NAD

NAD+ is a cofactor of various redox reactions, as well as a substrate of PARPs, and CD38 enzymes involved in the regulation of DNA repair, gene expression, and stress response. NAD+ is synthesized through the de novo, Preiss-Handler, and salvage pathways, with the NAMPT-dependent salvage pathway being the most active in mammals.
NAD+ is involved in the maintenance of cellular redox homeostasis through its function of shuttling electrons in various metabolic reactions. It also acts as a source of NADPH for the antioxidant defense system through the glutathione and thioredoxin systems. NAD+ also supports DNA repair through PARP-dependent ADP-ribosylation and epigenetic regulation through sirtuin-dependent histone deacetylation, which in turn regulates gene expression and chromatin structure. In mitochondria, NAD+ regulates energy metabolism through the activation of sirtuins, which in turn deacetylate and activate metabolic enzymes, leading to increased oxidative phosphorylation and reduced production of ROS. NAD+ is also involved in the regulation of circadian rhythms through the modulation of CLOCK-BMAL1 activity by SIRT1 and NAD+ oscillations.
Alteration of NAD+ levels during aging or under pathological conditions impairs these mechanisms, which in turn leads to mitochondrial dysfunction, oxidative stress, DNA damage, and chronic inflammation, contributing to aging and age-related diseases. In neurodegeneration, loss of NAD+ impairs DNA repair and axonal survival. In metabolic disorders, it decreases insulin secretion and lipid metabolism. In cancer, altered NAD+ metabolism favors tumor growth by supporting DNA repair and redox homeostasis.
In conclusion, NAD+ is a key metabolic regulator. The main mechanisms by which NAD+ can affect human physiology include redox homeostasis, DNA repair, epigenetic modulation, and mitochondrial function, which makes NAD+ a promising therapeutic target for the treatment of age-related and chronic diseases.

Fig. 1 Mechanism of action of NAD+. (Xie N.; et al. 2020)