Extending lifespan by 20% and increasing NAD+ levels! New discoveries about this "longevity vitamin"

In February 2025, an article titled "Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation" was published in the journal Cell Metabolism. The goal of this study is to explore the potential effects of ergothioneine supplementation on the healthy lifespan of aged animals and to elucidate the underlying mechanisms driving this effect.

1. Extend median lifespan by 20% and increase NAD+ levels

The article points out that ergothioneine can extend the lifespan and healthspan of elderly C. elegans and rats, and reveals the mechanism of action of ergothioneine in extending lifespan.

The study tested the effect of ergothioneine on the lifespan of C. elegans. Treatment with 5 mM ergothioneine from the first day of adulthood significantly extended the median lifespan by 20%. Nematodes treated with ergothioneine showed significantly improved activity, improved stress resistance, and reduced age-related biomarkers (intestinal autofluorescence, sometimes called lipofuscin or "senile pigment").

In addition, the study treated 9-month-old rats (adding 20 mg/kg ergothioneine to drinking water for 3 weeks) and then conducted exercise endurance tests. The study found that ergothioneine administration enhanced exercise endurance, muscle mass, and vascularization, while NAD+ levels in muscle were higher.

Mechanistic studies have found that ergothioneine can serve as an alternative substrate for the pro-longevity gene cystathionine gamma-lyase (CSE), leading to increased hydrogen sulfide (H2S) production and subsequent protein persulfation (PSSH). Ergothioneine treatment leads to increased mitochondrial respiration, ATP production, and cell growth, accompanied by increased NAD+ levels in vivo and in vitro. These changes occur through persulfation and activation of cytoplasmic glycerol-3-phosphate dehydrogenase (cGPDH), which increases NAD+ levels, thereby improving muscle mass, vascularization, myocyte stemness, and treadmill endurance in aged rats.

2. Ergothioneine: “Longevity Vitamin”

Ergothioneine is a naturally occurring amino acid. In 1909, Charles Tanret isolated a unique crystalline sulfur-containing compound while studying the ergot fungus that destroys rye grains. He later named it ergothioneine. In 1911, Barger and Ewins determined its structure and found that ergothioneine is a histidine betaine derivative.

Ergothioneine has both thiol and thione tautomers, and the thione tautomer is dominant at physiological pH, which makes ergothioneine extremely powerful antioxidant. Clinical data show that ergothioneine's ability to scavenge free radicals is 14 times that of glutathione and 30 times that of coenzyme Q10.

In 2018, Bruce Ames, an American biochemist and professor of biochemistry and molecular biology at the University of California, defined ergothioneine as a "longevity vitamin" in the article "Prolonging healthy aging: Longevity vitamins and proteins". Ames pointed out that appropriate supplementation of ergothioneine can reduce the risk of chronic diseases and premature aging. And unlike other nutrients in the human body, ergothioneine has a dedicated transporter protein OCTN-1, which can directly transport ergothioneine into the mitochondria, target the removal of free radicals, and fight against premature aging more efficiently. In addition, more and more studies have shown that ergothioneine is a "stress vitamin" for the body's self-defense. When subjected to stress stimulation (such as hunger, ultraviolet radiation, metabolic acidosis, etc.), the ergothioneine level in the body will increase, automatically turning on the body's defense mechanism to fight stress.

3. Multi-dimensional anti-aging effects of ergothioneine

Based on its strong antioxidant properties, high stability, and non-toxicity, ergothioneine has been gradually confirmed by more and more studies to play a positive role in human health. It has positive effects in anti-oxidation, anti-inflammation, skin health, urinary system health, intestinal health, cardiovascular system health, prevention of Alzheimer's disease, and improvement of sleep disorders. It has good application scenarios in the fields of biomedicine, beauty and health.

1) Improve cognitive function Oxidative stress is one of the main causes of neurodegenerative diseases. For example, oxidative stress caused by β-amyloid protein (Aβ) deposition plays an important role in the pathogenesis of Alzheimer's disease. Studies have shown that ergothioneine can protect brain health and improve cognitive function. It can penetrate the blood-brain barrier and enter the brain to play a role.

2) Support skin health Skin aging is a multifactorial process, including epidermal aging caused by ultraviolet radiation, dermal aging caused by collagen loss, and subcutaneous inflammation caused by cell apoptosis. Ergothioneine shows obvious anti-aging effects on different skin layers through its unique biological activity.

3) Eye protection Ergothioneine is present in high concentrations in eye tissues, including the lens, retina, cornea, and retinal pigment epithelium, which can help protect the eyes by scavenging chronic reactive oxygen free radicals (ROS), reducing intracellular ROS production, and inhibiting oxidation-induced epithelial-mesenchymal transition (EMT).

4) Sleep improvement Ergothioneine can penetrate the blood-brain barrier through a variety of biological mechanisms, inhibit the formation of peroxynitrite and the nitration of tyrosine residues to hinder brain nerve cell apoptosis, thereby reducing stress, relieving depression, and improving sleep difficulties.

5) Cardiovascular health studies have shown that ergothioneine can couple glutathione to reduce iron-based myoglobin, chelate transition metal iron to scavenge reactive oxygen and reactive nitrogen (ROS/RNS), free radicals generated during ischemia-reperfusion, regulate proinflammatory cytokines such as IL-1β, TNF-α, and ultimately prevent myocardial damage, indicating that ergothioneine's inhibition of inflammation-related pathways is the main mechanism for alleviating various cardiovascular diseases.