María Ángeles Cáliz‐Molina, Raúl López‐Fernández‐Sobrino, I. Pino-Pérez, Concepción Panadero‐Morón, María del Carmen Vilches-Pérez, M. Camacho-Cabrera, Almudena García‐Ruiz, L Pérez-Rosendo, Isabel Espadas, Alejandro Sola‐García, Mario Soriano‐Navarro, Franz Martı́n, Mónica Venegas‐Calerón, Joaquı́n J. Salas, Enrique Martínez‐Force, Luís C. Romero, Ángeles Aroca, Román González‐Prieto, Máximo Bernabeu‐Wittel, Vivian Capilla‐González, Christopher Hine, Alejandro Martín‐Montalvo
Hydrogen sulfide is a gasotransmitter with biological functions, including roles in antioxidant defenses, mitochondrial bioenergetics, and cellular signaling via cysteine persulfidation. Several longevity-promoting interventions enhance endogenous hydrogen sulfide generation. However, whether enhanced hydrogen sulfide generation extends healthspan and lifespan in mammals remains unknown. Here, we investigated the in vivo effects of the non-enzymatic hydrogen sulfide generation promoted by natural diallyl sulforated compounds. Diallyl sulforated compounds extended lifespan and improved the main aspects of healthspan, including glucoregulation, locomotor function, and neurocognition in wild-type male mice across their lifespan. At the histological and molecular levels, we observed reductions in hepatic lipid-droplet size, attenuation of transcriptional and proteomic signatures associated with mTOR and immune-related pathways, and increased cysteine persulfidation in proteins. In humans, greater protein persulfidation in individuals with polypathological conditions was associated with increased muscle strength and lower triglyceride levels, supporting its physiological relevance. Our findings uncover the potential of enhanced hydrogen sulfide generation to promote healthy aging.