The coenzyme NAD⁺ is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD⁺ levels is important for cells with high energy demands and for proficient neuronal function. NAD⁺ depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD⁺ decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD⁺ levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD⁺ biosynthesis, together with putative mechanisms of NAD⁺ action against aging, including recent preclinical and clinical trials. Recent discoveries have demonstrated an age-dependent decrease in cellular and/or tissue NAD⁺ levels in laboratory animal models. Moreover, NAD⁺ depletion has been linked to multiple hallmarks of aging. In premature aging animal models, NAD⁺ levels are decreased, while NAD⁺ replenishment can improve lifespan and healthspan through DNA repair and mitochondrial maintenance. Mitochondrial autophagy (mitophagy) has a major role in clearance of damaged and/or dysfunctional mitochondria, and compromised mitophagy has been linked to metabolic disorders, neurodegeneration [including Alzheimer's disease (AD) and Parkinson's disease (PD)] in addition to aging, and other age-related diseases. New evidence suggests that NAD⁺ precursors, such as nicotinamide and nicotinamide riboside, forestall pathology and cognitive decline in mouse models of AD. NAD⁺ supplementation can inhibit multiple aging features in animal models. This highlights essential roles for NAD⁺ in maintaining healthy aging, and suggests that NAD⁺ repletion may have broad benefits in humans.