Nicotinamide adenine dinucleotide (NAD⁺) is an essential coenzyme in redox reactions and co-substrate for signaling enzymes fueling both bioenergetic and regulatory processes. NAD⁺ decreases in concentration with age in worms, flies, mice and humans. NAD⁺ depletion causes multiple defects including mitochondrial dysfunction, dysregulated nutrient sensing, and epigenetic alterations, which are classic hallmarks of aging. NAD⁺ supplementation is simple, appears to be safe, and has beneficial effects in aged mice. Thus, decreased NAD⁺ availability may be a contributing and modifiable factor in age-related diseases. However, there are still fundamental gaps in understanding how NAD⁺ homeostasis is maintained and regulated. Our work provided a framework for studying systemic changes in NAD⁺ metabolism with age, and raises many key questions. What are the roles of specific NAD⁺ consuming enzymes? The dynamics of NAD⁺ at the level of individual cells and organelles? Does altered NAD⁺ metabolism impact stress robustness?