Ergothioneine improves healthspan of aged animals by enhancing cGPDH activity through CSE-dependent persulfidation

Ergothioneine (ET), a dietary thione/thiol, has been receiving growing attention for its possible benefits in healthy aging and metabolic resilience. Our study investigates ET's effects on healthspan in aged animals, revealing extension of lifespan and enhanced mobility in Caenorhabditis elegans, accompanied by improved stress resistance and reduced age-associated biomarkers. In aged rats, ET administration enhances exercise endurance, muscle mass, and vascularization, concomitant with increased NAD+ levels in muscle tissue. Mechanistically, ET acts as an alternative substrate for cystathionine gamma lyase (CSE), stimulating H2S production which increases protein persulfidation of more than 300 protein targets. Among these, protein persulfidation-driven activation of cytosolic glycerol-3-phosphate dehydrogenase (cGPDH) primarily contributes to ET-induced NAD+ increase. ET's effects are abolished in cells and animals lacking CSE or cGPDH, highlighting essential role of H2S signaling and protein persulfidation. These findings elucidate ET's multifaceted actions and provide insights into its therapeutic potential for combating age-related muscle decline and metabolic perturbations.