Enhanced non-enzymatic H2S generation extends lifespan and healthspan in male mice
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.
Authors
- Mónica Venegas‐Calerón (ORCID: https://orcid.org/0000-0002-1562-5025)
- Concepción Panadero‐Morón (ORCID: https://orcid.org/0000-0003-0726-4087)
- Enrique Martínez‐Force (ORCID: https://orcid.org/0000-0001-5324-9537)
- Christopher Hine (ORCID: https://orcid.org/0000-0003-1926-7939)
- María Ángeles Cáliz‐Molina (ORCID: https://orcid.org/0000-0003-0263-1263)
- Alejandro Martín‐Montalvo (ORCID: https://orcid.org/0000-0002-3886-5355)
- Máximo Bernabéu-Wittel (ORCID: https://orcid.org/0000-0003-4574-4110)
- Román González‐Prieto (ORCID: https://orcid.org/0000-0001-8997-2321)
- Vivian Capilla‐González (ORCID: https://orcid.org/0000-0003-2020-1662)
- Mario Soriano‐Navarro (ORCID: https://orcid.org/0000-0002-7245-2095)
- Luís C. Romero (ORCID: https://orcid.org/0000-0002-2414-4813)
- Isabel Espadas (ORCID: https://orcid.org/0000-0002-9811-9717)
- Ángeles Aroca (ORCID: https://orcid.org/0000-0003-4915-170X)
- Almudena García‐Ruiz (ORCID: https://orcid.org/0000-0001-9055-0185)
- Leopoldo Pérez-Rosendo
- Joaquı́n J. Salas (ORCID: https://orcid.org/0000-0002-3259-2587)
- Franz Martı́n (ORCID: https://orcid.org/0000-0002-5745-8704)
- Alejandro Sola‐García (ORCID: https://orcid.org/0000-0003-1974-6796)
- Raúl López‐Fernández‐Sobrino (ORCID: https://orcid.org/0000-0002-2418-2123)
- Inmaculada Pino-Pérez
- María Camacho-Cabrera
- María del Carmen Vilches-Pérez
Institutions
- Cleveland Clinic Lerner College of Medicine (US)
- Instituto de Bioquímica Vegetal y Fotosíntesis (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Instituto de la Grasa (ES)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- Hospital Universitario Virgen del Rocío (ES)
- Centro de Investigacion Principe Felipe (ES)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-12-19
- DOI
- https://doi.org/10.1016/j.cmet.2025.11.012
- Primary Topic
- Sulfur Compounds in Biology
- Type
- article
- Field-Weighted Citation Impact
- 0.00