Ehsan Arabzadeh

This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer’s disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30–45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (Aβ)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy—affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein—including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails—remain speculative and are presented as future research directions rather than established therapeutic interventions.

Recent studies have demonstrated that insulin and its receptors play a vital role in the central nervous system, supporting neuronal survival, regulating energy metabolism, and facilitating synaptic plasticity—processes fundamental to learning and memory. Therefore, disruption of insulin signaling and glucose metabolism in the central nervous system impairs cognitive function and plays a role in the induction of dementia, such as AD. In the central nervous system, increased insulin sensitivity and proper insulin signaling affect the molecular cascades underlying plasticity, learning, and memory. Therefore, increasing brain insulin sensitivity is a preventive and therapeutic strategy in the prevalence and prevention of neurodegenerative disorders. It has been confirmed that in muscle, liver, and brain tissues, regular exercise training (including aerobic, resistance, and high-intensity exercise) with standard intensity and frequency, undoubtedly plays an important role in improving insulin sensitivity. The effects of exercise training on improving brain insulin sensitivity can be explained by multiple mechanisms. Since muscle contraction can have endocrine effects by secreting secretomes (especially myokines), it seems that one of the precise mechanisms of the effect of exercise training and exercise-induced muscle contraction on brain insulin sensitivity is these myokines. This review examines the roles and mechanisms of multiple myokines in enhancing brain insulin sensitivity, along with the metabolic interactions between muscle and the central nervous system. Clinical tips for the type, dose, and intensity of exercise to increase myokines related to the central nervous system are also presented.

The objective of this study was to evaluate the combined and independent effects of exercise training and L-Arginine loaded chitosan nanoparticles (LA CNPs) supplementation on hippocampal Tau, App, Iba1, and ApoE gene expression, oxidative stress, β-secretase enzyme activity, and hippocampus histopathology in aging rats. Thirty-five male Wistar rats were randomly assigned to five groups (n = 7 in each): Young (8 weeks old), Old (20 months old), old + L-arginine supplementation (Old Sup), old + exercise (Old Exe) and old + L-arginine supplementation + exercise (Old Sup + Exe). LA CNPs were administered to the supplement groups through gavage at a dosage of 500 mg/kg/day for 6-weeks. Exercise groups were subjected to a swimming exercise program five days/week for the same duration. Upon the completion of their interventions, the animals underwent behavioral and open-field task tests and were subsequently sacrificed for hippocampus genetic and histopathological evaluation. For histopathological analysis of brain, Cresyl violet staining was used. Congo Red staining was employed to confirm amyloid plaques in the hippocampus. Expressions of Tau, App, Iba1, and ApoE genes were determined by real-time PCR. In contrast to the Old group, Old Exe and Old Sup + Exe groups spent more time in the central space in the open field task (p < 0.05) and have more live cells in the hippocampus. Old rats (Old, Old Sup and Old Exe groups) exhibited a significant Aβ peptide accumulation and increases in APP, Tau, Iba1, APOE-4 mRNA and MDA, along with decreases in SOD compared to the young group (p < 0.05). However, LA CNPs supplementation, exercise, and their combination (Old Sup, Old Exe and Old Sup + Exe) significantly reduced MDA, Aβ plaque as well as APP, Tau, Iba1, and APOE-4 mRNA compared to the Old group (p < 0.05). Consequently, the administration of LA CNPs supplements and exercise might regulate the risk factors of hippocampus cell and tissue.

Exercise training and omega-3 supplementation are known to have anti-inflammatory effects; however, the simultaneous effect of exercise training and omega-3 supplementation has received little attention so far. The present study aimed to investigate the effect of combined training (resistance endurance) and omega-3 supplementation on the levels of inflammatory and anti-inflammatory cytokines in older women. The 40 participating older adults, with an average age of 66.7 ± 4.13 years, were randomly assigned to four groups: placebo, omega-3, training and training + omega-3. Combined exercise training (consisted of 30 mins running with 40-70% of reserve heart rate and resistance training included ten exercises, two sets, and each set consisted of 18-20 repetitions) performed for eight weeks and three sessions per week. Omega-3 supplementation was 2,000 mg daily (two 1000 mg capsules, one in the morning and one at night). Blood sampling was performed in pre and post-test (48 h after the last training session and omega-3 supplementation) stages, and interleukin (IL)-6, tumour necrosis factor (TNF)-α, and IL-10 levels were measured by ELISA. The dependent t-test results (pre- and post-test) indicated that there was a statistically significant difference (decrease) in HOMA-IR index, body fat percentage, body mass index, IL-6, and TNF-α in training and training + omega-3 groups, post-exercise (). TNF-α was lower in the omega-3 () training () and training + omega-3 () groups compared to the placebo group, post exercise. Moreover, IL-6 levels in the training () group were lower than in the placebo group, post exercise. Combined training may reduce both TNF-α and IL-6 compared to placebo. In contrast, omega-3 alone or combined with combined training may only reduce TNF-α but not IL-6 concentrations compared to placebo.