The balance between NAD⁺ biosynthesis and consumption in ageing

Nicotinamide adenine dinucleotide (NAD⁺) is a vital coenzyme in redox reactions. NAD⁺ is also important in cellular signalling as it is consumed by PARPs, SARM1, sirtuins and CD38. Cellular NAD⁺ levels regulate several essential processes including DNA repair, immune cell function, senescence, and chromatin remodelling. Maintenance of these cellular processes is important for healthy ageing and lifespan. Interestingly, the levels of NAD⁺ decline during ageing in several organisms, including humans. Declining NAD⁺ levels have been linked to several age-related diseases including various metabolic diseases and cognitive decline. Decreasing tissue NAD⁺ concentrations have been ascribed to an imbalance between biosynthesis and consumption of the dinucleotide, resulting from, for instance, reduced levels of the rate limiting enzyme NAMPT along with an increased activation state of the NAD⁺-consuming enzymes PARPs and CD38. The progression of some age-related diseases can be halted or reversed by therapeutic augmentation of NAD⁺ levels. NAD⁺ metabolism has therefore emerged as a potential target to ameliorate age-related diseases. The present review explores how ageing affects NAD⁺ metabolism and current approaches to reverse the age-dependent decline of NAD⁺.