Daily Longevity Science Newsletter: August 25, 2025

Ergothioneine: a “Longevity Vitamin”?

Aug 25, 2025

A 16-week randomized, double-blind, placebo-controlled trial in older adults with subjective memory complaints evaluated daily supplementation with ergothioneine (ET; 10 mg or 25 mg; ErgoActive®) versus placebo. The investigators reported dose-dependent improvements in subjective prospective memory and sleep initiation, reaching significance at the 25 mg dose. An early within-group gain in composite memory was observed but did not persist relative to placebo at study end. Exploratory analyses demonstrated favorable safety and metabolic signals, including stable TMAO levels, improved liver enzymes, and a within-group increase in telomere length. While between-group cognitive differences were limited, the combination of safety, pharmacokinetic robustness, and preliminary efficacy signals supports the rationale for larger, longer trials to confirm potential benefits in cognitive aging and sleep regulation.

Relevant Trials

ErgoActive RCT (2025): In a 16-week, randomized, double-blind, placebo-controlled trial, 147 adults aged 55–79 with subjective memory complaints received daily ET at 10 mg or 25 mg (ErgoActive®) or placebo. Key findings included:

Dose‑dependent improvements in subjective prospective memory and sleep initiation, reaching statistical significance at the 25 mg dose.
A transient within-group improvement in composite memory (CNS Vital Signs) at week 4 with the 25 mg group, which did not differ from placebo by week 16.
Plasma ET concentration increased 3‑ to 6‑fold for 10 mg and 6‑ to 16‑fold for 25 mg by weeks 4 and 16 (p < 0.001), confirming dose- and time-dependent pharmacokinetics.
Favorable safety profile: No rise in TMAO levels; exploratory markers showed improved liver function tests and a within-group increase in telomere length.

A 2022 randomized, placebo-controlled study found that daily supplementation with 20 mg of ET significantly improved objective sleep architecture, including increased N2 sleep stage, reduced time in N1, and fewer awakenings after sleep onset (WASO), as assessed via polysomnography. These changes—key indicators of deeper, more restorative non-REM sleep—are consistent with better sleep quality and support earlier findings of ET’s neuroprotective promise.

Low plasma ET predicts faster cognitive decline in older adults attending memory clinics. A longitudinal study demonstrated that lower baseline ET levels were associated with poorer baseline cognition and accelerated decline in multiple domains (memory, executive function, attention, visuomotor speed), particularly among non-demented individuals. Mediating factors included white-matter hyperintensities and brain atrophy.

Mechanisms & Biomarkers

Brain access via a dedicated transporter.
ET is actively transported across the blood–brain barrier by the OCTN1 (SLC22A4) transporter, which is highly expressed in neural and immune cells. This allows ET to accumulate in the brain, where it can modulate neuronal redox balance, synaptic signaling, and neuroinflammation.

Cytoprotective antioxidant & mitochondrial support.
ET is a broad-spectrum antioxidant, capable of scavenging singlet oxygen, superoxide, hydrogen peroxide, hydroxyl radicals, and peroxynitrite. Preclinical work shows that ET protects mitochondrial DNA and respiratory chain enzymes, reduces lipid peroxidation, and maintains ATP production under oxidative stress. These effects are particularly relevant to neurodegenerative disease models such as Alzheimer’s and Parkinson’s.

Systemic marker links.
Human studies show that plasma ET declines with age, and reduced OCTN1 expression in microglia and neural stem cells suggests impaired uptake during aging. These deficits may contribute to increased vulnerability to oxidative stress, impaired neurogenesis, and higher risk of cognitive decline. Low plasma ET has been correlated with faster cognitive deterioration and earlier onset of disability in longitudinal cohorts, reinforcing its role as a potential longevity biomarker.

Therapeutics & Innovation

Where the evidence stands today.
The 2025 randomized controlled trial demonstrates that ET is safe, well-tolerated, and bioavailable, producing dose-dependent rises in plasma ET and favorable exploratory metabolic signals. Importantly, it showed benefits in subjective sleep initiation and prospective memory, though durable cognitive separation versus placebo was not observed at 16 weeks. Larger, longer trials—especially in individuals with lower baseline ET levels or heightened neurocognitive risk—are required to confirm efficacy.

Dosing & formulation.
Clinical investigations to date most often use 10–25 mg/day of purified ET. The most recent data involve ErgoActive®, a branded derivative, which showed encouraging signals but should be interpreted with standard scientific scrutiny pending independent replication.

From diet to clinic.
Unlike many antioxidants, humans cannot synthesize ET. It is obtained exclusively through diet, with mushrooms (oyster, porcini, shiitake, maitake) consistently ranking as the richest natural sources. This makes ET a unique example of a “longevity vitamin” candidate, positioned at the intersection of nutrition and therapeutic development.

Nutrition & Lifestyle

Food sources first.
Among natural foods, culinary mushrooms are by far the richest source of ET. Levels vary by species—oyster, porcini, shiitake, and maitake consistently provide the highest concentrations—but nearly all edible mushrooms contribute meaningfully. Incorporating them regularly into a Mediterranean-style dietary pattern provides a safe, evidence-based way to elevate ET intake while also enhancing dietary fiber, polyphenols, and micronutrients.

Supplement pragmatics.
Human studies most often test 10–25 mg/day of purified ET, including the recent 2025 RCT. These doses were well tolerated, increased plasma ET up to 16-fold, and did not raise TMAO (a marker of cardiovascular risk). However, there is no authoritative clinical dose established for disease prevention or treatment. Clinical efficacy on long-term outcomes—such as cognitive decline, cardiovascular events, or mortality—remains unproven. Anyone considering supplementation should discuss use with a clinician, particularly if managing comorbidities or taking concurrent medications.

Synergy matters.
ET is not a standalone therapy. Its potential brain- and healthspan-related benefits are most likely maximized when integrated into a lifestyle that already addresses neuroinflammation and metabolic health. This means prioritizing:

Sleep regularity and circadian alignment,
Physical activity (aerobic + resistance training),
Oral/periodontal health, and
Glycemic control through whole-food dietary choices.

Together, these synergistic strategies provide the strongest foundation for preserving brain function and promoting longevity, while ET remains under investigation.

Clinical Take

Promising adjunct, not a stand-alone therapy.
ET demonstrates strong biological plausibility—with confirmed transport into the brain via OCTN1, potent antioxidant and mitochondrial-protective properties, and early human signals for improved sleep and subjective memory. However, durable cognitive advantages over placebo remain unproven in randomized controlled trials, and clinical adoption requires stronger evidence.

Who might benefit most?
Emerging data suggest that individuals with low baseline ET levels, subjective sleep disturbance, or early cognitive complaints could represent the most responsive populations. Observational studies consistently associate higher plasma ET with slower cognitive and functional decline, while lower levels predict greater dementia risk—supporting a stratified trial approach.

What would change practice?
Clinical adoption would require replicated RCTs demonstrating:

Sustained cognitive and functional benefits over placebo,
Validated biomarker shifts, including neurofilament light (NfL), inflammatory panels, or neuroimaging correlates, and
Meaningful improvements in patient-centered outcomes, such as daily function, sleep architecture, or reduced dementia progression rates.

If confirmed, ET could transition from a promising nutraceutical to an evidence-based intervention for brain health and longevity.

Actionable Recommendations

For clinicians & researchers

Assess baseline ET context.
Incorporate dietary history—particularly mushroom intake—as a surrogate for ergothioneine exposure. In research settings, plasma ET quantification (where feasible) can enable stratification of participants and more targeted trial design.
Trial design considerations.
Future ergothioneine trials should enrich for low-ET or high-risk groups (e.g., older adults with subjective memory complaints, sleep disturbances, or metabolic vulnerability). Pre-specify sleep and cognition endpoints, and incorporate mechanistic biomarkers such as inflammation markers (CRP, IL-6), telomere dynamics, and neurofilament light (NfL) to establish biological relevance.

For longevity-focused readers

Diet first.
Aim for 2–4 servings of mushrooms per week (with oyster, shiitake, porcini, and maitake being particularly high in ergothioneine). This aligns with Mediterranean-style dietary patterns that support healthy aging.
Sleep as leverage.
If you choose to trial ergothioneine, pair it with sleep regularity—an area where human studies show benefit. Combine with exercise and cardiometabolic care for synergistic neuroprotective effects.
Supplement wisely.
Current human data support 10–25 mg/day for 8–16 weeks, with good tolerability. Track personal responses—such as sleep latency, sleep quality, and memory—using journals or digital cognitive tools. Always review with your clinician, and avoid substituting supplements for foundational lifestyle habits.

Reader Q&A

Q: Is ergothioneine proven to improve cognition?
A: Not definitively. The 2025 RCT showed dose-linked improvements in subjective memory and sleep, but the primary composite memory endpoint did not achieve sustained placebo-adjusted significance at 16 weeks. Larger, longer-duration trials are needed.

Q: Can I just eat mushrooms instead of supplementing?
A: Yes—culinary mushrooms remain the best natural source of ET, and regular dietary intake is strongly recommended. Supplements raise plasma ET more quickly, but superiority over food-based intake for long-term outcomes has not yet been established.

Q: Is ergothioneine safe?
A: In the RCT, 10–25 mg/day was well tolerated, with no rise in TMAO, and exploratory labs even suggested favorable liver markers. Nonetheless, supplementation should be discussed with a clinician, particularly in individuals with liver or kidney disease, polypharmacy, or pregnancy.

Clinical takeaway: Ergothioneine is shaping up as a promising adjunct for healthy brain aging—especially for sleep and subjective memory—while diet-first strategies remain the safest, most proven entry point today.