If you've been stacking NMN or NR to defend your NAD+ levels, a mushroom compound may be coming for your attention. A new Cell Metabolism paper reports that ergothioneine raised muscle NAD+ and improved treadmill endurance in aged rats. It did so through a hydrogen sulfide pathway nobody had mapped before. This is an animal and lab study, not a human trial, and that caveat matters throughout.
What is ergothioneine, and why is it called a 'longevity vitamin'?
Ergothioneine (ET) is a sulfur-containing amino acid derivative, a thione, that humans cannot make. We get it from food, and mushrooms are by far the richest source. Our bodies carry a dedicated transporter for it, which is a big part of why some researchers have nicknamed it a "longevity vitamin." Evolution doesn't usually build a special doorway for a molecule that does nothing.
The compound has long been studied as an antioxidant and cytoprotectant. This new work, from Milos Filipovic's group and collaborators including Michael Murphy, suggests ET also acts as a signaling lever, and that is the part biohackers should find interesting.
The worm result: longer life, better mobility
The researchers started with C. elegans, the roundworm workhorse of aging research. ET extended lifespan and improved mobility in aged worms. The treated worms also showed better stress resistance and fewer age-associated biomarkers.
Worm lifespan results are a classic first step, and they translate to mammals less often than headlines imply. Here they served mainly as a springboard for the rodent work.
The aged-rat result: endurance, muscle, and NAD+
In aged rats given ET (reportedly in drinking water for about four weeks), the team saw:
- Better exercise endurance, with animals running longer and farther on a treadmill
- Modestly higher muscle mass
- Greater muscle vascularization, meaning more blood-vessel support
- Higher NAD+ levels in muscle
NAD+ declines with age and is central to mitochondrial function, so a rise in muscle tissue lines up neatly with an endurance benefit. The paper frames this as relevant to age-related muscle decline, the territory of sarcopenia.
The hidden switch, in plain English
The mechanism is the real story. Here is the chain as the authors describe it:
- CSE gets a new substrate. Cystathionine gamma-lyase (CSE) is an enzyme that normally makes hydrogen sulfide (H2S). ET acts as an alternative substrate for it, nudging H2S production upward.
- H2S tags proteins. H2S drives persulfidation, a chemical modification that adds a sulfur group to cysteine residues and changes how a protein behaves. The team found more than 300 persulfidated targets.
- cGPDH switches on. One of those targets, cytosolic glycerol-3-phosphate dehydrogenase (cGPDH), is activated by persulfidation. cGPDH is part of a shuttle that helps regenerate NAD+ from NADH in the cell's cytoplasm.
- NAD+ rises. According to the authors, cGPDH activation is the main contributor to the ET-driven NAD+ increase.
The key proof is a knockout test. When CSE or cGPDH was missing, ET's effects disappeared. That makes the pathway look necessary rather than incidental.
How does this compare with NMN and NR?
NMN and NR are precursors. They supply raw material to the NAD+ salvage pathway, so the strategy is to give the cell more building blocks.
This study describes something different. ET appears to act through redox signaling, activating an enzyme that helps recycle NAD+ rather than adding substrate. The two approaches could in theory be complementary, but nobody has tested that. The paper contains no head-to-head comparison with NMN or NR, so any claim that ET is better, worse, or synergistic is speculation.
Practical takeaways for the curious
Food sources. Mushrooms lead, with oyster, king oyster, shiitake, and porcini generally reported as high. Smaller amounts show up in some beans, oat bran, and organ meats. Cooking doesn't appear to destroy ET easily.
Supplement doses. Commercial ET products typically provide about 5 to 25 mg per day. Human studies so far have used doses in roughly that range.
The rat dose is far higher. According to coverage of the study from Ergo-Log, the rat regimen translates to roughly 200 to 260 mg per day in a human, around ten times what human studies have used. Whether that is safe or effective for people is unknown. Nothing in this paper shows that a standard 5-25 mg capsule would raise NAD+ in human muscle.
The clear caveat: animal-only, no human proof yet
Be skeptical of anything that treats this as settled for people:
- No human data. This was a preclinical study in worms, rats, and cell systems.
- Dose mismatch. The effective rat dose, scaled to humans, is far above typical supplement amounts.
- Short duration. Long-term effects, safety at high doses, and effects on lifespan in mammals were not established here.
- Muscle NAD+ is not a clinical outcome. Higher tissue NAD+ and treadmill endurance in rats are encouraging signals, not proof of healthier aging in humans.
- Mechanism is not benefit. An elegant pathway is a reason to run trials, not a substitute for them.
Bottom line
This paper gives ergothioneine something it has lacked: a concrete, testable mechanism linking a dietary mushroom compound to NAD+ through CSE, H2S, persulfidation, and cGPDH. That is a real step beyond "it's an antioxidant." Eating more mushrooms is a low-risk move on general nutrition grounds. Whether ergothioneine will ever count as a proven NAD+ or muscle-aging intervention in humans depends on trials that haven't been done yet.
