A naturally occurring compound in mushrooms has attracted scientific interest for its potential effects on memory, inflammation, and neuronal survival, raising questions about its role in protecting the aging brain.
Review: Ergothioneine: A Natural Antioxidant Claimed to Prevent Neurodegeneration. Credit: Piterek / Shutterstock
In a recent review published in the journal Nutrients, researchers at the University of Rzeszow, Poland, critically reviewed evidence on the neuroprotective properties of ergothioneine (ET).
Neurodegenerative diseases reduce both healthspan and lifespan and compromise the quality of life and independence of the affected individuals and their caregivers. Currently, no cure exists for these diseases. Oxidative stress accompanies and possibly contributes to neurodegenerative diseases; antioxidants have been proposed as potential protective agents.
ET, a thiol antioxidant present in mushrooms and other foods, could be a promising prophylactic and therapeutic compound. Several studies have focused on the effects of ET in neurodegenerative diseases, with one previous review proposing that dietary ET deficiency may contribute to neurodegeneration, a hypothesis that remains unproven. In the present study, the researchers summarized evidence on the neuroprotective effects of ET and the underlying mechanisms.
ET and neurodegenerative diseases
Observational studies have reported inverse associations between circulating ET levels and the risk or presence of certain neurodegenerative diseases. In one study, blood ET levels decreased with age in a cohort of older adults; in the same study, individuals with mild cognitive impairment (MCI) had significantly lower blood ET levels than age-matched healthy subjects.
Further, lower serum ET levels were detected in people with Parkinson's disease (PD) than in healthy controls. A study analyzing relationships between blood levels of 991 metabolites and cognition found the strongest association with ET, with lower levels associated with worse cognition. Lower blood ET levels have also been detected in people with cognitive dysfunction and frailty.
A longitudinal study of 470 people without cognitive impairment at baseline reported that lower ET levels were associated with faster declines in global cognition and attention, memory, locomotor, and language functions. Another study found that lower blood ET levels in people with MCI were associated with a greater likelihood of progressing to Alzheimer's disease (AD).
But these associations cannot establish whether low ET levels contribute to neurodegeneration or result from increased antioxidant consumption during oxidative stress. The review also describes conflicting findings, including a study linking higher serum ET levels to increased AD risk.
Effects of ET administration
Associations between lower circulating ET levels and higher risks of neurodegenerative diseases have prompted research into whether restoring ET levels could aid in disease prevention and treatment. In cellular models of neurodegeneration, ET administration was found to have protective effects. For example, ET treatment protected mouse hypothalamic neurons from death by suppressing excessive production of reactive oxygen species (ROS).
ET improved cell viability and reduced ROS levels in human brain endothelial cells challenged with high concentrations of oxidants and glucose. Further, ET also reduced behavioral and cognitive deficits in mouse models of AD and PD. In a Caenorhabditis elegans PD model, ET treatment protected dopaminergic neurons, reduced α-synuclein aggregation and oxidative stress, and increased lifespan. Some cellular experiments used ET concentrations exceeding those achievable in humans, while animal studies often involved doses above typical dietary intake.
In humans, ET administration for up to 35 days was associated with statistically nonsignificant downward trends in blood and urinary biomarkers of inflammation and oxidative damage. In people aged 40–64 who were aware of attention or memory decline, 16-week ET administration significantly improved subjective sleep quality. In another trial, a 20 mg/day ET treatment for four weeks substantially ameliorated sleeping difficulties in individuals with sleep complaints and anxiety.
Because sleep disturbances can precede motor symptoms by several years in PD, the researchers proposed that ET might delay disease onset, but this remains unproven in humans. At week four, a 16-week ET treatment in people with subjective memory complaints temporarily improved composite memory in participants receiving the higher dose. A separate 12-week trial using mushroom extract tablets containing ET reported improved verbal memory in healthy participants and people with suspected MCI, but other mushroom compounds may have contributed.
Mechanisms of action
The protective effects of ET against neurodegeneration are hypothesized to stem from its antioxidant activity, but other mechanisms may also contribute. Various studies report that ET activates nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of endogenous antioxidant response, in distinct cell types. ET has been reported to exert anti-inflammatory effects. ET was shown to inhibit the release of pro-inflammatory cytokines from cultured microglia.
Administration of an ET-rich extract from Hericium erinaceus to AD mice decreased brain and blood levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Computational analyses identified several proteins involved in inflammation and cell survival as potential ET targets, suggesting that the compound may influence these biological processes. Experimental studies also suggest that ET may reduce the aggregation of amyloid-beta, tau, and α-synuclein and affect pathways involved in neuronal survival, but these effects remain unproven in patients.
Concluding remarks
Collectively, ET has demonstrated neuroprotective effects in experimental models and warrants further investigation as a potential preventive or therapeutic agent for neurodegenerative diseases. Its clinical effectiveness remains unproven, and the underlying mechanisms remain incompletely understood. ET supplementation or ET-rich diets have been proposed as possible ways to help prevent, delay, or limit neurodegeneration in the general population. Still, this recommendation is not yet adequately supported by human studies and warrants further research through larger, long-term randomized trials using purified ET.
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