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Aging is a major risk factor for the leading causes of mortality, and the incidence of age-related diseases including cardiovascular disease, kidney disease and metabolic disease increases with age. NAD⁺ is a classic coenzyme that exists in all species, and that plays a crucial role in oxidation–reduction reactions. It is also involved in the regulation of many cellular functions including inflammation, oxidative stress and differentiation. NAD⁺ declines with aging in various organs, and the reduction in NAD⁺ is possibly involved in the development of age-related cellular dysfunction in cardiorenal metabolic organs through the accumulation of inflammation and oxidative stress. Levels of NAD⁺ are regulated by the balance between its synthesis and degradation. CD38 is the main NAD⁺-degrading enzyme, and CD38 is activated in response to inflammation with aging, which is associated with the reduction in NAD⁺ levels. In this review, focusing on CD38, we discuss the role of CD38 in aging and the pathogenesis of age-related diseases, including cardiorenal metabolic disease.