NADH: the redox sensor in aging-related disorders.

Significance: NADH represents the reduced form of NAD+, and together they constitute the two forms of the Nicotinamide adenine dinucleotide whose balance is named as the NAD+/NADH ratio. NAD+/NADH ratio is mainly involved in redox reactions since both the molecules are responsible for carrying electrons to maintain redox homeostasis. NADH acts as a reducing agent and one of the most known processes exploiting NADH function is energy metabolism. The two main pathways generating energy and involving NADH are Glycolysis and Oxidative phosphorylation, occurring in cell cytosol and in the mitochondrial matrix, respectively. Recent Advances: Although NADH is primarily produced through the reduction of NAD+ and consumed by its own oxidation, several are the biosynthetic and consumption pathways, reflecting the NADH role in multiple cellular processes. Critical Issues: This review gathers all the main current data referring to NADH in correlation with metabolic and cellular pathways, such as its coenzyme activity, effect in cell death and on modulating redox and calcium homeostasis. Data were selected following eligibility criteria accordingly to the reviewed topic. A set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) have been used for a systematic search until January 2024 using MeSH keywords/terms (i.e., NADH, NAD+/NADH and NADH/NAD+ ratio, redox homeostasis, energy metabolism, aging, aging-related disorders, therapies). Future Direction: Gene expression control, as well as to the potential impact on neurodegenerative, cardiac disorders and infections suggest NADH application in clinical settings.