Oral niacinamide mononucleotide (NMN) and aerobic exercise have been shown to enhance niacinamide adenine dinucleotide (NAD⁺) in the body. NAD⁺ plays a critical role in the body and can directly and indirectly affect many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell aging, and immune cell function. It is noteworthy that the level of NAD⁺ decreases gradually with increasing age. Decreased levels of NAD⁺ have been causally associated with a number of diseases associated with aging, including cognitive decline, cancer, metabolic diseases, sarcopenia, and frailty. Many diseases related to aging can be slowed down or even reversed by restoring NAD⁺ levels. For example, oral NMN or exercise to increase NAD⁺ levels in APP/PS1 mice have been proven to improve mitochondrial autophagy, but currently, there is no regimen combining oral NMN with exercise. This review summarizes recent studies on the effect of oral NMN on the enhancement of NAD⁺ in vivo and the improvements in mitochondrial autophagy abnormalities in AD through aerobic exercise, focusing on (1) how oral NMN improves the internal NAD⁺ level; (2) how exercise regulates the content of NAD⁺ in the body; (3) the relationship between exercise activation of NAD⁺ and AMPK; (4) how SIRT1 is regulated by NAD⁺ and AMPK and activates PGC-1α to mediate mitochondrial autophagy through changes in mitochondrial dynamics. By summarizing the results of the above four aspects, and combined with the synthesis of NAD⁺ in vivo, we can infer how exercise elevates the level of NAD⁺ in vivo to mediate mitochondrial autophagy, so as to propose a new hypothesis that exercise interferes with Alzheimer’s disease (AD).

Alzheimer’s disease (AD) causes a decline in skeletal muscle function, which can further exacerbate the cognitive dysfunction of patients with AD. It has been widely established that exercise improves AD brain pathology, but the role of skeletal muscle in AD is still poorly understood. In this study, we investigated the effects of treadmill exercise on the exercise ability of APP/PS1 transgenic AD mice and explored potential gene expression changes in their skeletal muscle. The APP/PS1 mice were subjected to a treadmill exercise for 12 weeks, followed by the Morris water maze and the open field test. After behavioral experiments, the changes in morphology, area, collagen fiber deposition, and ultrastructure of the skeletal muscle were determined; the balance of skeletal muscle protein synthesis and decomposition was analyzed; and changes in gene expression were investigated using RNA-Seq. We found that this exercise strategy can promote the learning and memory abilities of AD mice, reduce their anxiety-like behavior, improve their exercise ability, alleviate skeletal muscle atrophy, and optimize the microstructure. It can also enhance skeletal muscle protein synthesis and decomposition and improve several signaling pathways, such as the JAK–STAT, Wnt, and NOD-like receptors while decreasing calcium, cAMP, cGMP–PKG, and other signaling pathways. Six KEGG enrichment signaling pathways were downregulated and five signaling pathways were upregulated in the AD mice compared with wild-type mice, and these pathways were precisely reversed after the treadmill exercise. The expression of transcription factors such as Fosb and Egr1 in the skeletal muscle of AD mice decreased, followed by a decrease in the regulated target genes Socs1, Srrm4, and Il1b, a trend that was reversed following the exercise intervention. After exercise, AD mice exhibited a similar gene expression to that of wild-type mice, indicating enhanced exercise ability. The potential regulatory pathways and related genes identified in this study provide valuable insights for the clinical management and treatment of AD.