 18, 19, 20 

Some researchers have suggested that EGT may interact with other cellular stress defenses in times of excessive oxidative burden, for example as a means to reduce oxidized glutathione (GSH).21 The sulfhydryl group of EGT appears primarily responsible for its antioxidant properties. As EGT exists as thione (the organosulfur analog of ketone) in aqueous solutions, it can scavenge strong free radicals, such as hydroxyl radicals, hypochlorite, and peroxynitrite.22 


Radioprotective and Antimutagenic Properties


Studies also indicate EGT possesses radioprotective (radiation-protective) properties.23, 24, 25, 26, 27, 27, 29, 30, 31, 32, 33, 34 Actually, EGT has been shown to possess radioprotective and antimutagenic properties. The proposed mechanisms of these protective effects are based on the ability of this molecule to donate H atoms to various free radicals, whereby these radicals are repaired and inactivated.


Anti-inflammatory Actions


EGT has been shown to exhibit anti-inflammatory actions.35, 36, 37, 38, EGT inhibits tumor necrosis factor-α-induced release of the inflammatory cytokine interleukin-8 (IL-8) in alveolar macrophages.39 EGT expression is upregulated by inflammatory cytokines. Myeloperoxidase (MPO)-generated halogenating molecules, such as hypochlorous acid and hypobromous acid (HOBr), in inflammatory regions are postulated to contribute to disease progression. It has been shown that EGT, derived from an edible mushroom, inhibited MPO activity as well as the formation of 8-bromo-2′-deoxyguanosine in vitro. The HOBr scavenging effect of EGT is higher than that of ascorbic acid (vitamin C) and glutathione. EGT was shown to inhibit the UV-B-induced inflammatory responses and DNA halogenation, suggesting that EGT is a promising anti-inflammatory agent from mushrooms.


Prevents Neuronal Injury and Neurodegeneration


EGT has also been shown to prevent neuronal injury and neurodegeneration.40, 41, 42, 43 Pathogenesis of neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington’s are attributed to increased production of free radicals. It is understood that free radical scavenging is the mechanism of clearing the stress in the neural cells. Studies of the anti-neurogenetic action of EGT in edible mushroom extracts have demonstrated that this bioactive molecule is responsible for neuroprotective activity.44 

Low levels of ergothioneine in older adults have been linked with cognitive decline. In preclinical studies, ergothioneine showed beneficial neuroprotective properties from oxidative stress, supporting overall cognitive health.45 Nature-based nutraceuticals like EGT from medicinal mushrooms are suggested as safe and efficacious therapeutic agents for neurodegenerative diseases.


 Assists With Toxic Metal Elimination


It was also discovered early on that EGT can chelate (bind to and eliminate) divalent metal ions, thus assisting toxic metal elimination. Various groups have demonstrated the ability of EGT to form complexes with divalent metal cations including copper (Cu2+), mercury (Hg2+ ), cadmium (Cd2+), and nickel (Ni2+).46, 47, 48 


Sources of Ergothioneine


Although a variety of foodstuffs such as oats contain EGT because they take it up from the soil, it is mushrooms that are the prime sources for humans. Edible mushrooms produce an array of phenolic compounds, and one such potential secondary metabolite is EGT.  It has been reported that mushrooms have 45 times higher EGT than other food items. Several commercial mushrooms contain high amounts of EGT, such as Agaricus bisporus (white, cremini, and portabella), Lentinula edodes (shiitake), Grifola frondosa (maitake), Pleurotus ostreatus (oyster mushroom), Trametes versicolor (turkey tail), Inonotus obliquus (chaga), Hericium erinaceus (lion’s mane). Lion's mane and oyster mushrooms have been shown to have the highest concentrations of ergothioneine. These mushrooms are available in powdered extracts. Although a daily recommended dose of ergothioneine has not been established yet, some studies are recommending 5-10 mg per day. For reference, the amount of ergothioneine in a single serving of mushrooms varies, ranging from 2.4 to 4.9mg, depending on the mushroom variety.


Mushrooms - A Multitude of Nutritious Benefits


 Mushrooms were previously regarded as a low-calorie, low-fat food with little beneficial nutrition. However, over the past few decades, research has focused on the roles of mushrooms as a nutritious component of the diet and in the prevention/treatment of many chronic diseases including cancer. Mushrooms are an excellent source of nutrients, such as riboflavin and other B vitamins, selenium, copper, and potassium, and are also rich in dietary fiber, chitin, and β-glucans. It has also been demonstrated that mushrooms can be an abundant source of vitamin D2 when exposed to UV light. 


Safety


EGT has been given a “generally recognized as safe (GRAS)” status by the FDA. It is sold in the market as a food supplement, nutraceutical, functional food, and cosmetics as well as a pharmaceutical additive due to its high safety. The pharmacokinetics of EGT in human subjects showed no known adverse effect up to 25 mg/day for 1 week. In animal models, LE administration up to 1600 mg per kg of body weight did not show any adverse effects or behavioral, or histopathological changes.49 Also, no mutagenic activity was observed in a bacterial reverse mutagenesis assay of the LE with a concentration of 5000 μg ml−1. 50


Summary


Ergothioneine is an amino acid that is widely distributed throughout the body, but levels have been shown to decline as we age.1 Humans cannot produce it, so it must be derived from diet or dietary supplementation. It is found in a variety of food sources, but with the highest concentrations in certain types of mushrooms. EGT has been shown to possess numerous antioxidant and cytoprotective effects including free radical scavenger activity, radioprotective properties, anti-inflammatory actions, and protection against UV radiation or neuronal injury. The safety of the EGT has been tested in animal models and human volunteers, and no adverse effect has been reported so far. Decreased blood and/or plasma levels of ergothioneine have been observed in some diseases, suggesting that a deficiency could be relevant to the disease's onset or progression. Therefore, EGT can be considered an important health-beneficial bioactive compound.


Please remember, it is important to speak with a healthcare provider before taking supplements or making any significant changes to your diet.


References

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  2. Melville, Donald B., William H. Horner, and Rose Lubschez. "Tissue ergothioneine." Journal of Biological Chemistry 206, no. 1 (1954): 221-228.

  3. Shires, Thomas K., Marvin C. Brummel, Josè S. Pulido, and Lewis D. Stegink. "Ergothioneine distribution in bovine and porcine ocular tissues." Comparative Biochemistry and Physiology Part C: Pharmacology, Toxicology and Endocrinology 117, no. 1 (1997): 117-120.

  4. Salt, Harold Bernard. "The ergothioneine content of the blood in health and disease." Biochemical Journal 25, no. 5 (1931): 1712.

  5. Leone, E., and T. Mann. "Ergothioneine in the seminal vesicle secretion." Nature 168, no. 4266 (1951): 205-206.

  6. Crossland, J., J. F. Mitchell, and G. N. Woodruff. "The presence of ergothioneine in the central nervous system and its probable identity with the cerebellar factor." The Journal of Physiology 182, no. 2 (1966): 427-438.

  7. Crossland, J., G. N. Woodruff, and J. F. Mitchell. "Identity of the cerebellar factor." Nature 203, no. 4952 (1964): 1388-1389.

  8. Briggs, I. "Ergothioneine in the central nervous system." Journal of Neurochemistry 19, no. 1 (1972): 27-35.

  9. Krnjević, K., Mirjana Randić, and D. W. Straughan. "Ergothioneine and central neurons." Nature 205, no. 4971 (1965): 603-604.

  10. Wu, Xiang, Ronald L. George, Wei Huang, Haiping Wang, Simon J. Conway, Frederick H. Leibach, and Vadivel Ganapathy. "Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta." Biochimica et Biophysica Acta (BBA)-Biomembranes 1466, no. 1-2 (2000): 315-327.

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  12. Nakamichi, Noritaka, Keigo Nakayama, Takahiro Ishimoto, Yusuke Masuo, Tomohiko Wakayama, Hirotaka Sekiguchi, Keita Sutoh, Koji Usumi, Shoichi Iseki, and Yukio Kato. "Food‐derived hydrophilic antioxidant ergothioneine is distributed to the brain and exerts antidepressant effect in mice." Brain and Behavior 6, no. 6 (2016): e00477.

  13. Nakamichi, Noritaka, Takayuki Taguchi, Hiroshi Hosotani, Tomohiko Wakayama, Takuya Shimizu, Tomoko Sugiura, Shoichi Iseki, and Yukio Kato. "Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: possible involvement in neuronal differentiation." Neurochemistry international 61, no. 7 (2012): 1121-1132.

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  18. Melville, Donald B., William H. Horner, and Rose Lubschez. "Tissue ergothioneine." Journal of Biological Chemistry 206, no. 1 (1954): 221-228.

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  26. Although the functional role of EGT in the skin is not known, its presence may suggest a role as a physiological protectant against ultraviolet (UV)-induced reactive oxygen free radical generation and damage. Much of the skin damage from UV radiation is mediated through the generation of ROS. 

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  43. Song, Tuzz-Ying, Chien-Lin Chen, Jiunn-Wang Liao, Hsiu-Chung Ou, and Ming-Shiun Tsai. "Ergothioneine protects against neuronal injury induced by cisplatin both in vitro and in vivo." Food and Chemical Toxicology 48, no. 12 (2010): 3492-3499.

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