Exercise and Brain Health in Aging: The Role of the Muscle-Brain Axis in Improving Cognitive Functions

Background and Purpose
Aging is accompanied by a range of physiological and structural changes within the brain that contribute to a progressive decline in cognitive functions, including memory impairment, deficits in attention, and more severe conditions such as dementia and Alzheimer’s disease . Exercise therapy has been demonstrated to exert beneficial effects on cognitive functions; however, the impact of different types and intensities of physical exercise may vary considerably . Moreover, the extent to which aging muscle can effectively stimulate physiological responses capable of eliciting adequate neuroprotective effects remains unclear . Empirical studies have shown that various forms of physical exercise—including aerobic, resistance, and mind-body modalities—positively influence brain health through multiple mechanisms. These mechanisms encompass the upregulation of neurotrophic factors, enhancement of cerebral blood flow, and attenuation of neuroinflammation . Additionally, evidence supports the notion that engaging in both physical and cognitive training synergistically mitigates age-related declines in physical and mental function, thereby underscoring the efficacy of dual-task training in addressing the functional deterioration associated with aging .
One of the principal pathways by which physical exercise exerts its effects on the brain is through activation of the muscle-brain axis, which involves the secretion of myokines such as irisin and cathepsin-B. These myokines traverse the blood-brain barrier, promoting neurogenesis and reducing neuroinflammation. Furthermore, physical exercise plays a critical role in preserving brain health by enhancing mitochondrial quality. Exercise-induced elevations in neurotrophic factors—including brain-derived neurotrophic factor (BDNF), irisin, insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF)—facilitate synaptic plasticity and mitigate neuroinflammation via diverse signaling pathways, thereby improving cognitive performance. For example, increased hippocampal BDNF levels, which rise in response to physical exercise, are associated with enhanced memory function and a reduced risk of Alzheimer’s disease .
Given that cognitive decline represents one of the most pressing health challenges confronting the aging population ,the identification and development of effective preventive strategies and interventions assume considerable social importance .
Nonetheless, there remains a lack of clear public health guidelines for prescribing physical exercise optimized to maximize its cognitive-enhancing potential in adults. Consequently, further research is imperative to refine exercise recommendations and address existing methodological limitations and physiological considerations .
The objective of this study was to conduct a narrative review assessing the impact of various types of physical exercise on cognitive functions in older adults, with a particular emphasis on the underlying molecular and cellular mechanisms, especially those mediated by the muscle-brain axis. The review first introduces diverse exercise modalities and their effects on cognitive health, followed by a discussion of key physiological mechanisms such as neurotrophic factor modulation, improved cerebral perfusion, inflammation reduction, and mitochondrial quality control. Additionally, the review explores the role of specific myokines secreted by skeletal muscle in regulating brain function and cognitive health through multiple pathways. It is anticipated that the insights provided by this review will contribute to the development of optimized exercise programs aimed at enhancing cognitive performance in older adults and will serve as a foundation for future research endeavors in this domain.
 
Materials and Methods
This narrative review involved a comprehensive literature search conducted across multiple databases, including ScienceDirect, Web of Science, Google Scholar, and PubMed, covering publications up to November 2024. The search strategy employed a combination of keywords encompassing terms related to exercise and physical activity (e.g., "exercise," "physical exercise," "exercise training," "aerobic exercise," "resistance training," "strength training," "body-mind exercises"), aging (e.g., "aging," "aged," "elderly," "senescent"), brain health and cognitive function (e.g., "brain," "brain health," "hippocampus," "central nervous system," "neurodegenerative diseases," "cognitive decline," "memory," "learning"), and molecular mechanisms (e.g., "muscle-brain axis," "myokines," "neurotrophic factors," "cerebral blood flow," "neuroinflammation," "mitochondrial quality control"). The search process was designed to capture a broad spectrum of relevant studies addressing the intersection of physical exercise, aging, and cognitive health.
 
Conclusion
In summary, this review provides novel insights into the effects of physical exercise on cognitive functions during aging, with a particular focus on the role of muscle-secreted myokines. While the evidence underscores the beneficial impact of physical exercise—especially combined exercise modalities—research in this field continues to face limitations. Therefore, additional studies are warranted to determine the most effective types, intensities, and optimal dosages of physical exercise necessary to achieve maximal cognitive benefits in older adults. Future research should also prioritize the investigation of long-term effects associated with various exercise modalities, the identification of optimal intensity and duration parameters, and the exploration of moderating factors such as gender, baseline physical and mental health status, and the presence of chronic diseases in modulating the response to physical exercise. These endeavors will be instrumental in developing personalized exercise regimens tailored to the unique needs of the elderly population.
 Article Message
Physical exercise constitutes a preventive and efficacious approach to mitigating cognitive decline and age-related neurodegenerative diseases. A synthesis of extant literature suggests that adopting a combined exercise strategy, incorporating diverse physical exercise types—particularly dual-task training—can elicit synergistic improvements in both physical and cognitive performance among older adults. Nevertheless, the optimal intensity and volume of physical exercise required to maximize cognitive benefits remain to be conclusively established, thereby emphasizing the need for further research to formulate evidence-based exercise guidelines in this domain.
Funding
This study received no external funding.
Authors’ Contributions
All authors contributed equally to the design, execution, and manuscript preparation of the present review.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgement
The authors express their gratitude to the Sports Sciences Research Institute of Iran and the Journal of Sport Physiology for facilitating the publication of this review article.