Introduction
What is EGT?
Antioxidant and cytoprotective properties
Mitochondrial function
Transporter (OCTN1) distribution in tissues
Dietary sources
Cognitive decline and neuroprotection
Cardiovascular and metabolic effects
Anti-inflammatory potential
Research Gaps
References
Further reading
Ergothioneine is a diet-derived antioxidant that may support healthy aging, cognitive function, and cardiovascular health. Current evidence suggests protective biological roles, but large clinical trials are still needed to define its therapeutic and nutritional significance.
Image Credit: DG Stock / Shutterstock.com
Introduction
Ergothioneine (EGT), a unique sulfur-containing amino acid, is emerging as a critical micronutrient that supports healthy aging, mitochondrial respiration, and metabolic function. Although it is not yet formally classified as a vitamin, several authors have proposed EGT as a candidate “longevity” or “stress” vitamin based on its specific transporter and long-term retention in tissues.1,3 This article discusses the physiological benefits of EGT, its biological roles, fungi-derived sources, and clinically suggested health benefits.
What is EGT?
EGT is a natural sulfur-containing amino acid derivative of histidine that was first isolated from the ergot fungus Claviceps purpurea in 1909.1
Animals and humans are incapable of naturally synthesizing EGT; therefore, this bioactive can only be obtained from dietary sources.1,3,6 EGT is primarily produced by fungi and certain bacteria, with mushrooms widely recognized as the most significant dietary source for humans.1
The Triage Theory, which was originally proposed by Bruce Ames in 2006, posits that when low levels of micronutrients are present, the body prioritizes their use for immediate survival and reproduction at the expense of functions that support long-term health.1 According to this theory, a chronic, low-level deficiency of a nutrient like EGT might not cause an acute, overt disease but may lead to cellular damage that accelerates the onset of age-related chronic illnesses like cardiovascular diseases (CVDs), cancers, and metabolic syndromes.1
Antioxidant and cytoprotective properties
At physiological pH, EGT exists in its stable thione tautomeric form, rather than its unstable thiol form.1,3,6 This chemical distinction makes EGT highly resistant to autooxidation, which is a unique property as compared to other thiols like glutathione that allows for its persistence in tissues.1,3,6
EGT is a versatile scavenger of reactive oxygen and nitrogen species, thereby protecting critical biomolecules, such as DNA, proteins, and lipids, from oxidative damage.1,3,6 Additional cytoprotective properties of EGT include chelating redox-active metal ions to prevent the generation of highly destructive hydroxyl radicals and modulating key inflammatory signaling pathways like nuclear factor-kappa B (NF-κB).3,6
Mitochondrial function
Recent studies have established an association between EGT and improved aerobic exercise performance in preclinical models, along with reduced oxidative stress and preserved early muscle recovery signaling.4 However, direct evidence that EGT enhances mitochondrial respiration in humans is currently lacking, and available animal data primarily indicate cytoprotection under exercise-induced stress rather than a confirmed primary role as an energy production modulator.3,4
Transporter (OCTN1) distribution in tissues
The human body utilizes metabolic energy to express solute carrier family 22 member 4 (SLC22A4) transporters. SLC22A4, also known as the ergothioneine transporter (ETT) and historically termed organic cation transporter novel type 1 (OCTN1), absorbs dietary EGT and mediates its tissue distribution and renal reuptake.5,6
Mechanistic investigations have revealed that SLC22A4 is not ubiquitously expressed; instead, it is concentrated in tissues and cells that are vulnerable to oxidative stress and inflammation, such as the bone marrow, developing red blood cells, monocytes, macrophages, and specific epithelial barriers, while its expression in the central nervous system remains uncertain.5
Dietary sources
The primary dietary sources of EGT are fungi.1 Nutriomics studies demonstrate that mushrooms contain significantly higher concentrations of EGT than any other human-palatable food group.1
However, EGT content in mushrooms varies widely among species. For example, specialty mushrooms such as oyster (Pleurotus ostreatus), shiitake (Lentinula edodes), maitake (Grifola frondosa), and lion's mane (Hericium erinaceus) generally contain higher levels than white button mushrooms (Agaricus bisporus).7
Although mushrooms are the most concentrated sources of EGT, trace amounts of EGT have been reported in beans, oats, and organ meats such as kidney and liver. This bioaccumulation of EGT in these products occurs from plants and animals acquiring EGT from fungi and bacteria present in the soil and their environment.1,3,6
Dietary Sources of the “Longevity Vitamin” Ergothioneine
Cognitive decline and neuroprotection
Several studies have reported that lower blood concentrations of EGT are consistently associated with a higher prevalence of cognitive impairment and an accelerated rate of cognitive decline in older adults.2,7,8 In a longitudinal memory clinic cohort, low plasma EGT predicted faster decline in multiple cognitive domains and functional measures over up to five years.2
Small pilot trials in older adults with mild cognitive impairment have reported modest improvements in learning and memory outcomes following EGT supplementation; however, sample sizes were limited, and the results require confirmation in larger studies.8
This correlational evidence is supported by emerging interventional data. A 16-week randomized, double-blind, placebo-controlled trial in healthy older adults with subjective memory complaints evaluated daily doses of 10 mg and 25 mg of EGT, revealing that supplementation was safe and well-tolerated; however, its effects on objective cognitive measures were limited.9
Specifically, a temporary improvement in composite memory was reported at four weeks in the 25 mg group, but it was not sustained. Nevertheless, dose-dependent improvements in subjective measures were observed, with the 25 mg dose significantly improving prospective memory and sleep initiation.9
Although these findings suggest some benefits, longer clinical trials are needed, particularly in individuals with lower baseline cognitive function or lower baseline plasma EGT levels.2,9
An extensive, population-based prospective study followed 3,236 participants for a median of 21.4 years. Among this cohort, higher plasma EGT concentrations were strongly and independently associated with a reduced risk of developing CVD, as well as lower rates of both cardiovascular and all-cause mortality.10
These associations remained significant, even after adjusting for traditional cardiometabolic risk factors. Mechanistic support primarily comes from cellular and animal studies, which demonstrate that EGT protects endothelial cells from oxidative stress and may limit ischemia–reperfusion damage and vascular dysfunction, rather than from large-scale human intervention trials.3,6
Anti-inflammatory potential
EGT modulates key inflammatory pathways, and genetic variants in its transporter (SLC22A4) have been associated with altered immune responses and susceptibility to chronic inflammatory conditions, such as Crohn's disease and rheumatoid arthritis. These associations reflect transporter-related immune dysregulation rather than direct evidence of EGT deficiency. Thus, efficient EGT transport into immune cells may be crucial for maintaining immune homeostasis.3,5
Research Gaps
Despite compelling evidence, significant research gaps remain, which have prevented the publication of EGT guidelines by public health authorities.
Optimal intake levels
Although human studies have safely used doses up to 25 mg/day, no established Recommended Dietary Allowance (RDA) or optimal intake level for EGT currently exists. The European Food Safety Authority (EFSA) has approved a novel synthetic EGT at a dose of 30 mg/day for adults; however, this dose is based on safety considerations rather than efficacy.3,6,9
Clinical trial data
Current knowledge on the effects of EGT is based on observational data in humans and preclinical mechanistic studies. Existing interventional trials are small-scale pilot studies that, while positive, are insufficient to establish definitive efficacy for preventing or treating chronic disease.2,7-10 Thus, there remains an urgent need for large-scale, long-term randomized controlled trials to confirm the causal relationship between EGT supplementation and clinical endpoints, such as dementia conversion rates and cardiovascular events.
References
- Beelman, R. B., Kalaras, M. D., Phillips, A. T., and Richie, J. P., Jr. (2020). Is ergothioneine a 'longevity vitamin' limited in the American diet? Journal of Nutritional Science 9. DOI:10.1017/jns.2020.44, https://www.cambridge.org/core/journals/journal-of-nutritional-science/article/is-ergothioneine-a-longevity-vitamin-limited-in-the-american-diet/31B9A91CEB3A61C8F72CCFD56B85704E.
- Wu, L. Y., Kan, C. N., Cheah, I. K., et al. (2022). Low Plasma Ergothioneine Predicts Cognitive and Functional Decline in an Elderly Cohort Attending Memory Clinics. Antioxidants 11(9); 1717. DOI:10.3390/antiox11091717, https://www.mdpi.com/2076-3921/11/9/1717.
- Paul, B. D. (2022). Ergothioneine: A Stress Vitamin with Antiaging, Vascular, and Neuroprotective Roles? Antioxidants and Redox Signaling 36(16-18); 1306-1317. DOI:10.1089/ars.2021.0043, https://www.liebertpub.com/doi/10.1089/ars.2021.0043.
- Fovet, T., Guilhot, C., Delobel, P., et al. (2022). Ergothioneine Improves Aerobic Performance Without Any Negative Effect on Early Muscle Recovery Signaling in Response to Acute Exercise. Frontiers in Physiology 13. DOI:10.3389/fphys.2022.834597, https://www.frontiersin.org/articles/10.3389/fphys.2022.834597.
- Gründemann, D., Hartmann, L., and Flögel, S. (2022). The ergothioneine transporter (ETT): substrates and locations, an inventory. FEBS Letters 596(10); 1252-1269. DOI:10.1002/1873-3468.14269, https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.14269.
- Cheah, I. K., Tang, R. M. Y., Yew, T. S. Z., et al. (2017). Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. Antioxidants and Redox Signaling 26(5); 193-206. DOI:10.1089/ars.2016.6778, https://www.liebertpub.com/doi/10.1089/ars.2016.6778.
- Uffelman, C. N., Doenges, K. A., Armstrong, M. L., et al. (2023). Metabolomics Profiling of White Button, Crimini, Portabella, Lion's Mane, Maitake, Oyster, and Shiitake Mushrooms Using Untargeted Metabolomics and Targeted Amino Acid Analysis. Foods 12(16); 2985. DOI:10.3390/foods12162985, https://www.mdpi.com/2304-8158/12/16/2985.
- Gede, A. M. M. I., Gu, Q., Phukhatmuen, P., et al. (2025). Advances and prospects of ergothioneine in the treatment of cognitive frailty. Annals of Medicine 57(1). DOI:10.1080/07853890.2025.2555742, https://www.tandfonline.com/doi/10.1080/07853890.2025.2555742.
- Zajac, I. T., Kakoschke, N., Kuhn-Sherlock, B., and May-Zhang, L. S. (2025). The Effect of Ergothioneine Supplementation on Cognitive Function, Memory, and Sleep in Older Adults with Subjective Memory Complaints: A Randomized Placebo-Controlled Trial. Nutraceuticals 5(3); 15. DOI:10.3390/nutraceuticals5030015, https://www.mdpi.com/1661-3821/5/3/15.
- Smith, E., Ottosson, F., Hellstrand, S., et al. (2019). Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease. Heart 106(9); 691-697. DOI:10.1136/heartjnl-2019-315485, https://heart.bmj.com/lookup/doi/10.1136/heartjnl-2019-315485.
Further Reading
Last Updated: Nov 16, 2025
Shiitake-based supplement may help prevent liver damage progression