ID: 42025545
Title: Sesamin ameliorates high-fat diet-induced inflammation and metabolic dysfunction in pregnant uterine smooth muscle via cGAS-STING inhibition.
Abstract: Maternal obesity and high-fat diets disrupt uterine metabolic homeostasis, leading to mitochondrial dysfunction, insulin resistance, and inflammation in uterine smooth muscle cells (USMCs), which may compromise pregnancy outcomes. Here, we investigated the role of the cGAS-STING pathway in mediating high-fat-induced metabolic and inflammatory dysfunction in USMCs and evaluated the therapeutic potential of sesamin, a bioactive compound from Cuscuta chinensis. Transcriptomic datasets from maternal serum and myometrium were analyzed to identify differentially expressed genes associated with inflammation, insulin resistance, and cGAS-STING activation. In vitro, USMCs were exposed to palmitic acid to mimic a high-fat environment, and mitochondrial integrity, mtDNA release, cGAS-STING activation, insulin signaling, and glucose uptake were assessed using TEM, ROS and JC-1 staining, qRT-PCR, Western blotting, and ELISA. In vivo, pregnant C57BL/6 mice were fed either a high-fat diet (HFD) or normal diet, with or without oral sesamin administration, and metabolic, mitochondrial, and inflammatory parameters were evaluated. High-fat exposure induced mitochondrial structural damage, ROS accumulation, and mtDNA leakage, which activated cGAS-STING signaling and upregulated pro-inflammatory cytokines (IL-1β, IL-18), impairing insulin signaling in USMCs. Selective mtDNA depletion or STING knockdown attenuated these effects. Sesamin bound STING with high affinity, inhibited cGAS-STING activation, restored insulin signaling, improved glucose uptake, and enhanced mitochondrial respiratory function. In HFD mice, sesamin reduced systemic inflammation, improved uterine insulin sensitivity, and normalized metabolic rates (VO₂, VCO₂, and RER). These findings demonstrate that high-fat-induced cGAS-STING activation underlies mitochondrial dysfunction, inflammation, and insulin resistance in USMCs. Sesamin mitigates these effects via dual regulation of STING signaling and mitochondrial function, highlighting its potential as a therapeutic agent for metabolic and inflammatory dysregulation in pregnancy.

ID: 42028013
Title: Natural senolytic activity of Rhodiola rosea extract alleviates age-associated phenotypes via paraptosis.
Abstract: The accumulation of senescent cells drives age-related diseases, and their removal (senolysis) has been reported to ameliorate pathological aging phenotypes. Here, we identified Rhodiola rosea extract (Rosea) as a senolytic agent through screening of edible natural products. In mice, Rosea eliminated irradiation-induced senescent cells and reduced the burden of senescent cells in adipose tissue during obesity, as well as in adipose tissue, skin, and skeletal muscle during aging. These effects were accompanied by improvements in metabolic abnormalities, physical function, skin abnormalities, and behavioral impairments. We further identified oligomers of epigallocatechin (EGC) and epigallocatechin gallate (EGCG), specifically EGC-EGCG and EGCG-EGCG, as the senolytic components. EGC-EGCG targeted vulnerabilities in calcium dynamics between the endoplasmic reticulum and mitochondria in senescent cells, thereby inducing paraptosis-like cell death. These findings suggest that Rosea, containing EGC-EGCG and EGCG-EGCG, represents a natural senolytic candidate capable of delaying, mitigating, or preventing the progression of age-related pathologies.

ID: 42142553
Title: Jintiange ameliorates age-related sarcopenia by inhibiting the cGAS-STING signaling pathway via maintaining mitochondrial homeostasis.
Abstract: Jintiange (JTG), a substitute for natural tiger bone, has been approved in China for the treatment of osteoporosis, osteoarthritis and rheumatoid arthritis. Clinical observations indicate that JTG can improve skeletal muscle atrophy and enhance skeletal muscle strength. However, the role and mechanism of action of JTG in sarcopenia remain unclear. This study aimed to investigate the therapeutic effects and the underlying mechanisms of JTG on age-related sarcopenia. The 12-month-old male mice were orally treated with three doses of JTG for 3 months. The grip strength, weight-loaded swimming time, muscle mass (quadriceps femoris, gastrocnemius, tibialis anterior and soleus muscles), and the cross-sectional area (CSA) of myofibers were measured. The transcriptomic sequencing, RT-PCR, Western blot, immunofluorescence, and immunohistochemistry were employed. Additionally, the other mice, after oral administration with JTG for 3 months, experienced a 3-month withdrawal period to observe the long-term effects of JTG on skeletal muscle. The treatment with JTG significantly enhanced grip strength and muscle mass, extended weight-loaded swimming time, elevated CSA, and up-regulated the expressions of muscular regulatory factors, as well as down-regulated the expressions of MuRF-1 and Atrogin-1 in the ubiquitin-proteasome system. The administration of 12-month-old mice with JTG for 3 months profoundly reduced the expression levels of senescence-associated secretory phenotypes and of age-related markers (β-gal, P53 & P16). JTG improved mitochondrial quality by promoting mitochondrial biogenesis through increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitochondrial transcription factor A (TFAM), restoring mitochondrial dynamics via regulation of mitofusin-1 (MFN-1) and fission 1 (FIS-1), and activating PINK1/Parkin-mediated mitochondrial autophagy. The benefit of JTG on maintaining mitochondrial homeostasis led to the reduction in the leakage of mitochondrial DNA (mtDNA) into cytoplasm, thereby attenuating the activation of cGAS-STING signaling pathway and lowering NF-κB-evoked chronic low-grade inflammation in skeletal muscle, ultimately ameliorating age-related sarcopenia. After drug withdrawal for 3 months, the mice in JTG-treated groups still displayed better muscular performance than those vehicle-treated mice with the same age (18-month-old). JTG benefits for alleviating aging conditions of skeletal muscle by maintaining mitochondrial homeostasis, thus, effectively ameliorates age-related sarcopenia by blocking the cGAS-STING signaling pathway.

ID: 42166975
Title: Ginsenoside Ro ameliorates d-galactose-induced sarcopenia by modulating oxidative stress, inflammation, and gut microbiota in mice.
Abstract: Sarcopenia is an age-related disorder primarily characterized by progressive muscle degeneration, and effective therapeutic interventions for this condition remain limited. Ginsenoside Ro (GRo) exhibits antioxidant and anti-inflammatory effects. However, the impact of GRo on skeletal muscle aging, myoblast differentiation, and mitochondrial dysfunction remains unexplored. The present study investigated the potential therapeutic efficacy of GRo against d-galactose (D-gal)-induced sarcopenia. This study employed C2C12 myotubes and C57BL/6 N mice as in vitro and in vivo models, respectively. The ameliorative effects of GRo on sarcopenia were comprehensively elucidated through behavioral assessments, biochemical analyses, histopathological evaluation, multi-omics profiling, network pharmacology, and molecular docking. In cell culture experiments, GRo treatment effectively attenuated muscle atrophy and reduced senescence-associated β-galactosidase (SA-β-gal) activity. Concurrently, GRo mitigated oxidative stress by inhibiting the production of reactive oxygen species (ROS) and restoring mitochondrial membrane potential. In the animal model, administration of d-gal induced significant muscle mass loss, decreased muscle strength, and impaired exercise tolerance in mice, accompanied by elevated oxidative stress levels and systemic inflammatory responses. However, GRo treatment reversed these adverse effects, as evidenced by increased muscle mass, improved myofiber size, and enhanced physical endurance in the treated mice. Additionally, GRo supplementation increased antioxidant activity, reduced the levels of pro-inflammatory cytokines, and restored adenosine triphosphate (ATP) content. Through 16S rDNA sequencing analysis, the study revealed that GRo modulated the composition of the gut microbiota, specifically promoting the growth of beneficial microbial taxa including Akkermansiaceae, Bifidobacteriaceae, Monoglobus, Colidextribacter, and Peptococcaceae. This study demonstrates that GRo targets the pathological mechanisms underlying age-related muscle degeneration by regulating oxidative stress, inflammatory responses, metabolic processes, and gut microbiota homeostasis.

ID: 42229217
Title: Vitamin D status and sarcopenia in older adults: population-based evidence for synergy with diabetes and experimental validation in an aged diabetic rat model.
Abstract: Vitamin D deficiency is common in older adults and may contribute to sarcopenia, but whether diabetes modifies this association and the underlying mechanisms remain unclear. We used a population-based and experimental validation framework. In epidemiological analyses, 7,520 older adults from two nationally representative cohorts were included (HRS wave 13, n = 3,246; ELSA wave 6, n = 4,274). Sarcopenia was defined according to EWGSOP2 criteria using low grip strength and low muscle mass estimated by a validated anthropometric equation standardized by BMI. Serum 25(OH)D was categorized as low (≤50 nmol/L) or higher (>50 nmol/L). Multivariable logistic regression with multiple imputation was used to assess overall and diabetes-stratified associations, as well as multiplicative and additive interactions. For experimental validation, an aged diabetic rat model with vitamin D deficiency was established, followed by vitamin D3 supplementation (2000 IU). Glycometabolic indices, muscle function and morphology, intramuscular lipid deposition, and senescence-related markers in gastrocnemius muscle were evaluated. Low 25(OH)D was associated with higher odds of sarcopenia overall. Among participants with diabetes, this association was stronger and reached statistical significance in ELSA (HRS: OR = 1.778, 95% CI 0.843-3.750; ELSA: OR = 2.242, 95% CI 1.055-4.764). In ELSA, the joint exposure to low 25(OH)D and diabetes was associated with increased sarcopenia odds (OR = 1.66, 95% CI 1.06-2.61), with evidence of additive interaction (RERI = 1.08, 95% CI 0.25-1.97). In aged diabetic rats, vitamin D deficiency aggravated hyperglycemia, insulin resistance, intramuscular lipid accumulation, and muscle senescence, whereas vitamin D3 supplementation improved muscle strength, myofiber cross-sectional area, and lipid infiltration. Low vitamin D status was associated with higher sarcopenia risk, particularly in diabetes. Experimental findings further support a protective role of vitamin D against diabetes-related muscle deterioration.

ID: 42257028
Title: Cathepsin B ablation alleviates VSMC phenotypic switching by modulating alternative macrophage polarization through the NLRP3 signaling pathway.
Abstract: The classical activation of pro-inflammatory macrophages contributes to neointimal hyperplasia by driving the excessive accumulation of phenotypically switched vascular smooth muscle cells (VSMCs), a process that underlies occlusive disorders such as atherosclerosis and restenosis. However, the impact of Cathepsin B (CTSB) on the regulation of macrophage polarization remains unclear. Analysis of the Gene Expression Omnibus (GEO) database revealed a significant upregulation of CTSB in advanced human atherosclerotic plaques. Furthermore, a time-dependent increase in CTSB expression was observed in carotid arteries following vascular injury. At the cellular level, CTSB expression was markedly elevated in pro-inflammatory M1 macrophages but suppressed in resolving M2 macrophages. A loss-of-function approach, utilizing AdshCTSB-transfected bone marrow-derived macrophages (BMDMs), demonstrated that CTSB knockdown promotes a shift in polarization, repressing M1 markers while inducing those characteristic of the M2 phenotype. This CTSB-mediated polarization switch subsequently attenuated the proliferation and migration of VSMCs while promoting their differentiation. Mechanistically, we identified NLRP3 as a direct target of CTSB. Knockdown of CTSB suppressed the NLRP3 inflammasome, an effect mediated through the cGAS-STING signaling pathway. The functional significance of this pathway was confirmed, as the STING agonist DMXAA abolished the polarizing effects of CTSB silencing. In vivo, global CTSB-knockout mice (CTSB-KO) exhibited amelioration of wire injury-induced intimal hyperplasia. In conclusion, our findings suggest that CTSB inhibition represents a promising therapeutic strategy for mitigating intimal hyperplasia. This approach operates by favoring alternative macrophage polarization, which in turn attenuates VSMC phenotypic switching, a process that is partially mediated by the inactivation of the cGAS-STING-NLRP3 axis.

ID: 42286673
Title: The cGAS-STING pathway contributes to cisplatin-induced skeletal muscle atrophy through altered proteostasis and myogenic signaling.
Abstract: Cisplatin chemotherapy is widely used for cancer treatment but frequently induces skeletal muscle atrophy, which compromises physical function and patient outcomes. The molecular mechanisms underlying this process remain incompletely understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, classically involved in innate immune responses, has recently been implicated in cellular stress and tissue dysfunction. Whether cGAS-STING signaling contributes to cisplatin-induced skeletal muscle atrophy remains unclear. We employed both pharmacological and genetic approaches. Wild-type (WT) mice received a single intraperitoneal injection of the STING agonist DMXAA prior to cisplatin administration. Genetic models included global cGAS and STING knockout mice, as well as skeletal muscle-specific cGAS knockout mice. Cisplatin was administered intraperitoneally (3 mg/kg/day) for four consecutive days. Body weight, skeletal muscle mass, myofiber cross-sectional area (CSA), and fiber diameter were assessed. Molecular and transcriptional analyses were performed using Western blotting, quantitative polymerase chain reaction, and RNA sequencing. Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass. Skeletal muscle-specific cGAS deficiency preserved muscle weight and myofiber diameter following cisplatin exposure. Although CSA was also assessed, no significant difference was observed between groups. Transcriptomic analysis identified 696 differentially expressed genes upon cGAS deletion, with enrichment in pathways related to inflammatory signaling, proteasome function, and autophagy. Further analyses in skeletal muscle-specific cGAS-deficient mice showed reduced expression of muscle atrophy-associated genes (FBXO32 and Murf1), together with preservation of key myogenic regulators after cisplatin treatment. Consistently, NF-κB signaling and interferon-stimulated gene expression were diminished, accompanied by altered Beclin1 responses and partial attenuation of selected autophagy-related genes. These findings support a role for cGAS-STING signaling in cisplatin-induced skeletal muscle atrophy, associated with enhanced innate immune and inflammatory signaling, proteolytic and autophagy-related alterations, and impaired myogenic regulation. Targeting the cGAS-STING pathway may represent a potential therapeutic strategy to mitigate chemotherapy-associated skeletal muscle atrophy.

ID: 42324036
Title: Molecular senescence, neuroendocrine metaflammation, and skeletal muscle insulin resistance in type-4 diabetes: from mitochondrial dysfunction to precision therapeutics.
Abstract: With the global population aged 65 years and older projected to exceed 1.5 billion by 2050, sarcopenia-driven insulin resistance is emerging as an urgent yet still under-recognised contributor to the diabetes burden in older adults, underscoring the timeliness of a focused molecular synthesis of this entity for guiding both diagnostic recognition and therapeutic prioritisation. Molecularly different, age-driven insulin resistance promotes skeletal muscle ageing, mitochondrial bioenergetic collapse, and prolonged neuroendocrine metaflammation in type-4 diabetes (T4DM). In ageing myocytes, poor IRS-1/PI3K/Akt signalling, GLUT4 trafficking anomalies, AMPK suppression, ROS-mediated mtDNA instability, and decreased OXPHOS capacity induce T4DM. Senescent muscle cells generate IL-6, TNF-α, and MCP-1 when p16INK4a/p21 checkpoints activate, forming a self-reinforcing inflammatory cycle. Myostatin overactivation, irisin decrease, and FGF21 imbalance influence glucose homeostasis. Metabolism declines due to hypothalamic insulin resistance, microglial inflammation, gut dysbiosis-driven TLR4/NF-κB signalling, and epigenetic remodelling via miR-29, miR-34a, and l Using precision biomarkers like GDF-15, β2-microglobulin, and p16INK4a with multi-omics phenotyping may change diagnosis. Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence. T4DM's molecular architecture and precision geriatric endocrinology translational targets are reviewed here.

ID: 42344418
Title: Research trends and potential molecular intersections between diabetic kidney disease and sarcopenia: a 21-year bibliometric and bioinformatics analysis.
Abstract: Diabetic kidney disease (DKD) and sarcopenia are increasingly recognized as clinically relevant and potentially interrelated conditions in diabetes, aging, metabolic dysfunction, and functional decline. However, the global research landscape, evolving hotspots, and potential molecular overlap between DKD and sarcopenia remain insufficiently characterized. Publications on DKD and sarcopenia from 2005 to 2025 were retrieved from the Web of Science Core Collection, Scopus, and PubMed. After data cleaning, document-type screening, and deduplication, bibliometric analyses were performed using R, VOSviewer, and CiteSpace to assess publication trends, collaboration networks, keyword co-occurrence, thematic evolution, and burst keywords. For exploratory and hypothesis-generating bioinformatics analysis, DKD- and sarcopenia-associated genes were retrieved from GeneCards based on relevance score thresholds defined at the tenths place (DKD ≥ 39.4; sarcopenia ≥ 63.0). Shared genes were identified by Venn analysis and further examined using STRING-based protein-protein interaction analysis, Cytoscape/CytoHubba topological screening, and Gene Ontology and KEGG enrichment analyses with clusterProfiler. DKD-sarcopenia research showed an overall increasing publication trend over the past two decades. Japan, China, the United States, Italy, and the United Kingdom were major contributors, and several Asian institutions showed prominent productivity. Keyword analyses indicated that hotspots mainly involved diabetes mellitus, sarcopenia, muscle strength, renal dysfunction, hemodialysis, inflammation, insulin resistance, physical performance, and aging-related metabolic disorders. Burst keyword and timeline analyses suggested a gradual shift from descriptive clinical and renal dysfunction-related topics toward functional assessment, comorbidity patterns, dialysis populations, and systemic metabolic complications. In the exploratory and hypothesis-generating gene overlap analysis, 761 overlapping candidate genes were identified between sarcopenia and DKD. These genes were mainly primarily found to be associated with oxygen and hypoxia response, energy metabolism, peptide hormone signaling, protein phosphorylation regulation, growth factor activity, insulin receptor binding, PI3K-Akt signaling, MAPK signaling, AGE-RAGE signaling in diabetic complications, FoxO signaling, HIF-1 signaling, diabetic cardiomyopathy, and cellular senescence. This study provides an updated bibliometric overview of DKD-sarcopenia research and identifies potential molecular intersections between the two conditions. The findings suggest that inflammation, metabolic dysregulation, hypoxia response, insulin/growth-factor signaling, and cellular stress may represent important directions for future investigation. However, the molecular findings are exploratory and hypothesis-generating rather than direct mechanistic evidence.

ID: 42348390
Title: Cellular senescence links muscle atrophy and posttraumatic osteoarthritis after ACL injury.
Abstract: Traumatic knee injury leads to posttraumatic osteoarthritis (PTOA) and significant skeletal muscle weakness, resulting in chronic disability. The current standard of care frequently fails to prevent musculoskeletal dysfunction, underscoring the need to identify therapeutic mechanisms of PTOA. Using an established preclinical anterior cruciate ligament (ACL) transection model of PTOA and leveraging an innovative SPiDER-senescence-associated β-galactosidase stain to discern senescent cells, we investigated cellular senescence at single-cell resolution and identified anti-inflammatory macrophages as a predominant contributor to the senescent cell burden in both muscle and knee joint after injury. Clearance of senescent cells using the senolytic dasatinib and quercetin (D + Q) mitigated injury-induced muscle atrophy and cartilage degradation, with greater senescent cell clearance within muscle compared with cartilage. We also provide clinical evidence of elevated senescent cell burden in the muscle of patients following ACL injury and with PTOA, which is obstinate to standard of care, highlighting cellular senescence as a strong therapeutic target to improve functional recovery after traumatic joint injury.NEW & NOTEWORTHY Posttraumatic osteoarthritis (PTOA) and disability are consequences of ACL injury, but the cellular effectors that facilitate this process are unknown. Our findings demonstrate increased senescent macrophage burden in the muscle and knee joint in a preclinical ACL injury model, as well as in patients who predict poor muscle quality and weakness. We provide evidence that treatment with senolytics is an effective strategy to improve tissue quality and function and mitigate PTOA severity.

ID: 42370191
Title: Cellular senescence in musculoskeletal diseases: biological mechanisms and clinical implications.
Abstract: Cellular senescence is a persistent state of irreversible growth arrest that occurs when cells encounter various stress signals. It is marked by elevated expression of cell cycle inhibitors, dysregulated gene transcription, and secretion of the senescence-associated secretory phenotype (SASP). These senescent features may exert both detrimental and beneficial effects on tissue homeostasis and systemic physiological integrity. In this review, the relevant pathological processes are categorized into three tissue types: skeletal muscle, bone, and cartilaginous tissue. We systematically delineate the mechanisms of cellular senescence underlying seven musculoskeletal diseases, including skeletal muscle injury and regeneration, sarcopenia, osteoporosis, fracture, osteonecrosis of the femoral head (ONFH), osteoarthritis (OA), and intervertebral disc degeneration (IDD), with a particular focus on the heterogeneity of senescent cells across distinct musculoskeletal diseases. On this basis, we further elaborated on relevant mechanisms and senescence-related targets, and analyzed senescence heterogeneity in diverse musculoskeletal tissues, senescence identification and integrated diagnostic approaches. Moreover, we discussed convergent pathways, the dual roles of senescent cells, and the critical evaluation of disease-specific versus common therapeutic vulnerabilities.

ID: 42402137
Title: A Melatonin-Catechol Hybrid Molecule Prolongs Lifespan via Regulating ROS and Reprogramming Mitochondrial Metabolism.
Abstract: Modulation of mitochondrial dynamics is a viable strategy for lifespan extension. Reactive oxygen species (ROS) play key roles in aging, acting either as signaling molecules to facilitate longevity-associated processes or as stimulators of oxidative stress, exerting deleterious effects on physiological functions. The hybrid molecule MC1 is designed by integrating melatonin and catechol moieties to reconstruct mitochondrial dynamics and selectively regulate the generation of ROS. MC1 combats cell senescence under oxidative stress and DNA damage, and reprograms the mitochondrial energy metabolism by inhibiting the tricarboxylic acid cycle and glycolysis, while initiating fatty acid oxidation to increase energy production. More importantly, MC1 significantly extends the lifespan of Caenorhabditis elegans, accompanied by an improvement in muscle strength and physiological functions. The lifespan-extending effect of MC1 arises from its intervention in mitochondrial membrane fusion, the electron transport chain, and differential modulation of ROS. Regulating mitochondrial dynamics and ROS production shows great potential for longevity extension.

ID: 42462036
Title: Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
Abstract: Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.

ID: 42473083
Title: Cigarette Smoke-Exposed Alveolar Epithelial Cell-Derived Exosomes Exacerbate Skeletal Muscle Dysfunction Through HDAC2 Signalling.
Abstract: Skeletal muscle dysfunction (SMD) is a common extrapulmonary complication of chronic obstructive pulmonary disease (COPD). Histone deacetylase 2 (HDAC2) is closely involved in the suppression of inflammatory transcription and is progressively reduced during COPD progression. Exosomes mediate intercellular communication by transferring bioactive cargos, including proteins. This study aimed to elucidate the molecular mechanism by which alveolar epithelial cell-derived exosomes regulate HDAC2 and contribute to COPD-related SMD. Exosome inhibitor GW4869 was used to assess the role of exosomes in skeletal muscle injury induced by chronic cigarette smoke (CS) exposure. Exosomes isolated from the bronchoalveolar lavage fluid (BALF) of CS-exposed mice and from cigarette smoke extract (CSE)-exposed mouse alveolar epithelial (MLE12) cells were applied to recipient mice and/or mouse myoblast (C2C12) cells to evaluate muscle phenotypes, myogenic differentiation and cellular senescence. Rescue experiments using HDAC2 overexpression or HDAC activator ITSA1 treatment, together with proteomics and protein interaction assays, were performed to elucidate the underlying molecular mechanisms. GW4869 treatment ameliorated CS-induced muscle dysfunction in mice, as evidenced by increased grip strength (222.4 ± 15.91 g vs. 159.2 ± 11.65 g, p < 0.001) and muscle fibre cross-sectional area (404.0 ± 5.15 μm2 vs. 172.0 ± 5.39 μm2, p < 0.001), along with decreased muscle atrophy and senescence markers. In vitro, exosomes derived from 8% CSE-exposed MLE12 cells (Exo-CSE) impaired myogenic differentiation, decreased myotube diameter (10.50 ± 0.74 μm vs. 29.27 ± 0.48 μm, p < 0.001) and increased the number of senescent cells (206.7 ± 5.13 vs. 9.33 ± 1.53, p < 0.001). Exo-CSE significantly reduced HDAC2 expression in C2C12 cells (0.18 ± 0.03 vs. 0.53 ± 0.04, p < 0.001), whereas HDAC2 overexpression or ITSA1 treatment rescued impaired myogenic differentiation and cellular senescence caused by Exo-CSE. Proteomic analysis identified proline/arginine-rich end leucine-rich protein (PRELP) as a key exosomal cargo, and exosomes derived from PRELP-silenced CSE-exposed MLE12 cells markedly restored HDAC2 expression in recipient C2C12 cells (0.42 ± 0.02 vs. 0.18 ± 0.03, p < 0.001). Mechanistically, PRELP disrupted the stabilizing interaction between heat shock protein family A member 5 (HSPA5) and HDAC2, accelerating HDAC2 degradation, likely through the ubiquitin-proteasome pathway. In vivo, the combination of PRELP knockdown and the HDAC activator ITSA1 synergistically alleviated CS-induced muscle atrophy and senescence. In COPD, CS-exposed alveolar epithelial cells release PRELP-enriched exosomes that promote SMD by disrupting HSPA5-mediated HDAC2 stabilization and accelerating HDAC2 degradation. Targeting the PRELP-HDAC2 axis may represent a potential therapeutic strategy for COPD-related SMD.

ID: 42511674
Title: Biomarkers and Early Mechanisms of Sarcopenia: Central Roles of Mitochondrial Dysfunction, Inflammaging, Cellular Senescence, and Neuromuscular Degeneration.
Abstract: Sarcopenia is a progressive age-related skeletal muscle disorder characterized by the loss of muscle mass, strength, and physical performance, leading to frailty, disability, and increased mortality. Although its clinical consequences are well recognized, the underlying biological mechanisms remain incompletely understood, limiting the development of early diagnostic strategies and targeted therapies. Increasing evidence indicates that sarcopenia results from complex interactions among mitochondrial dysfunction, chronic low-grade inflammation (inflammaging), cellular senescence, neuromuscular junction degeneration, and anabolic resistance. The present review critically summarizes the current evidence on the principal circulating and molecular biomarkers associated with these interconnected mechanisms. Mitochondrial dysfunction appears to represent an early upstream event that promotes excessive reactive oxygen species production, defective mitophagy, inflammatory activation, and cellular senescence. Chronic inflammation, mediated primarily through IL-6 and TNF-α, further accelerates muscle catabolism and regenerative failure, whereas senescence-associated pathways impair satellite cell function and muscle repair. Neuromuscular degeneration and anabolic resistance further contribute to progressive muscle atrophy and functional decline. Among the candidate biomarkers, GDF-15, FGF-21, IL-6, TNF-α, CAF22, p16INK4a, p21/CDKN1A, IGF-1, and myostatin appear particularly promising for characterizing the biological heterogeneity of sarcopenia. However, no single biomarker currently demonstrates sufficient diagnostic accuracy for routine clinical use. Instead, integrated multi-biomarker approaches combining mitochondrial, inflammatory, senescence-associated, neuromuscular, and anabolic markers may improve early diagnosis, risk stratification, and personalized therapeutic strategies. Future prospective longitudinal studies are required to validate these biomarkers and facilitate their translation into clinical practice.

ID: 42516952
Title: Exercise rejuvenates the "muscle-heart" crosstalk: skeletal muscle-derived exosomal miRNAs in cardiac aging.
Abstract: The deleterious intersection of sarcopenia and age-related heart failure represents a profound global health challenge. While skeletal muscle is increasingly recognized as a major endocrine hub, cannot fully account for the persistent epigenetic changes in the aged myocardium. This points to a key mechanistic gap in the "muscle-heart" inter-organ crosstalk. Following PRISMA guidelines, this systematic review (incorporating 51 rigorous in vivo and clinical studies) maps the bimodal skeletal muscle-derived extracellular vesicle (SkM-EV) and microRNA (miRNA) axis in cardiac aging. We delineate a pathological baseline where aging and sarcopenia trigger the release of senescence-associated extracellular vesicles (EVs). These toxic vesicular payloads actively propagate myocardial inflammaging, structural remodeling, and apoptosis. Conversely, regular exercise rejuvenates by this network via an epigenetic mechanism. Mechanical loading stimulates the systemic release of "exerkines"-exercise-conditioned EVs enriched with potent cardioprotective myomiRs (e.g., miR-1, miR-133a, miR-342-5p). By systematically categorizing these findings from single-molecule downstream targets (anti-apoptosis, anti-fibrosis) to macroscopic poly-pathway synergy (antioxidant and metabolic reprogramming), we construct a comprehensive molecular roadmap of EV-mediated myocardial rejuvenation. Ultimately, deciphering this vesicular signaling network will elucidate the fundamental epigenetic mechanisms underlying "exercise as medicine," and paves the way for novel translational horizons. We propose that targeting the bimodal SkM-EV axis will accelerate the development of EV-based liquid biopsies for sarcopenic cardiomyopathy and pioneer cell-free "exercise mimetics" for frail, exercise-intolerant aging populations.

ID: 42523681
Title: Hysterectomy accelerates sarcopenia risk in US women and mouse models.
Abstract: Sarcopenia represents a clinical condition with particular prevalence among postmenopausal women. Hysterectomy is a common gynecological surgical procedure associated with various complications. However, the relationship between hysterectomy and sarcopenia remains poorly investigated. This study aimed to explore the association between hysterectomy and sarcopenia risk. Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES, 2001-2018) was utilized for analysis. Sarcopenia was defined using the Foundation for the National Institutes of Health (FNIH) criteria based on ALM/BMI < 0.512 in women. Multivariable logistic regression and propensity score matching were applied to assess the association between hysterectomy and sarcopenia. In parallel, a senescence-accelerated mouse model (SAMP8) was used to examine the effects of hysterectomy on muscle function and related molecular pathways, including markers of protein degradation and ferroptosis. In the NHANES cohort, hysterectomy was associated with an increased risk of sarcopenia after adjustment for covariates (OR = 1.35; 95% CI: 1.00-1.82; p = 0.049). The association was stronger in women who had undergone both hysterectomy and oophorectomy (OR = 2.06; 95% CI: 1.45-2.93; p < 0.001). In SAMP8 mice, hysterectomy was associated with reduced grip strength, shorter endurance time, and decreased muscle fiber size. Molecular analyses suggested activation of the FOXO1-MuRF-1/Atrogin-1 pathway and changes consistent with ferroptosis-related signaling. Hysterectomy appears to be associated with an increased risk of sarcopenia in women, and this association is supported by findings from an experimental mouse model. These results suggest potential involvement of muscle protein degradation and ferroptosis-related pathways, although further studies are needed to clarify causality.

ID: 42542973
Title: Activation of the Lactate Receptor GPR81 Ameliorates Senescence Hallmarks and Improves Muscle Function in Cellular and Progeroid Models of Aging.
Abstract: Skeletal muscle aging is associated with increased lipid accumulation, or myosteatosis, leading to lipotoxicity and loss of muscle function. Here, we report that loss of the lactate receptor GPR81 in cellular and progeroid models of muscle aging is associated with impaired lipid oxidation and enhanced lipid accumulation. Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), impaired mitochondrial activity, and autophagy. Conversely, treatment of senescent myoblasts with GPR81 agonists enhanced lipid oxidation, leading to a decrease in lipid accumulation, ultimately resulting in decreased DNA damage, ROS accumulation, and enhanced ability to form myotubes. In agreement with our in vitro findings, we observed significant improvement in muscle regeneration and overall health of progeric mice that were treated with GPR81 agonists. Our findings suggest that GPR81 plays a key role in skeletal muscle lipid metabolism, and agonists of GPR81 might play a promising role in reversing age-associated lipid accumulation and loss of muscle function.

ID: 42568976
Title: Piroxicam accelerates diabetic foot ulcer healing via ERα-dependent mitochondrial protection and oxidative stress relief.
Abstract: The pathology of diabetic foot ulcer (DFU) is characterized by keratinocyte dysfunction, non-resolving inflammation, and oxidative stress. We aim to investigate the effects and mechanisms of piroxicam on DFU healing through regulating mitochondrial function and suppressing inflammation. DFU was established in male C57BL/6 J mice and ovariectomized female mice. Piroxicam (1% or 0.33%) solution or saline was then applied for 9 days. HaCaT cells were induced with high glucose (HG) and subsequently incubated with piroxicam (0, 1.2, 3.7, 11, 33, 100 nM). Piroxicam significantly promoted DFU healing and inhibited the fibrosis in male diabetic mice at a low dose. Consistently, piroxicam enhanced proliferation and migration, and inhibited inflammation, fibrosis, and cellular senescence in HG-induced HaCaT cells. Mechanistically, piroxicam alleviated HG-induced mitochondrial dysfunction by stabilizing the mitochondrial respiratory chain, increasing biogenesis, and enhancing mitophagy. These effects further attenuated oxidative stress and inhibited the cGAS-STING-NF-κB inflammatory pathway, thereby reducing the release of pro-inflammatory factors. Furthermore, molecular docking revealed that piroxicam bound to ERα, a finding further confirmed by a cellular thermal shift assay. HG induced a significant decrease in nuclear ERα protein levels, which was reversed by piroxicam, especially at 11 and 33 nM. Additionally, piroxicam's pro-healing and anti-inflammation effects were attenuated in ovariectomized female DFU mice. Piroxicam's protection of mitochondrial function and suppression of oxidative stress was also abolished upon blocking ERα by tamoxifen. In conclusion, piroxicam alleviates mitochondrial dysfunction and suppresses inflammatory responses by binding to ERα, which ultimately promotes DFU healing at low doses.

ID: 42572354
Title: Simulated Microgravity Induced Mesenchymal Stem Cell Senescence via the Activation of Cytosolic mtDNA-cGAS-STING Axis.
Abstract: Microgravity brings various pathological changes to astronauts, which may be related to the senescence of adult stem cells. However, how microgravity affects the senescence of stem cells remains barely known. In this study, it was found that microgravity simulated by Rotating Flat Chamber induced MSC senescence and promoted the expression of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), and C176, a STING inhibitor, alleviated the rotating culture-induced MSC senescence. Rotating culture also promoted the cytosolic leakage of mitochondrial DNA (mtDNA), while the depletion of mtDNA inhibited cGAS-STING activation and reversed MSC senescence. Knockdown of either BAK or BAX, proteins forming pores on the mitochondrial outer membrane, suppressed mtDNA leakage, cGAS-STING activation, and MSC senescence, suggesting that BAK/BAX mediates the activation of mtDNA-cGAS-STING axis and the associated MSC senescence. Recovering mitochondrial function by Mito TEMPO inhibited the activation of mtDNA-cGAS-STING axis and reversed MSC senescence. In vivo, using rat hindlimb unloading (HU) model to simulate microgravity, it was found that inhibition of STING ameliorated MSC senescence induced by HU. Together, our study demonstrated that simulated microgravity induces MSC senescence by the activation of cytosolic mtDNA-cGAS-STING axis and indicated cGAS-STING pathway as a therapeutic target of MSC senescence under microgravity.

ID: 42579361
Title: KDM4C inhibition reinforces NK cell cytotoxicity through the cGAS-STING pathway in TP53-mutated AML.
Abstract: TP53-mutated acute myeloid leukemia (AML) is associated with an extremely poor prognosis and is refractory to conventional chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). We identified high expression of lysine demethylase 4C (KDM4C) in AML, particularly in TP53-mutated AML. Pharmacological inhibition of KDM4C with QC6352 predominantly induced apoptosis in TP53-wild-type AML cells, whereas it caused limited apoptosis but pronounced senescence and growth arrest in TP53-mutated AML cells. In TP53-mutated AML cells, QC6352 induced senescence-associated cytosolic DNA accumulation and activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, leading to the upregulation of NK cell-activating ligands and enhancing NK cell-mediated cytotoxicity. In vivo, QC6352 effectively attenuated AML progression, and its combination with NK cell therapy further reduced leukemic burden and prolonged survival in mice. Collectively, these findings demonstrate that pharmacological KDM4C inhibition with QC6352 induces cellular senescence and enhances the intrinsic immunogenicity of TP53-mutated AML cells through activation of the cGAS-STING pathway. The study supports KDM4C inhibition as a potential therapeutic strategy for TP53-mutated AML, particularly in patients receiving NK cell-based immunotherapy or undergoing allo-HSCT.

ID: 42585804
Title: Edaravone dexborneol alleviates neuronal senescence injury by mitigating the innate immune response.
Abstract: Aging is a key risk factor for neurodegenerative diseases, contributing to progressive neuronal damage and closely linked to the onset and progression of conditions like Alzheimer's and Parkinson's diseases. However, the effect of edaravone dexborneol (EDB) on neuronal senescence remains unclear, which is an urgent scientific question to be addressed. In this study, we established models of neuronal senescence induced by oxidative stress and OGD/R. EDB treatment partially restored the proliferation inhibition of senescent cells. EDB treatment significantly decreased senescence markers, as indicated by reduced senescence-associated β-galactosidase staining and lower p16 and p21 protein expression. Subsequent research demonstrated that EDB improved mitochondrial membrane potential and replenished intracellular ATP levels. In the OGD/R-induced neuronal injury model, EDB treatment notably decreased the expression of senescence markers (p16/p21/p53). Mechanistic studies revealed that EDB not only alleviated oxidative stress but also inhibited the cGAS-STING-mediated innate immune signaling pathway. This study is the first to demonstrate that EDB mitigates mitochondrial damage to exert anti-neuronal senescence effects, offering a novel intervention strategy for aging-related neurodegenerative diseases.

ID: 42586256
Title: Formononetin mitigates age-related sarcopenia by blocking mitochondrial ferroptosis via SIRT1/PGC-1α signaling.
Abstract: Age-related muscle atrophy is closely associated with mitochondrial dysfunction and ferroptosis. This study established a D-gal-induced sarcopenia model in aged mice and a C2C12/GM17940 cell myotube senescence model, with young/control, old/D-gal, and formononetin (FMN) intervention groups. After shSIRT1 transfection and mitochondrial-targeted antioxidant Mito-C intervention, the effects and mechanism of FMN were detected by measuring mouse phenotypic indicators (lean mass, hindlimb muscle mass, grip strength) and cell indicators (viability, mitochondrial membrane potential, ROS, ATP, ferroptosis-related proteins). Results showed that FMN improved lean mass, grip strength, mitochondrial membrane potential, and ATP production, while reducing ROS and ferroptosis by regulating ACSL4, GPX4, and SLC7A11. Mechanistically, FMN exerted protective effects via the SIRT1/PGC-1α pathway, which was partially attenuated by SIRT1 knockdown or Mito-C. Collectively, FMN alleviates age-related sarcopenia by targeting mitochondrial function and ferroptosis, providing potential targets for sarcopenia treatment.

ID: 42587787
Title: HUSH, NEXT PROMPT: Epigenetics and the Nuclear RNA Exosome in Human Aging and Disease.
Abstract: The nuclear RNA exosome, a conserved 3'→5' ribonuclease complex, degrades the vast majority of RNA polymerase II output, including promoter upstream transcripts, enhancer RNAs, antisense transcripts, and retrotransposon-derived RNAs. Beyond this housekeeping role, the exosome acts as an epigenetic effector, and its dysfunction underlies a growing spectrum of human disease. Here we integrate recent structural, genomic, and disease-focused studies into a unified model of the exosome as a guardian of the epigenome. We describe how MTR4-containing adaptor complexes TRAMP, NEXT, and PAXT confer substrate selectivity, and how the exosome enforces heterochromatic silencing in concert with HP1 proteins and the Human Silencing Hub (HUSH) complex and preserves three-dimensional genome architecture at insulators and enhancers, such as the protocadherin locus where RNA surveillance, CTCF insulation, and heterochromatin converge. We then examine the consequences of failure: exosomopathies such as pontocerebellar hypoplasia, loss of DIS3- and PAXT-mediated tumor suppression in cancer, and age-related erosion of surveillance that permits transposable element de-repression, RIG-1/MDA5 and cGAS-STING-driven inflammation, cellular senescence, and neurodegeneration. We conclude that the exosome couples RNA decay to epigenetic state across the lifespan, positioning RNA surveillance as an emerging therapeutic target.

ID: 42588050
Title: Tuber borchii Extracts Buffer Galactose-Induced Skeletal Muscle Sarcopenia in C2C12 Myotubes.
Abstract: Background/Objectives: Sarcopenia involves a gradual decline in skeletal muscle mass that may occur during aging or in association with chronic pathological conditions. It markedly reduces muscle strength and mobility, thereby impairing quality of life. Because sarcopenia's severity directly correlates with frailty, it represents an important predictor of prognosis and disease risk. Current preventive and therapeutic strategies rely mainly on physical activity, which is not feasible for all patients. This study investigated the biological effects of two independently prepared Tuber borchii (T. borchii) extracts in an in vitro model of sarcopenic stress. Methods: The activity of T. borchii extracts was investigated in a cell-based model of sarcopenia, following previous observations that these preparations influence proliferation-related pathways, including ERK1/2 phosphorylation. Specifically, differentiated myotubes were exposed to D-galactose to reproduce atrophy-associated cellular changes, and the impact of T. borchii extracts on protein synthesis, turnover, and cell morphology was assessed. Results: T. borchii extracts enhanced protein synthesis and turnover in myotubes. Furthermore, the treatment significantly reduced the expression of key galactose-induced sarcopenia and atrophy markers, such as MuRF1. Morphological analysis confirmed this protective effect, showing that treated myotubes maintained greater thickness and exhibited a larger cross-sectional area despite exposure to the sarcopenic stimulus. Conclusions: These results indicate that T. borchii extracts can attenuate selected cellular alterations associated with muscle aging. Future identification of the most active components may support their development as nutraceutical supplements.

ID: 42594754
Title: 6-Shogaol attenuates liver fibrosis by driving hepatic stellate cell senescence through the cGAS-STING-NF-κB axis.
Abstract: Liver fibrosis represents a frequent pathological outcome of chronic hepatic insults. As a bioactive constituent of ginger, 6-shogaol has shown hepatoprotective potential. Hepatic stellate cell (HSC) activation is widely regarded as an important driver in the occurrence and advancement of liver fibrosis. However, whether 6-shogaol can regulate HSC activation remains to be dissected. To assess the anti-fibrotic effects of 6-shogaol and elucidate the molecular mechanisms, we focused on its impact on the fate of HSCs and the subsequent alleviation of liver fibrosis. A CCl₄-induced mouse model and LX-2 cells were employed to evaluate the antifibrotic efficacy of 6-shogaol and explore the underlying mechanisms. Unbiased combined transcriptomic and proteomic profiling was performed to identify candidate mechanisms, which were further validated in LX-2 cells, mouse HSC-enriched fractions derived from fibrotic livers, and through in vivo pharmacological and genetic loss-of-function approaches. Treatment with 6-shogaol alleviated hepatic injury, inflammation, and fibrogenesis in mice, while suppressing HSC activation. Mechanistically, integrated transcriptomic and proteomic analyses identified cGAS-STING-NF-κB axis-mediated senescence as a key mechanism underlying the anti-activation effect of 6-shogaol on HSC. Pharmacological blockade of individual nodes within this signaling cascade significantly reversed 6-shogaol-induced senescence and blunted its anti-activation effect in LX-2 cells. Consistently, short-term administration of 6-shogaol in fibrotic mice, followed by isolation of HSC-enriched fractions, further confirmed that 6-shogaol promotes senescence and engages the cGAS-STING-NF-κB axis in vivo. Finally, in vivo pharmacological blockade and STING knockdown markedly blunted the antifibrotic efficacy of 6-shogaol. Treatment with 6-shogaol attenuates liver fibrosis by driving HSC senescence through the cGAS-STING-NF-κB axis. These findings further expand the molecular understanding of the antifibrotic mechanisms of 6-shogaol and provide more mechanistic rationale for its therapeutic application.

ID: 42605704
Title: TRF2 Recovers Ischemic Postconditioning Cardioprotection in Aged Myocardiocytes by Regulating CSNK2A2 Localization and FUNDC1 Dephosphorylation.
Abstract: Ischemic postconditioning (I/Post), which is an effective intervention by activating endogenous cardioprotective pathways, recovers ischemia/reperfusion injury. However, this intervention is not as effective in older patients, and its mechanism needs to be further investigated. In this study, we found that myocardial telomeric repeat binding factor 2 (TRF2) protein expression in male aged mice (18 months of age) was lower than that in male adult mice (4 months of age). After ligation of the anterior descending branch of the heart to establish an in vivo model of ischemia/reperfusion injury, we found that TRF2 expression was further decreased after I/Post. To investigate the role of TRF2 in cardioprotection in I/Post in the senescent heart, we performed echocardiography, blood biochemical testing, and apoptosis-related detection after injecting adeno-associated virus type 9 overexpressing TRF2 into aged mice. We found that TRF2 improved myocardial I/Post protection in vivo. Knockdown of TRF2 in a cardiomyocyte cell line (HL-1) increased inflammatory factor release and aggravated mitochondrial and DNA damage in senescent myocardiocytes following hypoxic postconditioning (H/Post). TRF2 also inhibited activation of the cGAS/STING pathway by increasing mitophagy during H/Post in aged myocardiocytes. Moreover, TRF2 interacted with casein kinase 2 alpha 2 polypeptide (CSNK2A2) to regulate the dephosphorylation of FUN14 domain-containing protein 1 (FUNDC1), which contributed to the protective effect of hypoxic postconditioning.

ID: 42606684
Title: Long-chain chlorinated paraffins exposure induces premature ovarian failure by disrupting the balance of mitochondrial fission.
Abstract: Long-chain chlorinated paraffins (LCCPs) accumulate in reproductive organs due to their high persistence and bioaccumulation potential; however, the molecular mechanisms underlying their ovarian toxicity remain unclear. In this study, we used primary mouse granulosa cells, a human SVOG cell line, and an oral exposure model in female mice to systematically evaluate the ovarian damage effects of LCCPs and investigate the underlying signaling pathways. The results showed that concentrations of 0.02-2 µg/mL of LCCPs concentration-dependently reduced granulosa cell survival rates (by 12%-58%, P < 0.05), while significantly upregulating oxidative stress (MDA, ROS), inflammatory cytokines (IL-6, TNF-α), and aging markers (SA-β-gal activity). In vivo exposure led to morphological degeneration of ovarian tissue and a reduction in the number of primordial follicles, accompanied by decreased serum estradiol and elevated follicle-stimulating hormone (FSH) levels; these changes resemble the phenotype of clinical ovarian dysfunction. At the mechanistic level, LCCPs induce excessive mitochondrial fission by blocking the interaction between Drp1 and Parkin, leading to the leakage of mitochondrial DNA into the cytoplasm, which in turn activates the cGAS-STING pathway and ultimately drives granulosa cell senescence. These findings reveal a novel mechanism by which LCCPs mediate ovarian toxicity via the "excessive mitochondrial fragmentation- mtDNA leakage- cGAS- STING- cellular senescence" axis, providing direct experimental evidence for assessing the risks of persistent organic pollutants to female reproductive health.

ID: 42607021
Title: Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.
Abstract: : Background: Mitochondrial dysfunction serves as a fundamental driver of the aging process, precipitating progressive functional decline through complex molecular cascades. Summary: This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming. Crucially, we examine how mitochondria act as signaling hubs for inter-organ crosstalk. Through the secretion of mitokines (e.g., FGF21, GDF15) and the release of damage-associated molecular patterns (DAMPs), dysfunctional mitochondria trigger chronic inflammation via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 inflammasome (NLRP3) pathways, actively driving systemic aging within the skeletal muscle-brain and adipose/liver-cardiovascular axes. Additionally, this paper synthesizes current therapeutic interventions, ranging from lifestyle modifications and nicotinamide adenine dinucleotide (NAD+) precursors to frontier technologies like mitochondrial transplantation and gene editing. Key Messages: While promising in animal models, clinical translation of these interventions is currently hindered by limited long-term safety data and evidence gaps. Therefore, mitochondria-targeted studies incorporating integrated multi-organ phenotyping are urgently required to establish robust strategies for extending human healthspan.

ID: 42607424
Title: RLX-2 ameliorates post-traumatic joint contracture by inhibiting the cGAS-STING signaling pathway.
Abstract: Post-traumatic joint contracture (PTJC) is a debilitating fibrotic disorder whose underlying molecular drivers, particularly the involvement of cellular senescence, remain poorly elucidated. This study aimed to evaluate the therapeutic potential of Relaxin-2 (RLX-2) in attenuating knee joint fibrosis and to explore its regulatory effects on the cGAS-STING signaling axis. In vitro fibrotic phenotypes were recapitulated using TGF-β1-stimulated rat synovial fibroblasts. An in vivo PTJC model was established via surgical trauma combined with internal fixation-induced immobilization in rats. The anti-fibrotic and anti-senescent properties of RLX-2 were characterized by quantifying markers such as Collagen I, α-SMA, p16, and p53. Transcriptomic profiling via RNA-sequencing was employed to identify potential signaling hubs. The mechanistic involvement of the cGAS-STING pathway was further interrogated using the pharmacological inhibitor H-151 in both experimental settings. In vitro, RLX-2 treatment exerted a concentration-dependent inhibitory effect on TGF-β1-induced fibrogenic transition and cellular senescence. In the rat model, intra-articular administration of RLX-2 resulted in a significant reduction in synovial hyperplasia and extracellular matrix deposition. These phenotypic improvements were associated with the downregulation of senescence markers in the synovium. Mechanistically, RNA-seq analysis pointed toward the cGAS-STING pathway as a primary target of RLX-2. RLX-2 administration was associated with decreased phosphorylation of STING and its downstream effector TBK1. Notably, pharmacological blockade of STING by H-151 partially phenocopied the protective effects of RLX-2, suggesting a coordinated regulation of fibrosis and senescence. Our findings demonstrate that RLX-2 attenuates post-traumatic knee joint fibrosis in rats, a process associated with the modulation of the cGAS-STING-senescence axis. These results suggest that targeting the cGAS-STING pathway may represent a viable strategy for managing PTJC, with RLX-2 serving as a promising pharmacological candidate for further clinical investigation.

ID: 42613625
Title: SLC25A12 mitigates mitochondrial dysfunction in myoblast senescence, and alleviates cuproptosis-related changes under copper stress.
Abstract: Sarcopenia is an age-related muscle wasting condition that currently lacks specific diagnostic biomarkers and effective treatments. This study aimed to identify mitochondria-related biomarkers for sarcopenia via integrated multi-omics. Human transcriptomic datasets and machine learning algorithms were integrated to screen core mitochondria-related biomarkers for sarcopenia. In vivo validation was performed utilizing 24-month-old naturally aging mice exhibiting sarcopenia features. In vitro, SLC25A12 was either overexpressed or silenced in C2C12 myoblasts subjected to D-galactose-induced senescence or copper stress. Pathophysiological changes and molecular mechanisms were subsequently evaluated via immunofluorescence, mitochondrial functional assays, and Western blotting. Additionally, single-cell RNA sequencing combined with a Geneformer model was employed in MuSCs for in silico perturbation analysis. Transcriptomic and machine learning analyses identified SLC25A12 as a core mitochondria-related gene, exhibiting consistent downregulation in both human sarcopenia cohorts and 24-month-old aging mice. In vitro, SLC25A12 overexpression in C2C12 myoblasts significantly ameliorated senescence induced by D-galactose and preserved mitochondrial function, highlighted by increased EdU incorporation and restored membrane potential. Furthermore, under copper stress, elevated SLC25A12 levels effectively alleviated cuproptosis-related alterations, including restricting mitochondrial copper overload, suppressing DLAT oligomerization, and partially restoring impaired EdU incorporation. Conversely, SLC25A12 knockdown consistently aggravated these phenotypes in both models. Notably, in silico Geneformer-based perturbation of SLC25A12 in MuSCs predicted its regulatory roles in cellular senescence, mitochondrial function, and copper homeostasis. In vitro experiments further demonstrated that SLC25A12 overexpression partially restored suppressed PI3K/AKT signaling under senescent stress conditions. SLC25A12 expression ameliorates myoblast senescence and mitochondrial dysfunction, while also attenuating cuproptosis-related changes under copper stress. SLC25A12 knockdown exacerbates these phenotypes. Taken together, SLC25A12 represents a potential regulator and therapeutic target for skeletal muscle aging.

ID: 42619765
Title: Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease.
Abstract: Cellular senescence contributes to neurodegeneration in Alzheimer's disease (AD), yet brain-penetrant senotherapeutic strategies remain limited. Here, we identify long interspersed nuclear element 1 (LINE-1) retrotransposons as key regulators of neuronal senescence and the senescence-associated-secretory-phenotype (SASP) in AD. Using transdifferentiated induced neurons (iNs) that preserve donor-specific aging-associated molecular signatures, we show that pharmacological inhibition of LINE-1 with nucleoside reverse transcriptase inhibitors (nRTIs) or antisense oligonucleotides reduces p16 expression, suppresses SASP and interferon-stimulated gene programs, and attenuates paracrine induction of reactive astrogliosis. Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain. Although bulk analysis finds no significant differences in LINE-1 expression between AD and control neurons, long-read single-cell RNA sequencing of iNs identifies a subset of neurons with elevated LINE-1 activity which display transcriptional signatures of neurodegeneration, immune activation, and senescence are enriched in AD relative to controls. RNA velocity analysis indicates that LINE-1 activation precedes the induction of canonical senescence markers, supporting a causal rather than consequential role. Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression. Together, these findings establish a LINE-1/cGAS-STING axis as a driver of neuronal senescence in AD and highlight LINE-1 inhibition as a tractable senomorphic strategy for neurodegenerative disease.

ID: 42621049
Title: The dual role of the cGAS-STING signaling pathway in kidney diseases: from acute injury to chronic fibrosis - molecular mechanisms and precision therapeutic strategies.
Abstract: The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a central sensor of cytosolic DNA, plays a critical role in mediating innate immune responses. In recent years, research on this pathway in the field of kidney diseases has expanded explosively, extending from acute kidney injury (AKI) to various pathological conditions including chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and renal cell carcinoma (RCC). This review systematically summarizes the activation mechanisms and functional diversity of the cGAS-STING pathway in different kidney diseases. In AKI, mitochondrial DNA leakage, metabolic disturbances (lipid accumulation, lactate accumulation), and post-translational modifications (e.g., LDHB K156 lactylation) collectively activate this pathway, driving sterile inflammation. In CKD and renal fibrosis, the pathway promotes metabolic reprogramming, cellular senescence, and extracellular matrix deposition through canonical (TBK1-IRF3/NF-κB) and non-canonical (STING-PERK-eIF2α) signaling axes, as well as epitranscriptional regulation (e.g., METTL3-mediated m6A modification). In DKD and LN, its overactivation mediates podocyte injury and type I interferonopathy, respectively. Of note, in RCC, this pathway primarily exerts anti-tumor immune surveillance, highlighting its highly context-dependent functions. Although preclinical studies have demonstrated the therapeutic potential of various small-molecule inhibitors (e.g., RU.521, H-151) and natural product monomers or herbal formulas, clinical translation still faces four major challenges: the dual nature of pathway function (balancing host defense versus sterile inflammation), insufficient specificity and safety of existing inhibitors, lack of predictive biomarkers for therapeutic efficacy, and drug delivery difficulties arising from renal anatomical heterogeneity. To address these bottlenecks, this review proposes next-generation precision modulation strategies, including the development of tissue/cell-specific targeted delivery systems (e.g., biomimetic nanoscavengers), application of proteolysis-targeting chimera (PROTAC) technology, intervention in upstream metabolic and mitochondrial homeostasis, modulation of post-translational modifications, and combination therapies (e.g., with SGLT2 inhibitors, immune checkpoint inhibitors, or senolytics). Finally, we discuss key future directions in this field: advancing highly selective STING inhibitors/degraders into clinical trials, establishing combinatorial biomarker panels based on urinary mtDNA/cGAMP, and achieving precision medicine stratification based on patient-specific pathway activation subtypes. In conclusion, the cGAS-STING pathway has emerged as a central hub linking kidney injury to inflammation, metabolism, and fibrosis, and its precise modulation holds transformative therapeutic promise for hundreds of millions of patients with kidney diseases worldwide.

ID: 42624351
Title: Aging as cross-hallmark obstruction amplification: A sheaf-theoretic model of repair closure, senescence, inflammation, and regenerative failure.
Abstract: The twelve hallmarks of aging describe heterogeneous molecular, cellular, tissue, and systemic changes but do not by themselves explain how they become an organism-level loss of repair capacity. Aging is represented as a cost-constrained, stochastic loss of autopoietic repair closure. Hallmark processes are organized as coupled local-to-global constraint layers on a finite biological complex: global sections represent compatible repair modes, while a connecting morphism measures when coherent regulatory states generate material-repair incompatibilities. The principal accounting identity states that coupled repair reserve equals material-repair closure plus regulatory-interface closure minus cross-hallmark obstruction rank. The identity follows from standard exact-sequence and rank-nullity arguments; its biological content lies in the construction of the coupled aging object and the interpretation of obstruction rank as cross-hallmark repair incompatibility. A dynamical extension places repair under finite, fallible control, stochastic perturbation, delayed feedforward dependence, and an explicit viability domain, allowing additional surveillance to reduce global repair when coupling costs exceed local gains. A reproducible two-compartment example specifies stalk variables, restriction maps, coboundary matrices, H0, H1, connecting-map rank, and an approximate persistence interval. Published epigenetic-clock, skeletal-muscle regeneration, and senolytic results are literature-anchored mappings rather than empirical validation. The proposed invariants therefore target one structural dimension of aging: loss of achievable, globally compatible repair under finite biological control.

ID: 42624917
Title: Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.
Abstract: Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the senescence-associated secretory phenotype (SASP), including interferon-stimulated genes (ISGs). Here we confirm and extend previous observations that cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of nonproliferating senescent cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver. Further, palbociclib suppresses frailty and improves physical performance of aged mice. These findings demonstrate a role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising target for therapeutic repurposing.

ID: 42625172
Title: IL-35 promotes synovial fibroblast senescence via activation of cGAS-STING-TBK1-IRF3 pathway in rheumatoid arthritis.
Abstract: Interleukin-35 (IL-35) exerts immunosuppressive effects in rheumatoid arthritis (RA), but its direct impact on synovial fibroblasts (SFs) remains unclear. This study aimed to redefine the role of IL-35 in RA by uncovering its therapeutic mechanism through the induction of STING-dependent synovial fibroblast senescence. We first observed dysregulated IL-35 signaling in RA patients. In a collagen-induced arthritis (CIA) mouse model, recombinant IL-35 treatment effectively alleviated disease severity, reducing clinical scores, joint swelling, and pro-inflammatory cytokines. The pivotal discovery emerged from in vitro experiments: IL-35, but not TNF-α, directly promoted cellular senescence in RA synovial fibroblasts (RASFs). Mechanistically, IL-35 signaled through the glycoprotein 130 (GP130) receptor to activate the cGAS-STING-TBK1-IRF3 pathway, leading to upregulated senescence markers (p16, p21, p53). This STING activation was essential, as its inhibition abolished the pro-senescent effect. Crucially, in vivo knockdown of endogenous IL-35 exacerbated arthritis, and this aggravation was rescued by co-treatment with an IRF3 agonist. Our findings establish a novel protective axis in which IL-35 activates the STING pathway to drive RASFs into a senescent state, thereby inhibiting their pathogenic activity and ameliorating RA progression. Our work identifies IL-35 as a unique cytokine that confers protection by driving STING-dependent senescence in RASFs, highlighting this axis as a novel therapeutic target for RA.

ID: 42626086
Title: Integrative transcriptomic and experimental analyses prioritize TPT1 as a PANoptosis-associated candidate molecular marker in sarcopenia.
Abstract: Sarcopenia lacks sensitive molecular markers for early detection, and its relationship with integrated inflammatory cell-death programs remains unclear. PANoptosis integrates apoptotic, pyroptotic, and necroptotic signaling and therefore provides a plausible framework for investigating inflammatory-stress remodeling in aging skeletal muscle. We integrated four bulk-transcriptomic datasets from the Gene Expression Omnibus into a training cohort (66 controls; 37 sarcopenia) and used GSE111016 as an external validation cohort (20 controls; 20 sarcopenia). We intersected differentially expressed genes with a curated PANoptosis-associated gene set and then performed enrichment analysis; least absolute shrinkage and selection operator (LASSO), random forest and extreme gradient boosting (XGBoost) feature selection; nomogram and receiver operating characteristic (ROC) analyses; CIBERSORT immune-cell deconvolution; and single-nucleus RNA sequencing (snRNA-seq) reanalysis. We assessed tumor protein, translationally controlled 1 (TPT1) expression in D-galactose-treated mouse and C2C12 models. Among 608 differentially expressed genes, 47 overlapped with the curated PANoptosis-associated gene set. These genes were enriched in apoptotic signaling; cytokine, nuclear factor kappa B (NF-κB), tumor necrosis factor (TNF), and nucleotide-binding oligomerization domain (NOD)-like receptor pathways; regulated necrosis; extracellular-matrix remodeling; and impaired oxidative phosphorylation. Three machine-learning algorithms converged on neurotrophic receptor tyrosine kinase 1 (NTRK1), TPT1, and TNF receptor-associated protein 1 (TRAP1). TPT1 showed the strongest single-gene discrimination, with areas under the ROC curve of 0.819 (95% confidence interval [CI], 0.737-0.900) in the training cohort and 0.753 (95% CI, 0.598-0.907) in the external cohort. Immune-cell deconvolution linked the candidate genes to estimated mast-cell, plasma-cell, cluster of differentiation 8-positive (CD8+) T-cell, and macrophage proportions. Single-nucleus analysis of 97,154 nuclei from 17 donors showed broad TPT1 expression across myonuclear, satellite-cell, stromal, endothelial, and immune compartments, with lower expression in older muscle. Network and gene set variation analyses associated lower TPT1 expression with inflammatory, oxidative-stress, cell-death, and stress-adaptive pathways. In D-galactose-treated mice and C2C12 myotubes, muscle-wasting or senescence-like changes coincided with lower TPT1 protein abundance. This study prioritizes TPT1 as a candidate molecular marker associated with the bulk-transcriptomic sarcopenia phenotype. The aging-muscle and D-galactose analyses provide biological context but do not establish sarcopenia specificity or causality. Prospective clinical validation and functional perturbation studies are required.

ID: 42628192
Title: Perfluorodecanoic Acid (PFDA) induces ovarian toxicity and premature aging via mitochondrial dysfunction.
Abstract: Perfluorodecanoic acid (PFDA) is a perfluoroalkyl substance characterized by high environmental persistence and bioaccumulation potential, with a propensity to accumulate in the reproductive system. However, its toxicological effects on ovarian function remain poorly understood. This study employed mouse primary ovarian granulosa cells (mGCs) and a human ovarian granulosa cell line (SVOG) as in vitro models, combined with in vivo exposure experiments in female C57 mice. We systematically assessed cell viability, oxidative stress, inflammation, and senescence-associated phenotypes using MTT assays, ROS detection, Sa-β-gal staining, Western blotting, immunofluorescence, H&E staining, and immunohistochemistry. The results demonstrated that PFDA dose‑dependently reduced the viability and proliferation of mouse primary granulosa cells (mGCs) and human SVOG cells, as determined by CCK8 and EdU assays, induced oxidative stress and inflammation, and triggered cellular senescence. Furthermore, PFDA exposure led to ovarian follicular depletion, significantly decreased serum AMH and E2 levels, and increased FSH levels, recapitulating a premature ovarian insufficiency‑like phenotype. Mechanistically, PFDA impaired mitochondrial function, causing ROS accumulation and disrupting mitochondrial dynamics, leading to excessive mitochondrial fission. The release of mitochondrial DNA into the cytoplasm activated the cGAS-STING signaling pathway. The subsequent oxidative stress-inflammatory cascade drove ovarian cellular senescence.This study presents new experimental evidence on PFDA's reproductive toxicity and its impact on ovarian aging, providing a foundation for risk assessment and intervention strategies concerning this environmental pollutant.

ID: 42640588
Title: LMNA R527C pathogenic variant causes an inflammation-driven segmental progeroid syndrome via triggering DNA-sensing pathways.
Abstract: Homozygous pathogenic variants in Ig-like domain of LMNA cause severe segmental progeroid syndromes. Unlike typical HGPS, it remains elusive how these pathogenic variants cause segmental progeroid syndromes. We here reported that affected individuals with LMNAR527C/R527C pathogenic variant developed an atypical segmental progeroid syndrome characterized by autoimmune features. Mesenchymal stem cells (MSCs) derived from these affected individuals exhibited significant inflammation and cellular senescence. In mice, LmnaR527C/R527C pathogenic variant triggered chronic interferon signaling, exacerbated aging-related pathologies, and even induced thymic lymphomas following ionizing radiation. In addition, this pathogenic variant increased susceptibility to inflammation induced by a high-fat diet or LCMV infection. R527C pathogenic variant disrupted the interaction between Lamin A and DNA-binding proteins, causing abnormal protein aggregation and hyperactivation of the cGAS-STING. Importantly, blocking DNA sensing pathways suppressed inflammation, rescued senescence in affected individual-derived MSCs, and alleviated premature aging in LmnaR527C/R527C mice. These findings establish a homozygous LMNA pathogenic variant as a key driver of inflammation-driven segmental progeroid syndrome and highlight DNA sensing pathways as promising therapeutic targets.

ID: 42642438
Title: Mitophagy mitigates mitochondrial DNA-induced activation of cGAS-STING in autoimmune thyroiditis.
Abstract: Autoimmune thyroiditis arises from disrupted homeostasis of thyroid follicular epithelial cells and coordinated immune cell activation within the microenvironment. However, its pathogenesis is not fully understood. Here, we identify a mitochondrial (mt) DNA-cGAS-STING inflammatory axis as a driver of autoimmune thyroiditis in mice. By contrast, ubiquitin-dependent mitophagy mediated by PINK1 and Parkin was found to protect mice from disease. Mechanistically, mitochondrial dysfunction elevates mitochondrial reactive oxygen species levels, activating the ATM-CHK2 DNA damage response pathway, which in turn phosphorylates the autophagy adapter TAX1BP1 at Ser722. This modification promotes the recruitment of mitochondria to autophagosomes, thereby facilitating mitophagy. Impairing the ATM-CHK2-TAX1BP1 mitophagy pathway causes mtDNA leakage into the cytosol and triggers cGAS-STING-dependent inflammation. Notably, pharmacological inhibition of STING with C176 effectively slows autoimmune thyroiditis progression. Together, these findings define an mtDNA-driven pathogenic mechanism in autoimmune thyroiditis and identify STING as a potential therapeutic target.

ID: 42642519
Title: cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
Abstract: Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.

ID: 42646271
Title: Visceral Obesity and Its Complications: The Role of Bioelectrical Impedance Analysis in Longevity Medicine.
Abstract: Background: Visceral obesity is increasingly recognised not as a simple excess of adipose tissue, but as a systemic pathological condition characterised by profound metabolic, endocrine, and immune dysregulation. Visceral adipose tissue (VAT) operates as an autonomous neuro-immune-endocrine organ whose dysfunctional expansion drives insulin resistance, atherogenesis, and accelerated cellular ageing through mechanisms converging on chronic low-grade sterile inflammation, referred to as inflammaging. Objectives: This narrative review integrates evidence across four domains: (1) the multi-system clinical complications of visceral obesity and the methodological controversies surrounding its measurement; (2) the cellular heterogeneity, immunometabolic reprogramming, and molecular mechanisms through which excess VAT accelerates biological ageing, with a focus on genomic instability, mitochondrial dysfunction, the NAD+/sirtuin regulatory axis, cellular senescence, and inter-organ communication; (3) the role of bioelectrical impedance analysis (BIA)-particularly phase angle-as a non-invasive functional biomarker of biological age and longevity, positioned critically against alternative assessment methods; and (4) current knowledge gaps and priorities for future research. Methods: A narrative review of PubMed/MEDLINE, Google Scholar, and the Cochrane Library was conducted using MeSH terms and free-text keywords including visceral obesity, bioelectrical impedance analysis, phase angle, sarcopenia, inflammaging, mitochondrial dysfunction, cellular senescence, epigenetic clocks, NAD+, sirtuin, and longevity, supplemented by citation-tracking of retrieved reviews. English-language articles published up to April 2025 were considered, prioritising systematic reviews, meta-analyses, and prospective cohort studies; formal risk-of-bias tools and quantitative synthesis were not applied, consistent with a narrative review design. Results and Discussion: BIA-derived phase angle constitutes a macroscopic electrobiological correlate of inflammaging: low phase angle values in visceral obese subjects overlap with those of frail elderly individuals, reflecting impaired membrane integrity, loss of active cell mass, and altered ICW/ECW balance. However, this evidence base remains largely cross-sectional and correlative; the directionality and population-specific calibration of BIA-derived indices constitute the principal unresolved methodological questions. Integration with epigenetic clocks, circulating NAD+ levels, and gut microbiome indices offers a framework for dynamic biological age assessment, though prospective interventional validation is still lacking. Sarcopenic obesity, evaluated through EWGSOP2 combined with BIA-derived skeletal muscle mass index and handgrip dynamometry, represents a critical comorbidity demanding integrated therapeutic targeting. Conclusions: BIA provides a quantitative, accessible correlate for translating cellular metabolic health into clinically actionable parameters, complementary to rather than a replacement for anthropometric and imaging-based methods. Optimising phase angle and reducing VAT through anti-inflammatory nutrition, exercise, and nutraceutical strategies targeting the NAD+/sirtuin and mTOR/AMPK axes constitutes a measurable objective for the promotion of healthy longevity, contingent on the longitudinal, mechanistic studies identified as priorities in this review.

ID: 42652048
Title: Effects of Kongsheng Zhenzhong Pills on Neuroinflammation and cGAS-STING Pathway Activity in BV-2 Microglia.
Abstract: Background: Global aging has led to a rise in neurodegenerative diseases. Neuroinflammation constitutes a core pathological mechanism in these disorders. The Kongsheng Zhenzhong Pill (KSZZP), a modern preparation derived from a classical Chinese herbal formula, are reputed for their sedative and cognition-enhancing effects. However, the molecular mechanism underlying its modulation of microglia-mediated neuroinflammation remains unclear. The present study was designed to assess the intervention effects of KSZZP on LPS-induced neuroinflammation in BV-2 microglial cells and to preliminarily explore the potential molecular mechanisms involved. Methods: An in vitro neuroinflammation model was established in LPS-induced BV-2 microglial cells. The chemical components of KSZZP were identified using UPLC-Q-Exactive HFX technology. The pharmacological effects of KSZZP were evaluated by assessing cell activation, inflammatory response, oxidative stress, and apoptosis. Molecular docking and Western blotting were used to explore the specific mechanism of its action on the cGAS-STING pathway. Results: Chemical analysis identified 67 components in KSZZP, primarily flavonoids, prenyl lipids, and isoflavones. KSZZP treatment dose-dependently inhibited LPS-induced BV-2 microglial activation and significantly reduced pro-inflammatory factor release. Furthermore, it alleviated oxidative stress, mitigated mitochondrial ultrastructural damage, and inhibited apoptosis induced by LPS. Molecular docking revealed that key active components of KSZZP exhibit strong binding potential to cGAS and STING proteins. Western blotting further confirmed that KSZZP dose-dependently suppressed the expression of key cGAS-STING pathway proteins (cGAS, STING) and downstream proteins associated with M1 polarization (iNOS, TNF-α, COX-2). Conclusions: This study indicates that KSZZP alleviates LPS-induced microglial activation, neuroinflammation, oxidative stress, mitochondrial damage, and apoptosis, and these effects may involve the modulation of the cGAS-STING signaling pathway. Collectively, these findings provide a preliminary experimental basis for understanding the anti-neuroinflammatory mechanism of KSZZP and support its potential application in the prevention and treatment of neurodegenerative diseases.

ID: 42653188
Title: Plant-Derived Senotherapeutics in Cellular Senescence: A Scoping Review of Preclinical Evidence, Mechanistic Pathways, and Metabolomic-Guided Discovery.
Abstract: Senotherapeutic agents targeting senescent cell (SnC) accumulation represent a promising frontier in aging research. These agents encompass senolytics that selectively eliminate accumulated SnCs and senomorphics that suppress the pathological persistence of the senescence-associated secretory phenotype (SASP). Concerns regarding off-target effects of synthetic senolytics have intensified interest in plant-derived alternatives that offer multitargeted mechanisms and favorable safety profiles. This scoping review was conducted following Joanna Briggs Institute guidelines and PRISMA-ScR, mapped preclinical evidence on plant-derived senotherapeutics published between 2015 and 2025 across PubMed, Scopus, Web of Science, Wiley Library and Google Scholar. Of 1355 identified articles, 111 studies met inclusion criteria. Most characterized compound classes included flavonoids, non-flavonoid polyphenols and stilbenes, terpenoids and alkaloids, and combination and complex plant extracts. Mechanistically, BCL-2/BCL-XL apoptosis, PI3K/AKT/mTOR and p53/p21/p16INK4a modulation emerged as senolytic mechanisms, while NF-κB-mediated SASP suppression predominated among senomorphic agents. Ginkgetin-mediated cyclic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) inhibition was identified as a mechanistically novel target within natural senotherapy. Metabolomics demonstrated dual utility in guiding compound discovery from complex plant matrices (e.g., phenolamides from Allium hookeri) and mechanistic validation by characterizing senescence-associated metabolic remodeling, including retinoic acid metabolism restoration, lipotoxic metabolites attenuation, tricarboxylic acid (TCA) cycle, and choline-betaine-TCA cascade regulation. However, challenges in pharmacokinetic optimization, methodological heterogeneity in senescence induction and biomarker panels persist. Plant-derived senotherapy characterized through metabolomics-guided pipelines provides a compelling foundation for their progression toward clinical validation and functional food applications as accessible interventions for healthy aging and age-related disease management.

ID: 42653402
Title: Glycyrrhizin Ameliorates Learning and Memory Impairment via Inhibition of Neuroinflammation in an Alzheimer's Disease Mouse Model SAMP8.
Abstract: Neuroinflammation plays a central role in Alzheimer's disease (AD). Glycyrrhizin (GL), a major component of licorice, exhibits anti-inflammatory effects, but its effects on AD pathology remain unclear. To investigate the effects of GL (18β-glycyrrhizin, 18β-GL) and its stereoisomer (18α-glycyrrhizin, 18α-GL) on cognitive function, neuroinflammation, and AD pathology in senescence-accelerated mouse prone 8 (SAMP8; P8) mice, 40-week-old P8 male mice, an AD model due to aging, and the control (senescence-accelerated mouse resistant 1, SAMR1; R1) mice were treated with 18β-GL, 18α-GL and physiological saline (control) for 12 weeks (n = 6 in each group). Cognitive function was evaluated using a step-through passive avoidance test. Plasma levels of α-Klotho, IGF-1, 2',3'-cyclic GMP-AMP (2',3'-cGAMP), HMGB1, IL-6, and TNF-α were measured by ELISA. Hippocampal microglial activation (Iba1), amyloid-β (Aβ) deposition, and phosphorylated tau (p-Tau) were assessed by immunohistochemistry. Aged P8 mice showed impaired memory, decreased α-Klotho and IGF-1 levels, and increased inflammatory markers compared with R1 mice. GL significantly improved memory performance, reduced inflammatory markers, and suppressed Iba1 activation, as well as Aβ and p-Tau accumulation. These effects were associated with inhibition of the cGAS-STING pathway, as indicated by reduced 2',3'-cGAMP and HMGB1 levels. GL ameliorates AD pathology by inhibiting neuroinflammation, suggesting its therapeutic potential for AD.