Sulfur, one of the most abundant chemical elements on earth, has had important roles in biosphere evolution. Unique roles of sulfur in living organisms are mainly related to the redox reaction, whose functions include cytoprotection and energy metabolism. KEAP1–NRF2 system is a sulfur-utilizing cytoprotection mechanism, and its role in metabolic regulation has been attracting increasing attention. Persulfides, which have rapidly emerged as common biomolecules, also play important roles in cytoprotection and mitochondrial energy metabolism. Chemical regulation by persulfides and transcriptional regulation by the KEAP1–NRF2 system act in concert and make up a sulfur-utilizing dual system for cytoprotection and energy metabolism. Clarification of this system is expected to promote understanding of the aging process in organisms and aging-related diseases.