NAD+: An Old but Promising Therapeutic Agent for Skeletal Muscle Ageing

More than a century after the discovery of nicotinamide adenine dinucleotide (NAD⁺), our understanding of the molecule's role in the biology of ageing continues to evolve. As a coenzyme or substrate for many enzymes, NAD⁺ governs a wide range of biological processes, including energy metabolism, genomic stability, signal transduction, and cell fate. NAD⁺ deficiency has been recognised as a bona fide hallmark of tissue degeneration, and restoring NAD⁺ homeostasis helps to rejuvenate multiple mechanisms associated with tissue ageing. The progressive loss of skeletal muscle homeostasis with age is directly associated with high morbidity, disability and mortality. The aetiology of skeletal muscle ageing is complex, involving mitochondrial dysfunction, senescence and stem cell depletion, autophagy defects, chronic cellular stress, intracellular ion overload, immune cell dysfunction, circadian clock disruption, microcirculation disorders, persistent denervation, and gut microbiota dysbiosis. This review focuses on the therapeutic potential of NAD⁺ restoration to alleviate the above pathological factors and discusses the effects of in vivo administration of different NAD⁺ boosting strategies on skeletal muscle homeostasis, aiming to provide a reference for combating skeletal muscle ageing.