NAD homeostasis in human health and disease+

Nicotinamide adenine dinucleotide exists in two forms, including an oxidized (NAD) and a reduced (NADH) form, and plays a key role in intermediary metabolism, as obligatory partner in numerous oxidation/reduction reactions. Discovered over 100 years ago by Harden & Young (Harden & Young, 1906), NAD went through a period of relative anonymity until its renaissance 20 years ago, when it was reported as an essential substrate for the activity of sirtuins, a family of NAD‐dependent deacetylases which play an essential role in the regulation of energy metabolism and mitochondrial function (Houtkooper et al, 2012). Besides sirtuins, other NAD‐consuming enzymes have been identified during the last decades. This includes the poly(ADP‐ribose) polymerase (PARP) protein family (Leung, 2017) and the cyclic ADP‐ribose (cADPr) synthases, including CD38 (Aksoy et al, 2006) and CD157 (Ortolan et al, 2019). Together, these three families of enzymes regulate major biological processes in cells (Ansari & Raghava, 2010), making NAD homeostasis vital for proper cellular functioning.+++++

The importance of NAD for human health and disease is exemplified by the existence of genetic diseases caused by defects in the biosynthesis of NAD with often devastating consequences in terms of the clinical signs and symptoms in patients. Furthermore, the cellular dependence on NAD also becomes evident if we consider the fact that NAD depletion is a common factor in numerous diseases (Okabe et al, 2019). Importantly, several reports have been published in which NAD repletion by means of supplementation with NAD‐enhancing molecules was successful in ameliorating the outcomes of these conditions, including neurodegenerative disorders (Liu et al, 2013; Zhou et al, 2015; Schondorf et al, 2018), metabolic diseases (Revollo et al, 2007; Yoshino et al, 2011; Canto et al, 2012; Lee et al, 2015; Katsyuba et al, 2018), and age‐related complications (Mouchiroud et al, 2013b; Mills et al, 2016; Zhang et al, 2016).++++++

Although most of the research on the implications of NAD in health and disease has been carried out in animal models, NAD deficiency has also been reported to cause a number of medical conditions in humans, which can be subdivided into two groups including the primary and secondary deficiencies of NAD homeostasis. The first group involves the genetically determined deficiencies of NAD synthesis, due to deleterious mutations in genes coding for enzymes directly involved in NAD biosynthesis, from both de novo and salvage pathways. In contrast, the second group of diseases involves alterations of NAD metabolism induced by other factors, such as increased NAD consumption and/or a dietary deficiency of NAD precursors.++++++++