Search Results (338)

Three-dimensional (3D) spatial interaction data are fundamental to understanding genome architecture. Multi-modal deep learning models that jointly learn from 3D spatial data and orthogonal modalities, such as gene expression, face a critical computational challenge: the 3D spatial modality dominates computation by over one order of magnitude, creating a structural memory bottleneck that renders heavyweight model instances untrainable on single GPU. Existing distributed training methods rely on cost-model searching and treat model components uniformly, overlooking modality-specific memory asymmetries. We propose Automatic Modality-aware Parallelization (AMP), a framework that diagnoses memory bottlenecks from data configuration signals and prescribes a set of five strategies. At the core of this framework is a hidden-dimension tensor parallelism strategy ($S_5$) that partitions the 3D decoder’s hidden dimension across GPUs, transforming five non-standard operators into sharded forms with formal equivalence proofs. Evaluated on Hi-C data and RNA-seq from the HiRES single-cell mouse brain dataset across lightweight and heavyweight configurations, AMP converts out-of-memory (OOM) failures into successful training runs. Scaling from four to eight GPUs under heavyweight configurations, the 500 kb and 100 kb variants achieve 2.0× and 3.8× training speedups respectively, with mathematical equivalence to single GPU computation guaranteed by formal proofs. Full article

Xylazole is a sedative and analgesic agent widely used in Chinese veterinary practice, valued for its convenient administration and effectiveness. This study aimed to clarify its mechanism of action by investigating the effects on cAMP and monoamine neurotransmitters using both in vitro and in vivo rat models. In rat cortical neurons, Xylazole increased cAMP levels in a concentration- and time-dependent manner, transiently increased extracellular DA levels, which subsequently declined, consistently reduced extracellular NE levels, and enhanced extracellular 5-HT along with its metabolite 5-HIAA. In contrast, in vivo administration in adult rats reduced cAMP, DA, and NE levels across multiple brain regions, including the cerebrum, hippocampus, and brainstem, while increasing 5-HT and 5-HIAA. Notably, in the cerebellum group, cAMP was elevated after drug washout, a pattern not observed in the other brain regions. These findings reveal a striking divergence: in P7 cortical neurons, Xylazole triggers an α₂-adrenoceptor-dependent cAMP elevation, whereas in adult brain regions, a high concentration of locally delivered Xylazole leads to predominantly inhibitory cAMP changes, with a notable delayed increase in the cerebellum. Because of the non-physiological concentration used in reverse microdialysis, the in vivo neurochemical patterns should be regarded as exploratory regional responses, not as evidence of specific receptor-mediated mechanisms. Full article

Integrating neural and muscular signals into wearable robotics enables adaptive assistance during real-world tasks. This study proposes a multimodal neural interface for passive exoskeletons that combines electroencephalography (EEG) and electromyography (EMG) signals to classify motor gestures and estimate real-time cognitive and muscular effort, supported by finite-element-based biomechanical modeling. The system was implemented on the Ottobock Shoulder X passive exoskeleton© and validated using synchronous EEG–EMG acquisition via the LiveAmp platform©, a commercially available platform that was not developed specifically for this study. A hybrid CNN–LSTM architecture with deep fusion was employed to enhance robustness and responsiveness under realistic operating conditions. This study proposes a multimodal neural interface for the software-level adaptive assistance of passive upper-limb exoskeletons. While the physical device maintains a static mechanical profile, the proposed digital framework achieves adaptation by interpreting the user’s physiological and motor states. Ten healthy participants performed three functional tasks (screwing, moving the box, and lifting the box) under five assistive conditions. Finite element modeling (FEM) was used to characterize the torque–angle relationship of the passive exoskeleton and to support the interpretation of experimentally observed assistive torque profiles. The FEM model, used as an offline biomechanical analysis tool to aid in the interpretation of experimental results, has not been integrated into the real-time control loop. Results showed an average classification accuracy of 90%, an F1-score of 0.85, and inference latency below 180 ms, confirming real-time applicability. Cognitive indices such as the Cognitive Load Index (CLI) and Frontal Asymmetry Index (FAI) enabled adaptive modulation of assistance strategies without requiring active actuation, thereby preserving the device’s intrinsic passive nature. Comparative torque analysis highlighted the ergonomic benefits of passive systems in mid-range postures, while Finite Element Method (FEM) supported analysis clarified their limitations under highly dynamic loads compared to active solutions. These findings advance multimodal brain–machine interfaces for wearable robotics by integrating physiological sensing, deep learning, and biomechanical modeling, offering a safe, energy-efficient, and adaptive approach with potential rehabilitation, occupational ergonomics, and human–robot applications. Full article

Physiologically produced circulating β-amyloid (Aβ) exerts critical physiological functions. Although Aβ is a key player in Alzheimer’s disease (AD), it may initially be beneficial at the onset of infection. As an evolutionary conserved antimicrobial peptide (AMP), Aβ contributes to innate immune defense against pathogens. Host defense peptides such as Aβ and human cathelicidin (LL-37) not only kill pathogens through their antimicrobial activity but also exhibit high affinity for bacterial lipopolysaccharides (LPSs) and membrane receptors. LL-37, which is upregulated in the brain, binds to Aβ, modulating its aggregation; Aβ and LL-37 are protective under physiological conditions, but during chronic infection or dysregulation, their interaction becomes toxic and contributes to AD pathology. Similarly to Aβ, LL-37 can induce neuroinflammation by stimulating human microglia to release inflammatory cytokines, such as TNF-α and IL-6. Neuroinflammation is essential for protecting the brain from pathogens—when prolonged, it drives pathological processes underlying AD, Parkinson’s disease (PD), and other neurodegenerative disorders. Full article

Dietary polyphenols such as quercetin, resveratrol, and (−)-epigallocatechin-3-gallate (EGCG) have shown neuroprotective effects in epidemiologic and experimental studies of Alzheimer’s disease (AD), although clinical evidence remains limited. This review highlights the importance of investigating glucuronide and sulfate conjugates of these polyphenols, as well as their intestinal microbial metabolites, at bioavailable low nanomolar concentrations, particularly those capable of reaching the brain. Although many in vitro studies use micromolar concentrations of aglycones, the relevance of such concentrations to neuroprotection remains uncertain. While polyphenols are redox-sensitive, their direct antioxidant or prooxidant effects may be limited at nanomolar concentrations. Instead, their neuroprotective actions appear to be mediated through high-affinity interactions with molecular targets such as the 67-kDa laminin receptor (67LR). This receptor binds both aglycones and conjugates at low nanomolar concentrations through a peptide G region containing glycosaminoglycan- and palindromic sequence-related motifs. The same region also binds the prion–amyloid-β complex, suggesting that polyphenols may antagonize amyloid-β binding and thereby prevent its neurotoxicity. The peptide G region may also function as a redox sensor. Binding of polyphenols to 67LR activates cAMP signaling and downstream neuroprotective pathways involving CREB, SIRT1, and protein phosphatase 2A. In addition, nanomolar concentrations of resveratrol and quercetin inhibit quinone reductase 2, an enzyme associated with cognitive decline and reported to be elevated in AD. Given their low bioavailability in the brain and their distinct molecular targets, combining multiple polyphenols at low doses may produce additive or synergistic effects, enhance efficacy, and minimize potential toxicity in the prevention of AD. Full article

Brain aging is a complex biological process characterised by progressive neuronal and synaptic decline, in which disruption of mitochondrial quality control plays a central role. This system encompasses multiple synergistic components, including mitochondrial biogenesis, dynamic equilibrium, autophagic clearance, and energy metabolism. Aging induces dysfunction across these processes, precipitating mitochondrial fragmentation, functional decline, and energy crises, ultimately driving cognitive deterioration. Exercise is a promising non-pharmacological intervention for preserving brain health during aging, and its benefits may be mediated, at least in part, through modulation of mitochondrial quality control. Specifically, exercise has been shown to activate key signaling pathways such as AMPK/SIRT1/PGC-1α, thereby promoting mitochondrial biogenesis and metabolic adaptation. It may also regulate mitochondrial dynamics and mitophagy via pathways including cAMP/PKA/Drp1 and AMPK/mTOR. In addition, emerging evidence indicates that exercise may influence brain mitochondrial function through activity-dependent regulation of mitochondrial gene expression and systemic signaling factors. Furthermore, this review discusses potential differences between exercise modalities and highlights future directions for personalised intervention strategies, providing a theoretical basis for the application of exercise in delaying brain aging and preventing neurodegenerative diseases. Full article

Cognitive decline is a global public health challenge, yet the built environments where humans spend 90% of their time are only now being recognized as a means of preventive intervention. This paper presents a mechanistic framework describing how environmental and design features may influence hippocampal neuroplasticity, offering architects an evidence-based foundation for supporting brain health. We describe how eight environmental pathways, five activating features (design that promotes movement, enrichment, orientation features, daylight, views of nature) and three inhibiting features (air quality, noise, visual pattern stress) are hypothesized to converge on cAMP Response Element-Binding protein (CREB), a representative transcriptional integrator regulating Brain-Derived Neurotrophic Factor (BDNF) expression levels in the hippocampus. BDNF is a protein implicated in brain health outcomes including synaptic plasticity, neuronal survival, neurogenesis and cognitive function. Synthesizing evidence from neuroscience, exercise physiology, environmental psychology, toxicology, and visual neuroscience, we grade evidence strength for each pathway and identify the specific design variables involved. Evidence strength varies markedly across pathways: movement and enrichment rest on direct experimental and meta-analytic data, including human studies; air quality and noise rest on direct mechanistic evidence largely from animal and exposure studies; orientation features, daylight, and views of nature rest on indirect mechanistic inference; and visual pattern stress remains hypothesis-generating at the architectural scale. Enrichment and active design pathways show the strongest evidence for CREB activation, while noise, air quality, and non-natural visual patterns are associated with CREB inhibition. From this framework, we derive a consolidated set of design features organized by pathway, evidence strength, and temporal impact on brain health outcomes. These range from immediate synaptic plasticity to long-term neuroprotection. This mechanistic model offers a roadmap for a longer-term research program and outlines the formal structure required for future computational implementations. The framework can serve as a bridge connecting neuroscience to the emerging global movement on brain health that positions the built environment as an underutilized lever for supporting cognitive health across the lifespan. Full article

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), arise from highly interconnected molecular and cellular abnormalities that progressively lead to neuronal dysfunction, synaptic failure, and cell death. This review provides a unified framework to understand the interrelated molecular mechanisms driving these diseases, with a focus on identifying key disease-specific intervention nodes. Core contributors include oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, and emerging roles of peroxisomal dysfunction in redox imbalance, lipid dysregulation, and inflammatory amplification. Single-target therapies often show limited efficacy due to the complex, interconnected nature of these pathways. In contrast, polypharmacology, which targets multiple disease-relevant mechanisms simultaneously, offers a more promising therapeutic strategy. This review critically examines how pathway crosstalk drives neurodegenerative progression, with particular emphasis on mitochondrial–ROS–inflammatory signaling, aggregation–proteostasis failure, synaptic–neuroimmune dysfunction, and gut–brain communication. It evaluates various multi-node intervention strategies, including multi-target-directed ligands (MTDLs), molecular hybrids, natural products, drug repurposing, and nanocarrier-based delivery systems. Advances in network pharmacology, artificial intelligence (AI), bioinformatics, and multi-omics have enhanced the identification of actionable therapeutic nodes, candidate compounds, and brain-targeted delivery platforms. Notably, the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome and cyclic GMP–AMP synthase (cGAS)—stimulator of interferon genes (STING) pathways—play distinct roles in neuroinflammation, amplifying neuronal damage by releasing inflammatory cytokines and inducing mitochondrial dysfunction. However, successful translation into clinical practice remains constrained by challenges such as blood–brain barrier penetration, patient heterogeneity, and biomarker limitations. The review advocates for a shift towards mechanism-informed, patient-stratified polypharmacological strategies to better address the network pathology of neurodegeneration, despite significant translational hurdles. Full article

Glucose is the principal energy substrate for the brain. Hypo- and hyperglycemic episodes frequently occur in senescent people, contributing to functional and structural impairment of brain neurons and causing cognitive deficits in this population. In this study, we investigate whether long-term changes in the extracellular concentration of glucose affect viability and transmitter functions of septum-derived SN56 cholinergic neuronal cells through alterations in acetyl-CoA availability. Cells with low cholinergic expression (NCs) and cAMP/retinoic acid-induced high cholinergic expression (DCs) were investigated. Hypoglycemia brought about similar (approximately 20–30%) decreases in pyruvate dehydrogenase complex (PDHC) and ATP-citrate lyase (ACLY) activities and a 65% decline in lactate dehydrogenase (LDH) activity in NCs and DCs. Choline acetyltransferase (ChAT) and LDH activities in DCs were about 3–8 and 1.7–2.4 times higher than in NCs over the tested glucose concentration range, respectively. DCs appeared to be more resistant than NCs to hypoglycemia, as evidenced by lower glucose IC₅₀ values for cell count and intracellular LDH activity. On the other hand, some of functional properties of DCs, such as the cholinergic phenotype and their plasma membrane functions (trypan blue exclusion, TB+), were found to be more sensitive to hypoglycemia than those of NCs, as demonstrated by the higher IC₅₀ for glucose in DCs. Acetyl-CoA levels in DCs were 40% lower than in NCs, and decreased by about 25% with increasing hypoglycemia in both cell types. The cytotoxic effects of amyloid-β_25–35 (Aβ) and sodium nitroprusside (SNP; NO generator) were also tested. In 25 mM glucose medium, these toxic compounds exerted greater detrimental effects on DCs than on NCs. In contrast, in 1 mM glucose, more evident cytotoxicity of SNP and Aβ was observed in NCs. These data suggest that the higher rate of glycolysis in differentiated cholinergic septal neurons may be a protective mechanism against hypoglycemia. Full article

Background: Research indicates that hepatic gluconeogenesis mediates metabolic coupling between the liver and muscles via the Cori cycle and participates in liver–brain axis communication through its metabolic products and regulatory networks, thereby linking it to the pathogenesis of depression. Together, these mechanisms form the molecular basis for the antidepressant effects of exercise-regulated hepatic gluconeogenesis. Regular exercise promotes skeletal muscle contraction, causing the muscles to release more lactate into the circulatory system. Lactate acts as a substrate for gluconeogenesis and activates downstream signaling pathways, thereby enhancing the gluconeogenic response. During exercise, glycogenolysis directly provides energy, while lactate produced by glycolysis enters the liver via the Cori cycle to serve as a substrate for gluconeogenesis. By maintaining blood glucose homeostasis, this process ensures a stable energy supply to the brain, thereby improving cognitive and emotional functions. This study aims to elucidate how key substrates, regulatory factors, and rate-limiting enzymes involved in hepatic gluconeogenesis and exercise influence brain energy supply, cognitive function, and emotional regulation during depression. It seeks to identify the potential targets and mechanisms through which exercise exerts its antidepressant effects via hepatic gluconeogenesis, with the goal of providing a theoretical foundation for research into the mechanisms of depression and for clinical exercise interventions. Methods: This review conducted a comprehensive search of the recent literature on exercise, hepatic gluconeogenesis, and depression in major domestic and international databases. Adopting an interdisciplinary approach that integrates hepatic gluconeogenesis and exercise, it synthesizes existing evidence to explore the metabolic mechanisms by which exercise improves depression through the regulation of hepatic gluconeogenesis pathways. Results: Research has found that exercise may modulate hepatic gluconeogenic substrates and regulate the expression of cAMP-responsive element-binding protein in states of depression, regulatory factors such as liver kinase B1, forkhead box protein 01, hepatocyte nuclear factor 4 alpha, and peroxisome proliferator activated receptor gamma co activator factor 1 alpha are used to affect key rate limiting enzymes of hepatic gluconeogenesis, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, enhance hepatic gluconeogenesis processes, maintain blood glucose homeostasis, ensure brain energy supply, and improve depression. Conclusions: Exercise intervention targeting hepatic gluconeogenesis may be a potential therapeutic strategy for depression. Full article

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein (CREB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. Full article

Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines–exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle–brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK–PGC-1α–FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases. Full article

The relationship between epilepsy, obesity, and metabolic syndrome (MetS) has emerged as a rapidly evolving area of neurobiology inquiry. Emerging evidence suggests that epilepsy extends beyond neuronal hyperexcitability, reframing it as a systemic condition characterized by significant metabolic dysregulation. Converging supports a bidirectional relationship while seizures, antiseizure medications (ASM), and neuroinflammation induce exacerbate potentiate epileptogenesis through shared molecular pathways. At the cellular level, chronic epileptic activity induces oxidative stress, mitochondrial dysfunction, and the activation of microglia and astrocytes. This, in turn, leads to the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. These mediators traverse the blood-brain barrier (BBB), subsequently modifying insulin signaling, and disrupting glucose homeostasis, which collectively fosters a pro-inflammatory and insulin-resistant environment. Furthermore, antiseizure medications such as valproate can exacerbate these effects by directly impairing insulin receptor signaling and altering adipokine production, ultimately contributing to weight gain and systemic metabolic dysregulation. Obesity and MetS induce neuroinflammatory and excitotoxic states that promote seizure onset via leptin resistance, reduced adiponectin levels, and compromised AMP-activated protein kinase (AMPK) signaling. Emerging evidence emphasizes the gut-brain axis as a crucial regulator in this reciprocal interaction. Dysbiosis, altered microbial metabolites (e.g., short-chain fatty acids), and heightened intestinal permeability facilitate systemic inflammation and BBB disruption, enhancing neuronal excitability. Insulin resistance in the brain disrupts synaptic transmission, impairs mitochondrial biogenesis, and compromises redox equilibrium, perpetuating a pathological cycle linking metabolic stress to epileptic activity. This review synthesizes the cellular, molecular, and systemic pathways connecting epilepsy, obesity, and MetS, and proposes that epilepsy be reconceptualized as a neuro-metabolic disorder. Insights into these convergent pathways provide a rationale for novel therapeutic strategies that simultaneously target seizure control and metabolic regulation, encompassing microbiota modulation, antioxidant therapy, and insulin-sensitizing interventions with the overarching aim of restoring neuro-metabolic homeostasis. Full article

Obesity is characterized by abnormal adipose tissue expansion and energy metabolism imbalance. Browning of white adipose tissue (WAT), wherein white adipocytes acquire thermogenic properties similar to brown adipose tissue, represents a key mechanism for increasing energy expenditure. Although ginseng (Panax ginseng C.A. Meyer) is widely recognized as a health-promoting botanical, its role in WAT browning has not been fully elucidated. This review summarizes evidence that ginseng and its bioactive components regulate major thermogenic pathways, including β-adrenergic/cyclic adenosine monophosphate-protein kinase (cAMP-PKA) signaling, AMP-activated protein kinase (AMPK), and the peroxisome proliferator-activated receptor γ (PPARγ)/coactivator 1α (PGC-1α) axis, thereby upregulating key markers such as uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16) and type II iodothyronine deiodinase (DIO2). These effects promote mitochondrial function and fatty acid oxidation, reduce lipogenesis, alleviate inflammation, and improve insulin sensitivity, collectively fostering a microenvironment conducive to browning. Furthermore, fermentation has been found to enhance the bioactivity and thermogenic efficacy of ginseng. Recent evidence indicates that gut microbiota and their metabolites—such as short-chain fatty acids, unsaturated fatty acids, and bile acids—play a notable role in ginseng-induced thermogenesis via receptors including G-protein-coupled receptor 41/43 (GPR41/43), takeda G-protein-coupled receptor 5 (TGR5), and farnesoid X receptor (FXR). These multi-organ interaction networks involving the gut–fat, gut–liver, and gut–brain axes reflect the role of ginseng in integrating systemic metabolism. In summary, this review discusses the multi-level regulatory network through which ginseng promotes WAT browning, providing a mechanistic basis for its potential application in body weight and metabolic health management. Full article

Background: Aging-related cognitive decline is closely associated with microglial senescence and the resulting chronic neuroinflammation. Emerging evidence identifies the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway as a pivotal innate immune signaling pathway linking DNA damage to cellular senescence and the senescence-associated secretory phenotype (SASP), particularly in microglia. Targeting the formation or selective clearance of senescent cells thus emerges as a promising therapeutic approach to ameliorate cognitive dysfunction. Resveratrol has shown promise in modulating immune response and exerting anti-aging effects. However, the therapeutic potential and underlying mechanisms of resveratrol in mitigating age-associated microglial senescence and cognitive decline are not fully understood. Methods: In the present study, we employed a well-established murine model of accelerated aging induced by chronic intraperitoneal injection of D-galactose (D-gal) to elicit pronounced senescence-associated phenotypes and neuroinflammation. Resveratrol was administered via oral gavage daily for three weeks following D-gal injections. Behavioral assays were conducted to assess cognitive performance. Immunohistochemistry, quantitative PCR, and Western blot analyses were used to evaluate markers of cellular senescence, microglial activation and pro-inflammatory cytokine expression. In addition, in vitro assays in cultured microglia coupled with RNA sequencing were used to investigate the downstream signaling events following resveratrol treatment. Results: Chronic D-gal treatment induced significant cognitive impairment, enhanced microglial activation, elevated pro-inflammatory cytokine levels, and increased markers of cellular senescence in the brain. Resveratrol administration remarkably attenuated these effects, as evidenced by improved memory performance, reduced microglial senescence markers, and suppressed expression of Cxcl-10, Il-1β, and other SASP factors. Mechanistically, unbiased transcriptomic analysis revealed that the cGAS-STING signaling and neuroinflammation pathways were prominently dysregulated with double-stranded DNA-induced cellular senescence, which was effectively normalized by resveratrol in cultured microglia. Interestingly, resveratrol inhibited the translocation of STING from the endoplasmic reticulum to the Golgi apparatus and suppressed phosphorylation of TBK1, thereby blocking downstream STING signaling. Conclusions: These findings demonstrate that resveratrol mitigates microglial senescence and neuroinflammation and preserves cognitive function in D-gal-induced aging mice, at least partly through modulation of the cGAS-STING signaling. Therefore, targeting this pathway may represent a promising therapeutic strategy for age-related neuroinflammatory and cognitive disorders. Full article