Journal Article Review Epublish
PubMed: 40506775 DOI: 10.1186/s40001-025-02751-9
Exercise orchestrates systemic metabolic and neuroimmune homeostasis via the brain-muscle-liver axis to slow down aging and neurodegeneration: a narrative review.
Eur J Med Res 30(1):475
Authors: Jianda Kong, Yingao Xie, Rao Fan, Qinglu Wang, Ying Luo, Panpan Dong
Affiliations
- College of Basic Medicine, Qilu Medical University, Zibo, China. School of Physical Education, Qufu Normal University, Qufu, China.
- College of Basic Medicine, Qilu Medical University, Zibo, China. Clinical College, Jining Medical College, Jining, China. Qianfoshan Hospital of Shandong Province, Jinan, China.
- School of Physical Education, Qufu Normal University, Qufu, China.
- College of Basic Medicine, Qilu Medical University, Zibo, China. School of Sports Health, Shandong Sports University, Jinan, China.
- Department of Laboratory, Zibo Central Hospital, Zibo, China.
- College of Basic Medicine, Qilu Medical University, Zibo, China.
Abstract
Aging is a systemic process marked by progressive multi-organ dysfunction, metabolic dysregulation, and chronic low-grade inflammation ("inflammaging"), 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 myokines (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.
MeSH
Exercise, Muscles, Homeostasis, Aging, Brain, Multiple Chronic Conditions, Liver