Background: Nicotinamide adenine dinucleotide (NAD⁺) is a ubiquitous and essential coenzyme that functions as a central electron carrier in key metabolic pathways, including glycolysis, the citric acid cycle, and oxidative phosphorylation, thereby supporting cellular ATP production. Beyond its role in energy metabolism, NAD⁺ is critically involved in redox homeostasis, DNA repair, and cell signaling. It also regulates mitochondrial integrity by maintaining redox balance, promoting mitophagy, and activating sirtuins that drive mitochondrial biogenesis and function. Notably, tissue NAD⁺ levels decline with aging and under various pathological conditions. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in the NAD⁺ salvage pathway, converting nicotinamide into nicotinamide mononucleotide (NMN), a direct precursor of NAD⁺. By regulating this rate-limiting step, NAMPT controls intracellular NAD⁺ levels. Hence, NAMPT agonists represent promising therapeutic candidates for age-related neuromuscular and mitochondrial diseases. Objective: To develop orally administered small molecule NAMPT agonists and assess their efficacy in preclinical models of neuromuscular diseases. Results: SIR-X56 increases NAMPT activity in a variety of biological contexts, e.g. protein, cellular, whole blood and in vivo. SIR-X56 increases muscle NAD+ level in rodents, dogs and non-human primates, which NR (NAD+ precursor) could not. SIR-X56 has high bioavailability when administered orally and good safety profiles after chronic dosing. In DMD mice, SIR-X56 restores NAD+ level in skeletal muscle, significantly reduces muscle injury markers, and improves muscle function. In a Friedreich ataxia mouse model, SIR-X56 significantly reduces cardiac injury and extends lifespan. In aged mice, SIR-X56 significantly reduces the level of muscle degeneration markers and improves motor functions. Conclusions: Activating NAMPT may offer a promising strategy for managing neuromuscular disorders and aging-related degenerative diseases.