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.

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder, and its incidence rate is increasing at an alarming rate. Astrocytes exhibit a complex array of functions that play a critical role in the pathogenesis and progression of PD. These multifaceted functions substantially influence disease development and exacerbation. Although numerous studies have investigated the role of astrocytes in PD, the interactions between astrocytes and other cellular or molecular factors during the course of neurological deterioration in PD have not been comprehensively characterized. Therefore, this review aims to highlight the roles and functional characteristics of astrocytes in PD. Astrocytes are involved in maintaining the blood-brain barrier, clearing α-synuclein, metabolizing glutamate and fatty acids, and protecting neurons. The interactions among astrocytes, microglia, and oligodendrocytes exert dual effects on PD progression. Additionally, the recently recognized phenomena of ferroptosis and cuproptosis have been associated with astrocytic activity. The interplay and regulatory mechanisms linking these forms of cell death to apoptosis and pyroptosis of immune cells in the brain warrant further investigation. This review is intended for researchers, healthcare professionals, and clinicians involved in the study and treatment of PD and its related complications. To ensure comprehensive and unbiased coverage, a systematic literature search was conducted using major scientific databases such as PubMed, Scopus, and Web of Science. Keywords included “Parkinson’s disease”, “astrocyte”, “brain”, “signaling mechanisms”, and “α-synuclein”. Articles were selected based on their relevance to astrocyte–PD interactions, while studies lacking scientific rigor or relevance were excluded. In summary, this review synthesizes current understanding of astrocytic function and mechanisms in PD and proposes potential therapeutic directions based on these insights.

Palmitoylation is a reversible lipid modification regulated by palmitoyl transferases and acyl-protein thioesterases, in which palmitic acid is attached to protein cysteine residues. This modification plays a pivotal role in modulating membrane localization and protein stability, and its dysregulation is closely associated with various neurodegenerative diseases, including Parkinson’s disease (PD). In PD, synaptotagmin-11, encoded by the PD risk gene SYT11, has been shown to reduce physiological α-synuclein (α-syn) tetramer formation while promoting the aggregation-prone monomeric form in a palmitoylation-dependent manner. In the context of PD, inflammation generally precedes the abnormal aggregation of α-syn and the degeneration of dopaminergic neurons (DA). Microglial activation, regarded as an inflammatory state, is facilitated by the palmitoylation-dependent localization of NLRP3 to the trans-Golgi network, which promotes the activation and expression of the NLRP3 inflammasome, leading to DA neuron loss. Additionally, the DJ-1 protein, encoded by the risk gene PARK7, and the dopamine transporter both undergo palmitoylation and may contribute to disease progression. This review summarizes the emerging link between protein palmitoylation and PD pathogenesis. Understanding the dynamic regulatory mechanisms of palmitoylation and depalmitoylation may facilitate the development of targeted therapeutic strategies for PD.

Parkinson disease (PD) is the second largest and most common neurodegenerative disease globally, following Alzheimer disease. Its pathological features include the deformation and loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, as well as the aggregation of α-synuclein in the form of Lewy bodies. This leads to motor symptoms such as resting tremors, muscle rigidity, bradykinesia, and postural instability, as well as non-motor symptoms including cognitive, emotional, and sleep disorders. Currently, PD is mainly treated by medication and surgery. Medication, though widely used, has limited efficacy and causes adverse reactions. With the intensification of global aging and the annual increase in the incidence of PD, the limitations of existing treatment approaches have become increasingly prominent, and there is an urgent need to explore safer and more effective treatment strategies. Numerous clinical studies have demonstrated that exercise rehabilitation training can not only effectively ameliorate the motor and non-motor symptoms of PD patients, but also promote the generation of neurotrophic factors, neurotransmitters, and hormones, and regulate the dopaminergic system. Therefore, an in-depth exploration of the mechanisms and effects of different exercise rehabilitation training methods in the treatment of PD holds great significance for refining the comprehensive treatment plan for PD and enhancing the quality of life of patients. This article will conduct a comprehensive review of the mechanisms and effects of various exercise rehabilitation training methods in treating PD.