There is mounting evidence for the potential for the natural dietary antioxidant and anti-inflammatory amino acid l-Ergothioneine (ERGO) to prevent or mitigate chronic diseases of aging. This has led to the suggestion that it could be considered a ‘longevity vitamin.’ ERGO is produced in nature only by certain fungi and a few other microbes. Mushrooms are, by far, the leading dietary source of ERGO, but it is found in small amounts throughout the food chain, most likely due to soil-borne fungi passing it on to plants. Because some common agricultural practices can disrupt beneficial fungus–plant root relationships, ERGO levels in foods grown under those conditions could be compromised. Thus, research is needed to further analyse the role agricultural practices play in the availability of ERGO in the human diet and its potential to improve our long-term health.

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Ergothioneine (ERGO) is a potent antioxidant and anti‐inflammatory amino acid that is highly bioavailable to humans from the diet. ERGO is now regarded by some as a ‘longevity vitamin’ that has the potential to mitigate some chronic diseases of ageing and thereby increase life expectancy when present in adequate amounts. However, only limited knowledge exists regarding ERGO content in the human diet. Since ERGO is produced primarily by fungi, mushrooms are known to be the leading dietary source, but ERGO is found in relatively low amounts throughout the food chain as a result of soil‐borne fungi or bacteria passing it on to plants through their roots. Some conventional agricultural practices that negatively impact soil fungi, such as excessive soil disturbance (ploughing), can significantly reduce ERGO content of food crops when compared to regenerative practices such as eliminating tillage of the soil (no‐till). This has led us to the concept that ERGO may be a definitive connection between soil health and human health.

Background: Ergothioneine (ERGO) is a unique antioxidant and a rare amino acid available in fungi and various bacteria but not in higher plants or animals. Substantial research data indicate that ERGO is a physiological antioxidant cytoprotectant. Different from other antioxidants that need to breach the blood–brain barrier to enter the brain parenchyma, a specialized transporter called OCTN1 has been identified for transporting ERGO to the brain. Purpose: To assess whether consumption of ERGO can prevent the progress of Alzheimer’s disease (AD) on young (4-month-old) 5XFAD mice. Methods and materials: Three cohorts of mice were tested in this study, including ERGO-treated 5XFAD, non-treated 5XFAD, and WT mice. After the therapy, the animals went through various behavioral experiments to assess cognition. Then, mice were scanned with PET imaging to evaluate the biomarkers associated with AD using [¹¹C]PIB, [¹¹C]ERGO, and [¹⁸F]FDG radioligands. At the end of imaging, the animals went through cardiac perfusion, and the brains were isolated for immunohistology. Results: Young (4-month-old) 5XFAD mice did not show a cognitive deficit, and thus, we observed modest improvement in the treated counterparts. In contrast, the response to therapy was clearly detected at the molecular level. Treating 5XFAD mice with ERGO resulted in reduced amyloid plaques, oxidative stress, and rescued glucose metabolism. Conclusions: Consumption of high amounts of ERGO benefits the brain. ERGO has the potential to prevent AD. This work also demonstrates the power of imaging technology to assess response during therapy.