Ergothioneine

Ergothioneine is a sulfur-containing histidine betaine, predominantly in its thione tautomeric form, synthesized exclusively by fungi, certain bacteria, and cyanobacteria; humans obtain it through diet, with mushrooms (porcini, oyster, shiitake) as the richest common sources. After ingestion it is actively transported into cells by OCTN1 (SLC22A4), expressed at high levels in metabolically demanding tissues including the brain, bone marrow, kidney, and muscle; ergothioneine is OCTN1's principal endogenous substrate. Unlike classical thiols, it does not auto-oxidize at physiological pH and does not catalyze hydroxyl-radical generation via the Fenton reaction, giving it selective cytoprotective properties against reactive oxygen and nitrogen species without pro-oxidant side-effects. Bruce Ames proposed ergothioneine as a putative "longevity vitamin" in 2018 under his triage theory, arguing that sub-optimal intake silently accelerates aging-related damage before frank deficiency appears. Plasma ergothioneine declines with age and in frailty. In the Malmö Diet and Cancer cohort (n = 3,236; median 21.4-year follow-up), ergothioneine was the metabolite most strongly associated with reduced cardiovascular mortality (HR ≈ 0.79 per SD) and all-cause mortality (HR ≈ 0.86 per SD) (Smith et al. 2020). A Singapore memory-clinic cohort (n = 470; average ~4-year follow-up) found that lower plasma levels predicted faster decline in memory, executive function, and processing speed (Wu et al. 2022). Randomized controlled trials in humans are limited and causality remains unestablished.