NAD(+) metabolism: A therapeutic target for age-related metabolic disease

Abstract Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor by virtue of its redox capacity, and as such regulates a wealth of metabolic transformations. However, the identification of the longevity protein silent regulator 2 (Sir2), the founding member of the sirtuin protein family, as being NAD(+)-dependent reignited interest in this metabolite. The sirtuins (SIRT1-7 in mammals) utilize NAD(+) to deacetylate proteins in different subcellular compartments with a variety of functions, but with a strong convergence on optimizing mitochondrial function. Since cellular NAD(+) levels are limiting for sirtuin activity, boosting its levels is a powerful means to activate sirtuins as a potential therapy for mitochondrial, often age-related, diseases. Indeed, supplying excess precursors, or blocking its utilization by poly(ADP-ribose) polymerase (PARP) enzymes or CD38/CD157, boosts NAD(+) levels, activates sirtuins and promotes healthy aging. Here, we discuss the current state of knowledge of NAD(+) metabolism, primarily in relation to sirtuin function. We highlight how NAD(+) levels change in diverse physiological conditions, and how this can be employed as a pharmacological strategy