A Matter of Balance: Heme Oxygenase-1 at the Crossroads of Healthy and Pathological Aging.
Increasing life expectancy has led to a growing prevalence of age-related disorders, including dementia, cardiovascular disease, frailty, osteoporosis, sarcopenia, and cancer. Heme oxygenase-1 (HO-1), a stress-inducible enzyme that degrades heme into carbon monoxide (CO), biliverdin which is then reduced to bilirubin by the biliverdin reductase enzyme, and iron, has emerged as a key regulator of several hallmarks of aging, including oxidative stress, inflammation, autophagy, mitochondrial dysfunction, and cellular senescence. This review evaluates age-associated changes in HO-1 expression across major organs and examines the roles of HO-1 and its metabolites in age-related diseases, with particular emphasis on dementia and cardiovascular disorders. Current evidence suggests that the biological effects of HO-1 depend not only on expression level but also on temporal regulation, tissue specificity, and the balance between protective and deleterious downstream pathways. Future research should focus on defining physiological and therapeutic ranges of HO-1 activity in different tissues, sexes, and stages of aging, while clarifying the distinct contributions of CO, bilirubin, and iron metabolism. Such studies may enable precision-medicine approaches that harness HO-1 modulation to promote healthy aging and prevent age-related diseases.