THE EVOLVING ROLE OF THE NAD+/NICOTINAMIDE METABOLOME IN SKINHOMEOSTASIS, CELLULAR BIOENERGETICS, AND AGING
Human skin is exposed to daily environmental insults, particularly solar radiation, that triggers a range ofmolecular responses. These perturbations to the normal homeostatic state can lead to cellular dysfunctionand, ultimately, impacts tissue integrity and accelerates skin aging (photoaging). One of the responses isincreased oxidative stress which has been shown to disrupt cellular bioenergetics. This can be detectedby depletion of the nucleotide energy metabolites NAD+ and ATP as both an acute transient decreaseand, over time, a more permanent chronic reduction due in part to cumulative damage of mitochondria.NAD+ and its primary precursor nicotinamide have been known for some time to impact skin homeostasis based on linkages to dietary requirements, treatment of various inflammatory conditions, photoaging,and prevention of cancer. Cellular NAD+ pools are known to be lower in aged skin and treatment withnicotinamide is hypothesized to restore these levels, thereby mitigating cellular bioenergetics dysfunc-tion. In dermal fibroblasts, nicotinamide is able to protect against oxidative stress to glycolysis, oxidativephosphorylation as well as increase mitochondrial efficiency via sirtuin-dependent selective mitophagy.Recent research has found that NAD+ cellular pools are more dynamic than previously thought, oscil-lating in tandem with free nicotinamide, and serves as a regulatory point and feedback loop in cellularmetabolism regulation, maintenance of mitochondrial efficiency, and circadian rhythmicity. Since UV-induced oxidative stress in skin can disrupt these processes, continued molecular understanding of therole of NAD+ and nicotinamide in skin biology is important to identify interventions that would helpmaintain its normal homeostatic functions and efficient cellular bioenergetics.