Nicotinamide adenine dinucleotide (NAD+) is an important coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins and poly(ADP-ribose) polymerases (PARPs).
NAD+ was first identified for its role in regulating metabolic rates in yeast extracts and later as the major hydride acceptor in redox reactions. This ability of NAD+ to accept a hydride ion, forming its reduced version, NADH, is critical for metabolic reactions of all living life forms and regulates the activity of dehydrogenases involved in multiple catabolic pathways, including glycolysis, glutaminolysis and fatty acid oxidation. The accepted electrons in these reactions are then donated to the electron transport chain to form ATP in eukaryotes. NAD+ can also be phosphorylated to form NADP+, which also acts as a hydride acceptor to form NADPH and is used in protection against oxidative stress and in anabolic pathways that require reducing power, such as fatty acid synthesis.
In addition to energy metabolism, NAD+ is used as a cofactor or substrate by hundreds of enzymes1 and therefore has multiple roles in the regulation of cellular processes and cellular functions, many of which are still being investigated. Links between NAD+ levels and health were established almost a century ago. In 1937, Conrad Elvehjem discovered that the disease pellagra (characterized by dermatitis, diarrhoea and dementia) is caused by a dietary deficiency of niacin and resulted in low NAD+ and NADP+ levels. Recently, low NAD+ levels were linked to multiple disease states, including metabolic and neurodegenerative diseases, and lower NAD+ levels are now known to correlate with ageing in rodents and humans. As a result, there is renewed interest in understanding how NAD+ metabolism impacts the origin of diseases, particularly ageing-related diseases. In this regard, restoring NAD+ levels with the NAD+ precursors nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) has emerged as an important therapeutic approach to treat age-related diseases and appears to have beneficial effects in vivo, at least in rodent models.
In this Review, we focus on the past 5 years of work in the NAD+ field. In particular, we examine the molecular mechanisms by which NAD+ precursors and ultimately NAD+ levels influence physiology and healthspan in ageing and disease states. Those mechanisms are likely to be complicated and multifactorial, and so we discuss them in multiple sections. First, we review new findings on how the primary NAD+ biosynthetic and degradative pathways are modulated during ageing. Second, we discuss the possible consequences of lower NAD+ levels on molecular processes that are important to ageing-related disease, including DNA repair, regulation of epigenetics and gene expression, regulation of cell metabolism and redox balance. Third, we describe the NAD+-dependent mechanisms in ageing, including metabolic disorders, deregulation of the immune system, cellular senescence and neurodegeneration. Finally, we review the numerous recent high-quality preclinical studies that investigated methods to restore NAD+ levels to treat ageing-related diseases. These include numerous studies using NAD+ precursors, and small-molecule drugs that promote NAD+ biosynthesis. We finish by discussing these different strategies and the results of these studies to outline the prospects of therapies based on modulation of NAD+ levels in promoting human healthspan and lifespan.
