Bidirectional relationships between muscle and brain health in the aging process

As global demographics shift toward an aging population, the interconnected challenges of frailty, cognitive decline, and muscle health have emerged as critical public health concerns. By the year 2050, approximately one-quarter of the world’s population will be aged 65 years or older, with cognitive impairment affecting about 40% of this demographic to varying degrees.[1] While these conditions have traditionally been studied in isolation, mounting evidence suggested they shared common pathophysiological mechanisms and mutually reinforced one another through complex bidirectional pathways. Understanding this intricate relationship is essential for developing effective preventive and therapeutic strategies. The notion that muscle health directly influenced cognitive function represented a focus shift in our understanding of neurodegenerative diseases. Recent research has revealed that skeletal muscle was not merely a mechanical apparatus for movement but an endocrine organ that communicated with the brain through multiple mechanisms. This muscle-brain axis operated through several key pathways, including the release of myokines, modulation of systemic inflammation, regulation of insulin sensitivity, and improvement of cerebrovascular function.[2] A compelling study by Kotani et al. demonstrated the connection in male patients with chronic obstructive pulmonary disease (COPD), where those with mild cognitive impairment exhibited significantly lower knee extensor strength compared to cognitively intact individuals.[3] This finding underscored that muscle weakness may serve as an early indicator of cognitive decline, even in populations where respiratory disease might be expected to dominate the clinical picture. Sarcopenia, the age-related loss of muscle mass and function, has increasingly been recognized as more than a geriatric syndrome affecting mobility – it appeared to be intimately linked with cognitive deterioration. The prevalence of sarcopenia in adults over 60 years ranged from 10% to 27%, with rates climbing sharply after the age of 80 years.[4] Critically, individuals with sarcopenia demonstrated 1.5–2-fold increased risk of developing cognitive impairment and dementia compared to those with preserved muscle mass.[5] The mechanisms linking sarcopenia to cognitive decline were multifaceted. Muscle tissue produced brain-derived neurotrophic factor, insulin-like growth factor-1, and irisin – all of which supported neuroplasticity, neurogenesis, and synaptic function.[6] When muscle mass declined, production of these neuroprotective factors diminished, potentially accelerating cognitive decline. In addition, sarcopenia was associated with chronic low-grade inflammation, characterized by the elevated levels of interleukin-6, tumor necrosis factor-alpha, and C-reactive protein, all of which have been implicated in neurodegeneration.[7] Frailty represents the clinical manifestation of accumulated deficits and reduced physiological reserve across multiple physiological systems, positioning it as a critical convergence point between muscle health and cognitive function. Defined by criteria including unintentional weight loss, exhaustion, weakness, slow walking speed, and low physical activity, physical frailty affected approximately 10%–15% of community-dwelling older adults and up to 50% of those in long-term care facilities.[8] The relationship between frailty and cognitive decline operated bidirectionally. Frail older adults demonstrated higher risk of developing dementia, while those with mild cognitive impairment were significantly more likely to become frail.[9] This reciprocal relationship suggested shared underlying pathophysiology, including mitochondrial dysfunction, oxidative stress, hormonal dysregulation, and chronic inflammation. Interestingly, research on going-out behavior during the COVID-19 pandemic revealed that older adults with higher social capital and exercise motivation were less likely to restrict their activities, suggesting that psychological and social factors intersect with physical frailty to influence health outcomes.[10] This finding highlighted that frailty encompassed not only physical but also psychological and social dimensions, all of which impact cognitive health. Perhaps, the most compelling evidence for the muscle-brain-frailty connection came from intervention studies demonstrating that physical activity can simultaneously improve muscle function, reduce frailty, and enhance cognitive performance. Physical exercise induced neuroplastic changes through multiple mechanisms: increased cerebral blood flow, enhanced expression of neurotrophic factors, reduced amyloid-β accumulation, decreased neuroinflammation, and improved insulin sensitivity.[11,12] A meta-analysis examining the effects of physical exercise on older adults found that multicomponent training programs combining aerobic, resistance, and balance exercises produced significant improvements in cognitive function, particularly in executive function and memory domains, while simultaneously enhancing physical performance and reducing frailty markers.[13] The benefits appeared to be dose-dependent, with moderate to vigorous intensity exercise producing more substantial cognitive gains than light-intensity activities.[14] The study by Canlı and Karataş demonstrated that a 24-week cognitive motor coordination exercise program significantly improved both mental status (measured by Mini-Mental State Examination) and physical performance (measured by Physical Performance Test) in nursing home residents, while control group participants experienced decline in both domains.[15] This finding was particularly significant because it showed that combined cognitive-motor interventions may be more effective than either approach alone – a concept supported by the notion that cognitively engaging physical activities stimulated both muscular and neural adaptation. Research investigating the frequency of going outdoors as a predictor of functional change in community-dwelling frail older adults demonstrated that regular outdoor mobility was associated with better maintenance of both physical and cognitive function over time, suggesting that real-world physical activity embedded in daily life contexts may be particularly beneficial.[16] Emerging evidence suggested that nutritional interventions, particularly the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets, can modulate the muscle-brain-frailty relationship. These dietary patterns emphasized anti-inflammatory foods rich in omega-3 fatty acids, polyphenols, antioxidants, and vitamins that support both muscle and brain health.[17] The MeDi, characterized by high consumption of fruits, vegetables, whole grains, olive oil, fish, and moderate wine intake, has been associated with reduced risk of both sarcopenia and cognitive decline. Mechanistically, the diet’s high content of long-chain omega-3 polyunsaturated fatty acids (LC-n3-PUFAs), particularly docosahexaenoic acid and eicosapentaenoic acid, supported neuronal membrane fluidity, enhanced synaptic function, and reduced neuroinflammation while simultaneously promoting muscle protein synthesis and reducing muscle catabolism.[18] Higher adherence to the MIND diet has been associated with slower cognitive decline and reduced Alzheimer’s disease risk, with benefits observed even in the presence of typical brain pathology.[19] Importantly, these dietary patterns also appeared to preserve muscle mass and function, suggesting they may simultaneously address multiple components of the frailty-dementia spectrum. Studies examining nutritional status in frail older populations have consistently shown that adequate protein intake and micronutrient sufficiency are essential for maintaining both muscle mass and cognitive function.[20] While physical activity and nutrition provided bottom-up support for brain health through systemic physiological mechanisms, cognitive interventions offered top-down approaches to enhancing neural function. Cognitive training, cognitive stimulation, and cognitive rehabilitation have all demonstrated efficacy in improving cognitive performance in older adults, including those with mild cognitive impairment.[21] Interestingly, cognitive training has been shown to improve not only targeted cognitive domains but also to enhance brain connectivity, particularly within the frontoparietal network and default mode network – regions critical for executive function and memory.[22] This neuroplastic response appeared to be enhanced when cognitive training was combined with physical exercise, supporting the concept of a synergistic muscle-brain-frailty relationship.[23] Longitudinal studies have demonstrated that combined physical and cognitive training interventions produced more substantial and longer-lasting improvements in both domains compared to single-modality approaches, suggesting that the muscle-brain axis operated bidirectionally and can be optimally targeted through integrated interventions.[24] The recognition that frailty, cognitive impairment, and muscle health were closely interconnected has profound implications for clinical practice and research. First, it is suggested that screening for cognitive impairment should be routine in older adults presenting with sarcopenia or frailty, and conversely, that assessment of muscle function and frailty should be standard in those with cognitive concerns. The finding that lower extremity muscle strength predicted cognitive impairment in COPD patients illustrated how muscle assessment could serve as an accessible biomarker for cognitive risk in various populations.[3] Second, it argued for multicomponent interventions that simultaneously target multiple domains. Combined physical exercise, cognitive training, and nutritional optimization may produce synergistic benefits that exceed those achievable through single-modality approaches. The success of cognitive motor coordination exercises in improving both physical and cognitive outcomes in nursing home residents exemplifies this principle.[15] Third, it highlighted the importance of early intervention. Given that the relationship between muscle loss, frailty, and cognitive decline operated bidirectionally and reinforced itself over time, interventions implemented before substantial deficits accumulated were likely to be most effective. Studies of community-dwelling older adults have shown that even among those without overt frailty or cognitive impairment, higher levels of physical activity and better nutritional status predict superior cognitive and functional trajectories over subsequent years.[25] Research examining the relationship between life-space mobility and cognitive function has demonstrated that individuals who maintain broader ranges of daily activity – venturing beyond their immediate home environment – exhibited better preservation of executive function and processing speed, likely due to the combined cognitive and physical demands of navigating complex environments.[26] Despite growing recognition of the muscle-brain-frailty nexus, several challenges remained. The optimal type, intensity, frequency, and duration of physical activity for cognitive and functional benefits were not yet definitively established and may vary based on the individual factors including genetics, baseline fitness, comorbidities, and frailty status.[27] Similarly, the relative contributions of different dietary components to the neuroprotective and muscle-preserving effects of healthy dietary patterns required further elucidation. Moreover, most intervention studies have been conducted in relatively healthy, community-dwelling older adults, with less evidence available for those already experiencing significant frailty or cognitive impairment. Research examining exercise interventions in frail older populations has shown promising results, but questions remain about the minimal functional capacity required to benefit from various intervention modalities.[28] The role of novel biomarkers – including myokines, neuroimaging measures, and molecular markers of mitochondrial function and inflammation – in predicting individual responsiveness to interventions represented an important area for future investigation. Such markers could enable personalized intervention approaches tailored to each individual’s pathophysiological profile. In addition, implementation challenges must be addressed. Many older adults faced barriers to engaging in structured exercise programs, including mobility limitations, lack of access to appropriate facilities, financial constraints, and motivational factors. Home-based and technology-assisted interventions may help overcome some of these barriers, but their efficacy relative to supervised programs requires further study.[29] The relationship between frailty, cognitive impairment, and muscle health represented far more than simple comorbidity – it reflected fundamental interconnections among physiological systems that became increasingly apparent with aging. Muscle tissue functions as an endocrine organ communicating with the brain, while brain health influences physical activity levels and muscle function through motivation, motor planning, and neuroendocrine regulation. Frailty emerges as the clinical phenotype resulting from accumulated deficits in both domains. This integrated understanding calls for a focus shift in how we approach cognitive decline and frailty in older adults. Rather than viewing these as separate conditions requiring distinct interventions, we should recognize them as manifestations of shared underlying processes amenable to common therapeutic strategies. Multicomponent interventions combining physical exercise, cognitive engagement, and nutritional optimization showed particular promise for simultaneously improving muscle health, reducing frailty, and preserving cognitive function. As our population continues to age, developing effective strategies to maintain the muscle-brain-frailty nexus will be critical for promoting healthy aging and preserving independence and quality of life in older adults. The evidence increasingly suggested that such strategies existed and were accessible – the challenge now is to implement them systematically and equitably across populations. Data availability statement Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.