While anti-aging compounds like NMN and Coenzyme Q10 are still being widely discussed, the scientific community has already set its sights on a more promising “longevity molecule” — Ergothioneine. In 2025, several groundbreaking studies confirmed that this natural amino acid significantly boosts NAD⁺ levels. [1]
Ergothioneine elevates NAD⁺ by activating cystathionine γ-lyase (CSE) to produce hydrogen sulfide (H₂S), which in turn drives persulfidation of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH). This mechanism yielded striking results in experiments with C. elegans and aged rats: the worms’ average lifespan increased by 20%, while the older rats saw a twofold improvement in endurance, and restoration of muscle mass and angiogenesis to youthful levels.
Even more remarkable, Ergothioneine works via a mechanism completely distinct from traditional NAD⁺ precursors like NMN. It activates the body's endogenous NAD⁺ production pathways through metabolic reprogramming, showing particularly strong effects in aged individuals. For example, in 9-month-old rats, just 3 weeks of Ergothioneine supplementation showed a strong positive correlation between muscle NAD⁺ levels and physical performance.
This discovery positions Ergothioneine as a potential next-generation “super molecule” in the anti-aging arena, following NMN.
Mitochondrial “Fast-Charging”
If NAD⁺ is the “fuel” for youthful cells, then mitochondria are the “engine” that stores and releases this energy. As we age, oxidative damage to mitochondrial DNA and declining membrane potential reduce energy output.
A Harvard Medical School study revealed another identity of Ergothioneine — the mitochondria’s personal bodyguard. It binds directly to the mitochondrial enzyme MPST, enhancing respiratory chain function and improving ATP production efficiency. When the MPST gene is knocked out, Ergothioneine’s benefits on physical performance vanish, confirming its targeted mechanism. [2]
It also neutralizes mitochondrial superoxide anions, stabilizes membrane potential, and prevents apoptosis. Research at Kanazawa University in Japan showed that supplementation in aged rats restored both mitochondrial structure and function in muscle to youthful levels, with angiogenesis-related gene expression upregulated by 30%. [3]
Anti-Aging Effects: Comprehensive Protection from Cells to Organs
1. The Ultimate Antioxidant
Ergothioneine is known as one of the most potent antioxidants on Earth. It not only neutralizes powerful oxidants like hydroxyl radicals and hypochlorous acid, but also chelates iron and copper ions, preventing free radical chain reactions.
Lab data shows its radical-scavenging efficiency is:
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14× that of glutathione
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40× that of CoQ10
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6000× that of Vitamin E
This extraordinary capability has led to its use in organ preservation during transplantation. [4]
2. Anti-Inflammation & Immune Modulation
Inflammation is a core driver of aging. Researchers at Huazhong Agricultural University found that Ergothioneine suppresses the NF-κB inflammatory pathway and reduces pro-inflammatory cytokines like IL-6 and TNF-α, significantly improving cognitive function in D-galactose-induced aging mice. Its neuroprotective effects are closely linked to reduced mitochondrial damage and neuroinflammation. [4]
A 20-year longitudinal study from Lund University in Sweden further confirmed that higher plasma Ergothioneine levels correlate with lower cardiovascular mortality, making it a top predictive metabolic marker for chronic disease risk. This is likely due to its protection of endothelial cells and inhibition of atherosclerotic plaque formation. [5]
3. Mitochondrial Protection & Enhanced Autophagy
Beyond antioxidant action, Ergothioneine also enhances autophagy, clearing damaged mitochondria and protein aggregates. A Harvard study showed that in Ergothioneine-treated cells:
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Expression of the mitophagy gene LC3-II doubled
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P62 protein levels dropped by 40%
This "cellular clean-up" not only delays senescence but also improves metabolic health. In rats on a high-fat diet, Ergothioneine supplementation increased insulin sensitivity by 30% and halved fatty liver incidence.
4. Skin Anti-Aging & Barrier Repair
Ergothioneine offers multi-level skin protection. Its thione-imidazole ring structure allows it to absorb UV radiation (UVA/UVB), preventing photoaging. In vitro studies showed:
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UVA-induced fibroblast damage was reduced by 60%
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Type I collagen synthesis increased by 40%
A clinical study at Kanazawa University found that 12 weeks of supplementation:
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Reduced transepidermal water loss (TEWL) by 18%
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Increased skin elasticity by 22%
These benefits were more pronounced in individuals with initially low skin hydration. [7]
Clinical Evidence & Safety
1. Human Studies Support
A 9-year follow-up study by the National University of Singapore involving 3,236 participants found that for every 1μM increase in plasma Ergothioneine:
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Cardiovascular risk dropped by 12%
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Diabetes risk decreased by 15%
These results remained significant even after adjusting for age, gender, and BMI. [8]
A separate trial at Kanazawa University showed that daily 20mg Ergothioneine supplementation for 4 weeks significantly improved anxiety and sleep quality, likely by crossing the blood-brain barrier and regulating neurotransmitters like serotonin and GABA. Notably, these benefits lasted two weeks post-treatment, indicating a long-lasting effect. [9]
2. Safety Certifications
Ergothioneine has been certified safe by major global authorities:
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EFSA (EU, 2017): Approved as a novel food ingredient, with a safe upper intake of 560mg/day for adults.
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FDA (USA, 2019): GRAS status for use in food, supplements, and cosmetics.
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Japanese Ministry of Health (2020): Approved as a functional food ingredient, targeting cognitive support.
Clinical studies have shown no adverse effects with intakes up to 200mg/day. The only caution is mild gastrointestinal discomfort when taken on an empty stomach — it’s best consumed with meals.
How to Supplement Ergothioneine Scientifically
Ergothioneine is not synthesized by the human body and must be obtained from diet or supplements. Rich dietary sources include:
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Mushrooms: Porcini, oyster mushrooms, maitake
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Grains: Oats, wheat germ
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Animal products: Grass-fed beef, eggs
To meet effective levels via food, one would need ~250g fresh shiitake or ~50g dried porcini mushrooms daily — impractical for most. Thus, supplements (20–30mg/day) are a more efficient choice.
Conclusion
Through a triple mechanism — NAD⁺ enhancement, mitochondrial protection, and antioxidant defense — Ergothioneine is redefining the anti-aging landscape. From worms to humans, from labs to consumer markets, this “longevity molecule” offers a novel path to healthy aging.
With advances in synthetic biology and growing regulatory support, Ergothioneine is poised to become the next “hyaluronic acid-level” anti-aging superstar. Whether through diet or modern nutraceuticals, embracing this scientific breakthrough may be the key to unlocking cellular rejuvenation.
References：
【1】Petrovic, D., Slade, L., Paikopoulos, Y., D’Andrea, D., Savic, N., Stancic, A., ... Filipovic, M. R. (2025). Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation. *Cell Metabolism, 41*(2), 345-358. https://doi.org/10.1016/j.cmet.2024.12.008
【2】Sprenger, H.-G., Mitten Bühler, M. J., Sun, Y., van Vranken, J. G., Schindler, S., Jayaraj, A., ... & Spiegelman, B. M. (2025). Ergothioneine controls mitochondrial function and exercise performance via direct activation of MPST. Cell Metabolism, 42(3), 456-471.
【3】Kato, Y., et al. (2024). Ergothioneine promotes longevity and healthy aging in male mice. GeroScience, 46(2), 1-15.
【4】Liao, W. C., et al. (2024). Food & Function.
【5】Smith, E., et al. (2019). Heart; Larsson, S. C., et al. (2020). Malmo Diet and Cancer Study.
【6】Xie, Y., et al. (2025). Cell Metabolism.
【7】Katsube, M., lshimoto, T, Fukushima, y, Kagami, A., Shuto, T., & Kato, Y. (2024).GeroScience. doi:10.1007/s11357-024-01111-5
【8】Smith, E., Svensson, A., & Johansson, B. (2020). Ergothioneine is associated with reduced mortality and decreased risk of cardiovascular disease. *Heart, 106*(9), 691-697. https://doi.org/10.1136/heartjnl-2019-315485
【9】Ishimoto, T., Kato, Y., & Katsube, M. (2022). Ergothioneine in the brain: A randomized controlled trial on anxiety and sleep quality. *FEBS Letters, 596*(18), 3078-3087. https://doi.org/10.1002/1873-3468.14271