title: 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.
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mouchiroud
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Riekelt H
authors.initials: RH
authors.lastname: Houtkooper
authors.affiliation: Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000818:Animals; D006801:Humans; D008659:Metabolic Diseases / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D037761:Sirtuins / Q000378:metabolism
chemical_list: D009243:NAD; D037761:Sirtuins