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).

Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer’s disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients.

Fat is a “double-edged sword”: while it is a necessary substance for the body, the long-term intake of excessive fat will cause obesity, with the liver subjected to lipotoxicity as it accumulates. It will then continue to deteriorate, eventually leading to liver failure, which is a negative impact of high-fat food intake. Research has shown that exercise can reverse the side effects of a chronic high-fat diet and help the body to mitigate the harmful effects of lipotoxicity. In our study, it was found that moderate-intensity cardio-training (MICT) and high-intensity interval exercise (HIIT) effectively protected the livers of high-fat diet (HFD) ApoE^−/− mice against lipotoxicity. Previous results demonstrated that 12 weeks of HFD resulted in a significant elevation of CD36 in the livers of C57BL/6J mice, while knockdown of CD36 did not reduce the accumulation of fat in the liver. Therefore, we used ApoE^−/− mice as experimental subjects. Although HFD caused the development of hyperlipidemia and atherosclerosis, it is interesting to note that, due to the knockdown of ApoE, the livers of ApoE^−/− mice in the non-exercise group did not show significant lipid deposition; however, after 12 weeks of MICT and HIIT, the livers of ApoE^−/− mice showed significant lipid deposition. After we analyzed the lipid metabolism in their livers, we found that this was caused by the promotion of transport of peripheral fat into the liver due to exercise. Moreover, 12 weeks of exercise effectively reduced atherosclerosis, and the livers of ApoE^−/− mice in the exercise group were not damaged by lipotoxicity. The results showed that a 12-week exercise treatment activated AMPK in the livers of HFD ApoE^−/− mice through the APN–AdipoR1 signaling pathway, improved hepatic lipid metabolism disorders, and promoted the nuclear translocation of TFEB to enhance autophagic–lysosomal lipid scavenging. After the peripheral lipid is input into the liver due to exercise, the energy generated through gluconeogenesis can be used to replenish the energy consumed by exercise and maintain the normal operation of various functions in the liver, based on which the high autophagic flux in the liver can be maintained and the lipid clearance rate can be enhanced to protect the liver from lipotoxicity.

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.

Flywheel eccentric training is a type of training that combines concentric and eccentric contractions by creating inertial resistance with a flywheel device. This study compared the effects of high-intensity flywheel eccentric training and traditional barbell training on the anaerobic capacity and lower-limb strength of female college basketball players. Sixteen female Chinese University Basketball League (CUBAL) athletes from a university were recruited and randomly divided into flywheel eccentric training and traditional barbell training groups, with eight athletes in each group. They underwent two training sessions per week for 8 weeks. The athletes were assessed for their anaerobic capacity (blood lactate concentrations, peak anaerobic power, mean anaerobic power, fatigue index, 30-m sprint, T-test, and 17×15-m shuttle run), and lower-limb strength (1RM back squat, CMJ, peak power output (PPO), and isokinetic muscle strength) before and after the training intervention. After the training intervention, there was a significant difference between the flywheel eccentric training and traditional barbell training groups in each test index when compared to before and after the within-group experiment (P < 0.05). Between groups, there were significant differences in 3 min blood lactate concentrations (P < 0.05, d = 1.09), peak anaerobic power (P < 0.05; d = 1.10), mean anaerobic power (P < 0.05; d = 1.21), fatigue index (P < 0.05; d = 1.20), 30-m sprint (P < 0.05; d = 1.38), T-test (P < 0.05; d = 1.12), 17×15-m shuttle run (P < 0.05; d = 1.31), 1RM back squat (P < 0.05; d = 1.08), CMJ (P < 0.05; d = 1.11), peak power output (PPO) (P < 0.05; d = 1.26), and isokinetic muscle strength (P < 0.05). This study revealed that high-intensity flywheel eccentric training significantly enhanced the players’ anaerobic capacity and lower-limb strength and led to better performance than traditional barbell training across all measures.