Selenium and selenoproteins in age-related metabolic diseases: mechanistic insights and translational perspectives

Selenium is an essential trace element incorporated into selenoproteins, which regulate redox balance, thyroid hormone metabolism, protein folding, and stress signaling. The relationship between selenium and metabolic health is complex, with growing evidence of a U-shaped association. This review synthesizes current evidence on selenium and selenoproteins in age-related metabolic diseases, with a focus on MASLD, obesity, and cardiovascular disease. Mechanistic data from experimental models are integrated with human observational and intervention studies to evaluate how selenium status, chemical form, dose, and timing influence metabolic outcomes. Evidence indicates a narrow biological window for selenium. Selenium deficiency impairs glucose metabolism and antioxidant defenses and promotes liver injury. However, excessive selenium exposure in selenium-replete individuals may exacerbate insulin resistance, adiposity, and cardiometabolic risk. Several selenoproteins, including GPX1, SELENOP, SELENOM, SELENON, SELENOS, SELENOK, DIO2, and SELENOH, are implicated in various metabolic pathways, acting as protective mediators or disease-associated regulators. Their roles depend on tissue type, expression level, and disease stage. Current evidence does not support widespread selenium supplementation but prioritizes dietary sources, restricts supplementation to cases of confirmed or probable deficiency, and emphasizes the U-shaped risk profile associated with selenium exposure.