Cáliz-Molina et al. demonstrate that hydrogen sulfide generators found in garlic extend lifespan and enhance metabolic, neurocognitive, and locomotor function in male mice. These molecules induce hepatic lipid-droplet remodeling and modulate aging-associated pathways at transcriptomic, proteomic, and persulfidomic levels. In humans, increased cysteine persulfidation correlates with relevant aspects of health.