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), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca²⁺. Additionally, we demonstrated a significant reduction in the number of DA neurons in the SN region and a notable activation of ferroptosis, alongside a significant decrease in the antioxidant pathway NRF2/SLC7A11/GPX4. In summary, our data elucidate that ferroptosis in the midbrain SN region preferentially occurs in astrocytes under the dysregulation of oligodendrocytes, leading to ferroptosis in DA neurons. Thus, our study highlights the crucial role of oligodendrocyte-astrocyte crosstalk in driving neuronal inactivation and inflammatory expansion in PD.

T cells play a pivotal role in the immune system by distinguishing between various harmful pathogens and cancerous cells within the human body and initiating an immune response. Within the tumor microenvironment (TME), immune effector T cells encounter both immunosuppressive cells and factors that hinder their functionality. Additionally, they endure robust and persistent antigenic stimulation, often leading to exhaustion and apoptosis. However, the stemness of T cells, characterized by their ability to survive and self-renew over extended periods, represents a primary target in immune checkpoint therapies such as anti-PD-1 therapy. T cell stemness encompasses specific memory T cell subsets and progenitor-exhausted T cells with stem cell-like properties. Therefore, understanding the impact of the TME on T cell stemness, including factors like K⁺, lactate, and H⁺, holds significant importance and can facilitate the mitigation of terminal T-cell depletion, the identification of potential resilient biomarkers or therapeutic targets resistant to immune checkpoint therapies, and ultimately lead to sustained anti-tumor effects. Thus, it offers a novel perspective for advancing tumor immunotherapy.

Purpose: The incidence and severity of Clostridium difficile infection (CDI) have markedly increased over the past decade. However, there is very limited epidemiological data on CDI in China so far, specifically no data in Shandong Province. The aim of this study was to evaluate diagnostic algorithm for CDI and to gain data on molecular epidemiology of CDI in the Shandong Province of China. Materials and methods: Nonrepetitive unformed fecal specimens (n=504) were investigated by the glutamate dehydrogenase (GDH), C. difficile toxin A&B (CDAB) tests and toxigenic culture. Furthermore, 85 isolates were characterized by toxin gene detection, multilocus sequence typing, ribotyping and antimicrobial susceptibility testing. Results: The algorithm of combining GDH and CDAB tests could define diagnosis of 54.2% CDI cases and excluded 90% of non-CDI. Further adding the toxigenic culture to the algorithm enhanced the detection sensitivity to 100%. Toxigenic strains comprised 84.7% of isolates, including A+B+CDT- (71.8%, 61/85), A-B+CDT- (11.8%, 10/85) and A+B+CDT+ (1.2%, 1/85) isolates. RT046/ST35 (13.9%, 10/72), RT014/ST2 (12.5%, 9/72) and RT017/ST37 (12.5%, 9/72) were the more common genotypes among toxigenic C. difficile strains. The clinical severity score of A-B+CDT- toxin genes genotype (3.50 +/- 0.85) was significantly higher than the A+B+CDT- type (2.59 +/- 0.93) (P<0.05). RT046/ST35 isolates were highly prevalent and had high clinical severity scores (3.80 +/- 0.92). Variations in resistance from different sequence types (STs) were observed. Toxigenic strains showed higher resistance rates to erythromycin, clindamycin and ciprofloxacin compared to nontoxigenic strains (P<0.05). Conclusion: The epidemiology of C. difficile in Shandong Province differed from other regions in China. Comprehensive optimized diagnosis strategy and continuous surveillance should be established and applied in order to curb the spread of toxigenic C. difficile strains, especially for hospitalized patients.

Background: Copper plays an important role in the human body and is potentially related to the development of diabetes. The mechanism of copper death gene regulating immune infiltration in diabetes has not been studied. Methods: Download microarray data from healthy normal and diabetic patients from the GEO database. The identification of differentially expressed genes (DEGs) was analyzed by gene enrichment. Using String online database and Cytoscape software to interact with the protein interaction network and make visual analysis. Using Wilcox analyze the correlation between the copoer death gene and diabetic mellitus. Analysis of the correlation between immune penetration cells and functions, and the difference between the diabetes group and the control group, screening the copper death gene associated with diabetes, and predicting the upper top of microRNA (miRNA) through the Funrich software. Results: According to the identification of differential genes in 25 samples of GSE25724 and GSE95849 data sets, 328 differential genes were identified by consensus, including 190 up-regulated genes and 138 down-regulated genes (log2FC = 2, P < .01). KEGG results showed that neurodegeneration-multiple disease pathways were most significantly upregulated, followed by Huntington disease. According to Cytohubba, the TOP10 genes HCK, FPR1, MNDA, AQP9, TLR8, CXCR1, CSF3R, VNN2, TLR4, and CCR5 are down-regulated genes, which are mostly enriched in neutrophils. Immunoinfiltration-related heat maps show that Macrophage was strongly positively correlated with Activated dendritic cell, Mast cell, Neutrophil, and Regulatory T cell showed a strong positive correlation. Neutrophil was strongly positively correlated with Activated dendritic cell, Mast cell, and Regulatory T cell. Differential analysis of immune infiltration showed that Neutroph, Mast cell, Activated B cell, Macrophage and Eosinophil were significantly increased in the diabetic group. Central memory CD4 T cell (P < .001), Plasmacytoid dendritic cell, Immature dendritic cell, and Central memory CD8 T cell, etal were significantly decreased. DBT, SLC31A1, ATP7A, LIAS, ATP7B, PDHA1, DLST, PDHB, GCSH, LIPT1, DLD, FDX1, and DLAT genes were significantly associated with one or more cells and their functions in immune invasion. Forty-one miRNA. Conclusions: Copper death is closely related to the occurrence of diabetes. Copper death genes may play an important role in the immune infiltration of diabetes.