Exercise orchestrates systemic metabolic and neuroimmune homeostasis via the brain–muscle–liver axis to slow down aging and neurodegeneration: a narrative review

Jun 12, 2025European journal of medical research

How Exercise Helps Balance Body Metabolism and Brain Immune Health Through the Brain-Muscle-Liver Connection to Slow Aging and Brain Decline

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Abstract

Exercise may enhance mitochondrial function and promote neuronal survival through multiple inter-organ interactions.

Aging is associated with systemic dysfunction and chronic low-grade inflammation, contributing to neurodegenerative diseases.
Exercise can stimulate communication between the brain, muscles, and liver, potentially counteracting age-related decline.
Mitochondrial function and energy metabolism in skeletal muscle may improve through specific cellular signaling pathways activated by exercise.
Exercise is linked to increased levels of neurotrophic factors that support brain health and cognitive function.
Hepatic activation of certain proteins during exercise could help mitigate insulin resistance and reduce inflammation.
Exercise may balance immune responses and enhance the clearance of toxic proteins associated with neurodegeneration.

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Aging is a systemic process marked by progressive multi-organ dysfunction, metabolic dysregulation, and chronic low-grade inflammation (""), which collectively drive neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Emerging evidence underscores the brain-muscle-liver axis as a central hub for maintaining energy homeostasis and neuroimmune crosstalk during aging. Here, we elucidate how exercise orchestrates inter-organ communication to counteract age-related decline through metabolic reprogramming, immunomodulation, and neuroprotection. Mechanistically, exercise enhances mitochondrial biogenesis and oxidative capacity in skeletal muscle via AMPK/PGC-1α signaling, restoring fatty acid oxidation and glucose metabolism while producing (e.g., BDNF and IL-6) that promote neuronal survival and synaptic plasticity. Concurrently, hepatic SIRT1 activation promotes lipid metabolism, mitigates insulin resistance, and reduces systemic inflammation, hence preserving brain energy supply. In the aging brain, exercise stimulates neurogenesis, suppresses neuroinflammation via NF-κB inhibition, and elevates BDNF levels, which synergistically enhance cognitive resilience. vitally, exercise modulates the neuro-immunometabolic axis by balancing pro- and anti-inflammatory cytokines (e.g., IL-6's hormetic role), optimizing immune cell function, and enhancing autophagy-mediated clearance of toxic aggregates (Aβ, α-synuclein). These adaptations are further amplified by epigenetic reprogramming, including but not limited to Nrf2-driven antioxidant responses and circadian rhythm synchronization. Our synthesis highlights exercise as a pleiotropic intervention that transcends single-organ influences, instead leveraging multi-tissue networks to delay aging and neurodegeneration. Unresolved challenges-personalized exercise regimens, molecular biomarkers for efficacy prediction, and combinatorial therapies with pharmacologic agents-underscore the need for translational studies integrating omics technologies and circadian biology. By bridging mechanistic insights with clinical applications, this review positions exercise as a cornerstone of precision medicine for aging populations.

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Exercise orchestrates systemic metabolic and neuroimmune homeostasis via the brain–muscle–liver axis to slow down aging and neurodegeneration: a narrative review

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