FOXO4-DRI

Cerebral small vessel disease burden relates to cognitive decline via impaired amyloid clearance in the general population.

Chi-Heng Zhou, Fei Han, Feng Gao +10 more

Our aim is to examine the interplay between cerebral small vessel disease (CSVD) pathology, Alzheimer's disease (AD) related amyloid-β (Aβ) clearance, and cognition in general population. Cross-sectional structural equation modeling (SEM) was conducted to evaluate CSVD burden, cognition, and plasma Aβ42/40 ratios in 1026 participants without dementia from a prospective community-based cohort. CSVD burden was quantified using five established MRI markers, while cognition was assessed with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), verbal fluency test, and reverse digit span. Models were adjusted for age, sex, education, body mass index, vascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, and smoking), antihypertensive medication use, and APOE4 carrier status. Greater CSVD burden was significantly associated with poorer cognition (B = -2.607 ± 1.016, β = -0.167, p = 0.010), with white matter hyperintensity volume (∆R2 = 0.3%, p = 0.016) and brain parenchymal fraction (∆R2 = 0.4%, p = 0.019) contributing most strongly. CSVD burden was also negatively correlated with plasma Aβ42/40 ratios (B = -0.280 ± 0.074, β = -0.140, p < 0.001), which partially mediated the CSVD-cognition association (B = -0.241 ± 0.087, β = -0.015, p = 0.006). These findings underscore potential CSVD involvement in AD-related pathology across aging.

The GPCR Connection: Linking Alzheimer's Disease and Glioblastoma.

Ana B Caniceiro, Sofia P Agostinho, Luiz F Piochi +2 more

Alzheimer's disease (AD) and glioblastoma multiforme (GBM) are biologically distinct age-related brain disorders with opposing clinical phenotypes. AD is characterised by progressive neurodegeneration and cognitive decline, whereas GBM is characterised by aggressive cellular proliferation and a poor prognosis. Despite these differences, converging evidence indicates that both conditions share molecular pathways and network-level dysfunction that emerge during brain ageing. Central to this convergence are G protein-coupled receptors (GPCRs), which act as integrative signalling hubs that regulate inflammation, metabolism, calcium (CA2+) homeostasis, and cell survival. In AD, GPCR signalling modulates amyloid-β production and clearance, Tau phosphorylation, intracellular CA2+ dynamics, and glial-driven neuroinflammation. In contrast, the same receptor families promote tumour growth, angiogenesis, immune evasion, and therapeutic resistance in patients with GBM. Core intracellular cascades, such as PI3K-AKT-mTOR and MAPK-ERK, are dysregulated in both diseases and function as shared signalling backbones, with outcomes dictated by cellular context rather than receptor identity. CXCR4, LPA₁, and FPR1 exemplify this duality, driving either oncogenic proliferation or neuronal dysfunction, depending on the biological environment. Recent advances in integrative multiomics, computational modelling, artificial intelligence, and organoid systems have revealed GPCR-centred regulatory nodes and accelerated the identification of druggable targets. Collectively, these findings suggest that AD and GBM, although pathologically antithetical, share a molecular fingerprint shaped by ageing-associated inflammation, metabolic disruption, cellular senescence and dysregulated GPCR networks. Deciphering this context-dependent duality may enable precision therapeutic strategies to either restore neuronal integrity in AD or suppress malignant programmes in GBM while fostering cross-fertilisation between neurodegeneration and neuro-oncology research.

Bridging loneliness and mobility: an integrated community-based rehabilitation model for older adults.

Hatice Cecen-Celik, Gülnihal Deniz

As populations age, older adults increasingly experience challenges that extend beyond physical changes to include loneliness, reduced social connections, and lower life satisfaction. Although physical rehabilitation and social participation initiatives have been widely examined, they are commonly addressed as separate domains. Consequently, evidence on integrated community-based rehabilitation (CBR) programmes that simultaneously support physical functioning and psychosocial well-being remains limited. This study examined the effects of a structured, multidimensional CBR programme delivered within a university-based lifelong learning initiative for older adults in Türkiye.

Senescence-like cells recruit γδ T cells to drive prolonged hyposmia after SARS-CoV-2 infection in mice.

Shunya Tsuji, Sosuke Nakano, Koyu Ito +19 more

Persistent hyposmia is a hallmark of post COVID-19 conditions, yet the mechanisms sustaining olfactory dysfunction after viral clearance remain poorly understood. Here, using mouse models of SARS-CoV-2 infection, we show that virus-induced senescence-like changes in uninfected olfactory mucosal fibroblasts persist long after viral clearance and drive prolonged olfactory dysfunction. These senescence-like cells secrete SASP factors, including IFNγ, CXCL9, and CXCL11, thereby recruiting γδ T cells to the olfactory mucosa. The accumulated γδ T cells produce excessive IL-17A, which acts on IL-17 receptor A expressed on olfactory sensory neurons, leading to sustained impairment of their function. Genetic ablation of senescence pathways (p16/p21 double knockout), pharmacological elimination of senescent cells with the senolytic drug ABT263, or olfactory neuron-specific deletion of IL-17 receptor A each significantly alleviate prolonged olfactory dysfunction. These findings identify a senescence-γδ T cell-IL-17A axis as a key driver of prolonged hyposmia following SARS-CoV-2 infection in mice.

Elimination of senescent cells fails to attenuate disease progression in an ALS mouse model.

Lisha Fang, Zhiyong Bai, Dong Yang +3 more

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving progressive motor neuron degeneration, resulting in muscle weakness and paralysis. Current therapeutic options provide only modest benefit, and the etiology of ALS remains incompletely understood. Emerging evidence implicates cellular senescence in the central nervous system (CNS) of ALS pathogenesis, with senescent astrocytes identified in both animal models and patients.

Mitochondrial Quality Control as a Central Pharmacological Target in Aging.

Kuan-Hao Tsui, Shih-Hsuan Cheng, Boyang Wang +7 more

Mitochondrial dysfunction is a convergent hallmark of biological aging and a mechanistically attractive target for gerotherapeutic development. Yet translation of mitochondria-focused interventions has been limited by pathway complexity, tissue heterogeneity, and insufficiently harmonized endpoints. This review synthesizes recent original evidence through a unifying mitochondrial quality control (MQC) framework comprising four interdependent modules: removal (mitophagy and mitochondrial-derived vesicles), repair (mitochondrial proteostasis and UPRmt/ISR signaling), remodeling (fission-fusion control and cristae architecture), and renewal (biogenesis coupled to turnover). We map druggable nodes across these modules and organize therapeutic efforts into five pharmacological classes: autophagy/mitophagy enhancers (including pathway-brake inhibitors and emerging mitophagy-targeting chimeras), NAD+/sirtuin-AMPK-mTOR axis modulators, mitochondria-targeted redox modulators, cristae/mPTP/cardiolipin-directed stabilizers, and mitochondria-targeted delivery platforms. Drawing on recent human studies and late-stage mitochondrial therapeutic programs, we highlight practical lessons on dosing schedules, baseline vulnerability, and the importance of pairing molecular engagement with performance endpoints. We then outline a translational strategy that prioritizes flux-aware readouts and triangulates mechanism with function using in vivo bioenergetics (31P-MRS), blood-based cellular respiration (PBMC/platelet assays and composite indices), and circulating stress/damage signals (cell-free mtDNA species and mitokines). Finally, we discuss key bottlenecks including tissue selective exposure, long term safety for maintenance therapies, and inconsistency in clinical endpoints, and we propose actionable directions such as biomarker guided precision geroscience, intermittent or sequential combination strategies that balance clearance with renewal, and next generation chemical biology approaches to improve target specificity. Collectively, this framework seeks to accelerate the development of pharmacotherapies targeting mitochondrial quality control with clinically interpretable endpoints in aging.

Brimonidine Therapy for Protection From Noise-Induced Hearing Loss.

Jing Cai, Na Zhang, Yongdong Song +8 more

Noise exposure is a known cause of hearing loss, and only a few effective preventive drugs are available. Therefore, in this study, we aimed to investigate the protective effects of brimonidine on noise-induced inner ear hearing impairment in mice and explore its underlying mechanisms and long-term outcomes. Mice were randomly divided into control, noise exposure, and brimonidine groups. A 62-week follow-up was conducted after noise exposure. Brimonidine inhibited the noise-induced increase in inner ear glutamate concentration and downregulated inflammatory factors and immunoglobulins. Brimonidine decreased glutaminase and VGLUT2/3 expression and reduced glutamate synthesis and vesicle transport without affecting its clearance, thereby decreasing glutamate excitotoxicity and protecting synapses and spiral ganglion neurons long term. Mice exposed to noise could temporarily restore their hearing thresholds; however, their auditory function in old age remained significantly worse than those that received brimonidine-mediated cochlear protection in youth. These findings highlight the importance of enhancing noise protection from an early age.

Pathophysiology of chronic subdural hematoma-new insights.

Misa Trieu, Ajith J Thomas

Chronic subdural hematoma (CSDH) is an increasingly common disorder characterized by persistent accumulation of blood products and inflammatory exudate within the dural border cell (DBC) layer. Its pathogenesis represents a self-sustaining cycle of inflammation, pathological angiogenesis, and impaired resolution. Injury of the head, which may be traumatic or nontraumatic, initiates cleavage of the DBC layer, leading to fibroproliferative membrane formation mediated by collagen synthesis and TGF-β1/SMAD signaling. The resulting outer membrane develops fragile neovasculature, driven primarily by vascular endothelial growth factor, facilitating recurrent microhemorrhage and fibrinolysis perpetuating hematoma expansion. Chronic inflammation sustains disease progression through macrophage polarization, cytokine release, and increased vascular permeability, processes amplified by age-related immune dysregulation and hypoxia-induced factor-1alpha signaling. Impaired tissue repair due to metabolic deficits further limits resolution. Concurrent dysfunction of meningeal lymphatic drainage and fibrotic arachnoid granulations compromises clearance of blood degradation products and inflammatory mediators, while matrix remodeling and cerebrospinal fluid ingress contribute to hematoma persistence. This narrative review presents a pathophysiologic framework highlighting CSDH as a dynamic inflammatory-angiogenic disorder. Pharmacological strategies targeting inflammation, angiogenesis, fibrinolysis, hypoxia, and matrix remodeling hold potential as complements or alternatives to established treatments, including surgical drainage and middle meningeal artery embolization. As the burden of CSDH on healthcare systems rises, translational research and controlled clinical trials will be critical to developing mechanism-driven, multimodal management paradigms.

Cellular senescence and metabolic aging in type 2 diabetes: mechanistic insights and translational implications.

Ammaar Riyaz Syed, Radwan Abdulaziz Aloti, Bassam Jehad Awad +4 more

Type 2 diabetes mellitus (T2DM) is traditionally conceptualized as a disorder of insulin resistance and β-cell dysfunction driven by metabolic overload. Increasing evidence now implicates cellular senescence-a stress-induced state of durable cell-cycle arrest accompanied by a pro-inflammatory senescence-associated secretory phenotype (SASP)-as a biologically distinct contributor to metabolic dysfunction. Senolytic therapies, which selectively eliminate senescent cells by targeting senescent cell anti-apoptotic pathways (SCAPs), have therefore emerged as potential disease-modifying interventions.

Ageing and the lymphatic system: Implications for immunity, brain health, and possible therapeutic interventions.

M N Rojas Velazquez, E Gousopoulos, S Wolf +2 more

The lymphatic system is essential for maintaining interstitial fluid balance, supporting immune surveillance, and clearing metabolic waste, yet its role in ageing has only recently come into focus. With age, lymphatic vessels and lymphoid organs undergo structural and functional decline, leading to impaired transport, disrupted immune cell trafficking, and chronic low-grade inflammation. These changes contribute to systemic inflammaging and are increasingly implicated in cardiovascular disease, metabolic dysfunction, and neurodegenerative disorders. In the central nervous system, deterioration of the glymphatic and meningeal lymphatic systems compromises cerebrospinal fluid circulation and the clearance of amyloid-β, tau, and other metabolites, thereby accelerating cognitive decline. In this review, we examine the molecular and cellular mechanisms that underline lymphatic ageing, including junctional remodeling, extracellular matrix stiffening, altered lymphangiogenic signaling, and endothelial senescence. We critically assess the consequences of lymphatic dysfunction for systemic and brain health, highlighting unresolved controversies such as the extent to which lymphatic changes are primary drivers of pathology, the limitations of rodent models and indirect imaging readouts, and the lack of ageing-resolved single-cell maps in human tissues. Finally, we discuss therapeutic avenues ranging from antioxidant and pro-lymphangiogenic strategies to lifestyle interventions and reconstructive microsurgery. Together these insights position the lymphatic system as a central, yet underexplored, determinant of resilience in ageing and a promising target for future gerotherapeutic interventions.

Galectin-9high Neutrophils Exacerbate Radiation-Induced Frailty.

Zhuo Cheng, Le Ma, Yan Chen +11 more

Local radiation injury-induced frailty seriously impacts the quality of life of patients undergoing radiotherapy or nuclear accident casualties and causes a significant medical and economic burden. However, the underlying mechanisms of the frailty remain unknown. In this study, a unique population of hyperactive GAL-9high neutrophils is identified with characteristics of elevated ROS, NETs, and IFN-γ, prolonged lifespan, etc. These neutrophils infiltrate into multiple organs to induce injuries, also disrupt the bone marrow microenvironment, drive sustained bone marrow myeloid-biased differentiation, and resist clearance by bone marrow macrophages, serving as a crucial factor to exacerbate frailty. GAL-9 protein is demonstrated to play a vital role in the regulation of neutrophil hyperactivity. EccDNA shedding after skin radiation injury is shown to activate the JAK1/2-STAT1 pathway in splenic GMP cells, which is a potential origin of GAL-9high neutrophils. In summary, our results highlight the significance of the previously unrecognized hyperactive GAL-9high neutrophils to exacerbate frailty through a 'skin-spleen-bone marrow-multiple organs' axis after local radiation injury.

High-linear energy transfer radiation disrupts natural killer cell surveillance of senescent intestinal cells in the mouse intestine.

Santosh Kumar, Shubhankar Suman, Heng-Hong Li +3 more

High-Linear Energy Transfer (LET) ion radiation, such as 28Si ions, is densely ionizing and poses a significant risk to astronauts during long-duration space missions. We previously showed that mice exposed to high-LET ionizing radiation (IR) exhibit greater accumulation of senescent cells in the intestine than those exposed to equivalent doses of low-LET γ-rays. However, the mechanisms driving this persistent senescence remain unclear. Given the role of Natural killer (NK) cells in senescent cell clearance, we investigated the impact of IR on intestinal NK cell function. At 60 days post-irradiation, intestinal tissues from 28Si-exposed mice showed a significant reduction in NKp46⁺ NK cells and decreased expression of molecules associated with NK activation and epithelial interactions. NK cell subtype analysis further revealed a decline in functionally mature populations involved in recognizing stressed cells. In parallel, intestinal epithelial cells (IECs) displayed altered expression of NK cell regulatory ligands, including reduced activating signals and increased inhibitory signaling associated with Qa-1b (non-classical MHC class Ib). Mechanistically, these changes were linked to activation of p38 Mitogen-Activated Protein Kinase (MAPK) signaling. Using irradiated intestinal organoids, we observed that pharmacological inhibition of the p38 MAPK pathway decreased Qa-1b expression and enhanced NK cell cytotoxic activity. Causality experiments further demonstrated that Qa-1b directly regulates NK cell-mediated cytotoxicity against senescent IECs. Collectively, these findings indicate that high-LET IR compromises intestinal immune surveillance by impairing NK cell function through a p38 MAPK-Qa-1b signaling axis, providing mechanistic insight into radiation-induced immune dysregulation.

Life Cycle and Circadian Rhythms in Central Resident Immunity and Neuropsychiatric Pathology.

Zhixin Lim, Ha Linh Nguyen, Yuanyuan Zeng +12 more

The central resident immune system, commonly known as the glial system, comprises various glial cells that play a critical role in neuropsychiatric disorders. However, a systematic review exploring the relationships between the life cycles and daily rhythms of these immune cells and the pathological features of neuropsychiatric disorders is lacking. These immune cells exhibit unique developmental origins and circadian characteristics, resulting in rhythmic variations in functions such as phagocytosis, immune clearance, neurogenesis, and neurotransmitter recycling. These properties are crucial for understanding the pathological mechanisms underlying developmental disorders like major depressive disorder, autism spectrum disorder, and schizophrenia, as well as age-related conditions such as Alzheimer's and Parkinson's diseases. The daily rhythms of these immune cells correlate with diurnal variations in emotion, cognition, and motor function, involving shared processes like oxidative stress and neuroinflammation. This article systematically reviews the composition, life cycle changes, and circadian characteristics of central immune cells, highlighting their roles in neuropsychiatric diseases.

Redox signaling in chronic airway diseases: pathogenic mechanisms and therapeutic implications.

Mario Cazzola, Paola Rogliani, Luigino Calzetta +3 more

Chronic airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis, impose a significant global health burden. A central unifying feature of these diseases is redox imbalance, which is characterized by an excess of reactive oxygen and nitrogen species (ROS/RNS) that overwhelms the body's antioxidant defenses, causing cellular dysfunction, inflammation, and tissue damage. Physiological ROS/RNS are essential for immune regulation and transcriptional control, but chronic oxidative stress disrupts these processes, driving disease progression. In asthma, eosinophil- and epithelial-derived ROS worsen airway hyperresponsiveness, induce mucus overproduction, and reduce steroid effects. COPD involves neutrophil-dominated inflammation, mitochondrial dysfunction, protease- and oxidant-mediated extracellular matrix degradation, and accelerated senescence. Bronchiectasis features persistent neutrophilic oxidative injury, microbial colonization, impaired mucociliary clearance, and progressive airway destruction. Exogenous oxidants, cigarette smoke, biomass fuels, pollutants, and pathogens further burden antioxidant systems, including superoxide dismutases, catalase, glutathione peroxidase, and Nrf2-regulated pathways. Redox dysregulation also contributes to post-COVID sequelae, promoting ongoing airway inflammation, fibrosis, and systemic complications. Therapeutic strategies targeting redox imbalance, mainly thiol-based antioxidants, Nrf2 activators, NADPH oxidase inhibitors, and mitochondria-targeted antioxidants, show mechanistic promise but face challenges in specificity, bioavailability, and clinical translation. Advancing precision redox medicine requires biomarker-guided patient stratification, high-resolution redox proteomics, single-cell and organoid models, and spatial imaging to identify disease-specific redox endotypes. Modulating pathological oxidative stress while preserving physiological signaling offers a novel avenue to improve outcomes. Understanding redox biology in airway disease highlights the potential of precision antioxidant strategies as adjuncts to conventional therapies, representing a paradigm shift in managing chronic airway disorders.

Exploring Early Antifungal Activity of Rezafungin as a Stepping-Stone for Shorter Treatment Duration for Candidemia: Pooled Analysis of 2 Randomized Trials.

Luis Ostrosky-Zeichner, Jalal A Aram, Mark Redell +5 more

Guidelines recommend ≥2 weeks of antifungal therapy after candidemia clearance and for invasive candidiasis (IC). This post-hoc analysis evaluates Day 7 pooled data from the phase 2 STRIVE and phase 3 ReSTORE trials to explore early antifungal activity.

Astrocytic K+ regulation during neurodegenerative diseases.

Evgeniia Samokhina, Yossi Buskila

Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in specific areas of the central nervous system. Historically, a "neurocentric" paradigm viewed glial cells, such as astrocytes, as cells that provided adequate support for neuronal energy metabolism and controlled local cerebral blood flow. However, studies from the past two decades found that astrocytes are involved in synaptic function through different mechanisms, including the uptake of extracellular glutamate molecules and potassium ions following synaptic neuronal transmission. Also, astrocytes respond to neurotransmitters and neuromodulators through alterations of intracellular ion concentrations (e.g., Na+, Ca2+, K+) and the release of gliotransmitters. Astrocytes play a pivotal role in preserving potassium homeostasis within the central nervous system through their potassium channels, a process known as "potassium clearance." Impaired astrocytic potassium clearance mechanisms can result in neuronal hyperexcitability, leading to increased glutamate release, overactivation of glutamate receptors, and cytotoxicity. Recent studies suggest that these factors can cause cell death and neurodegeneration, and further indicate a region-specific glial dysfunction in neurodegeneration, which reflects the heterogeneity of glial cell function and sensitivity across different brain regions. Overall, this manuscript offers novel insights into a relatively new concept that glial cells can actively shape neuronal activity and survival.

Revitalizing mitochondrial quality control: targeting mitochondria-derived vesicles in Parkinson's disease.

Jimna Mohamed Ameer, Sneha Mary Alexander, K Navya +2 more

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the midbrain substantia nigra, resulting in debilitating motor and non-motor symptoms. No disease modifying therapy is currently available for PD patients. Mounting evidence implicates impaired mitochondrial quality control (MQC) as a central driver of PD pathogenesis. MQC maintains mitochondrial integrity and function through coordinated mechanisms such as mitochondrial biogenesis, dynamics, mitophagy, the ubiquitin-proteasome system, and the formation of mitochondria-derived vesicles (MDVs). MDVs are small vesicular structures that selectively sequester and transport damaged mitochondrial components to lysosomes for degradation, representing a rapid and localized quality control pathway distinct from mitophagy. Beyond their degradative role, MDVs also participate in inter-organelle signalling and intercellular communication, suggesting a broader influence on neuronal homeostasis. Disruption of MDV biogenesis, trafficking, or clearance has been emerging as a key contributor of mitochondrial dysfunction and neurodegeneration in PD. This review synthesizes current understanding of MDV biology, its integration within the MQC network, role in PD pathogenesis and explores how targeting MDV pathways may offer novel diagnostic and therapeutic strategies to modify disease progression in PD.

Chicoric acid enhanced brain cholesterol efflux and reduced Aβ pathology via LXR-ABCA1 signaling in Alzheimer's models.

Daiyue Li, Yu Zhang, Ruonan Wang +6 more

Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways.

Neuroinflammation in stroke-A review of implications for precision immunomodulation.

Tatyana Zharikova, Elizaveta Petrova, Igor Makarov +3 more

Stroke remains a leading cause of mortality and long-term disability worldwide, and secondary injury mechanisms-particularly neuroinflammation-continue to limit functional recovery despite advances in reperfusion therapies. Post-stroke neuroinflammation is not a static or uniformly deleterious process but a temporally evolving and spatially heterogeneous continuum shaped by cellular transcriptional plasticity, metabolic reprogramming, and systemic modifiers such as aging and comorbidities. Across hyperacute, acute, subacute, and chronic phases, microglia, astrocytes, and neurovascular unit components undergo dynamic state transitions that may either exacerbate neuronal injury or promote debris clearance, angiogenesis, synaptic remodeling, and circuit reorganization. Emerging transcriptomic and spatial profiling studies challenge simplified polarization frameworks and highlight the need for multidimensional models of immune activation. We propose a precision-based framework in which neuroinflammation is interpreted through the integration of temporal dynamics, cellular heterogeneity, and responsiveness to rehabilitation. Within this context, the concept of an "immune window" underscores the importance of aligning immunomodulatory interventions with phase-specific inflammatory states to enhance neuroplasticity without suppressing reparative signaling. Although targeted strategies-including cytokine inhibition, metabolic reprogramming, gene-editing approaches, and biomarker-guided stratification-show mechanistic promise, translational progress has been limited by model heterogeneity, blood-brain barrier constraints, safety concerns, and insufficient validation in aged and comorbid populations. Future advances will depend on biomarker-driven patient stratification, phase-informed trial design, and integration of immunomodulation with reperfusion and rehabilitation. Rather than indiscriminate suppression, calibrated and context-aware immunoregulation may represent the most rational path forward in optimizing stroke recovery.

Cellular senescence: Between protection and pathologies.

I Klak, A Ptak-Belowska, G Krzysiek-Maczka

Cellular senescence is a stable and irreversible state of proliferative arrest triggered by diverse stressors, inclh3uding DNA damage, oncogenic signaling, oxidative stress, and metabolic imbalance. Once regarded as a culture artifact, senescence is now recognized as a fundamental biological program that governs tissue homeostasis, development, aging, and disease. Based on its origin, senescence can be divided into two principal categories: damage-induced, encompassing replicative, oncogene-induced, and therapy-induced forms, and developmentally programmed, which orchestrates tissue patterning and remodeling during embryogenesis. These processes converge on the activation of p53/p21 and p16/RB tumor suppressor axes, sustained DNA damage response (DDR), and the establishment of the senescence-associated secretory phenotype (SASP). Acute senescence serves beneficial roles in tumor suppression, wound healing, and embryonic morphogenesis by transiently activating SASP-mediated immune clearance. However, persistent senescence becomes detrimental, promoting chronic inflammation, tissue dysfunction, and cancer progression. Within the tumor microenvironment, chronic SASP signaling driven by nuclear factor kB (NF-κB), CCAAT/enhancer-binding protein beta (C/EBPβ), and Signal Transducer and Activator of Transcription 3 (STAT3) fosters epithelial-to-mesenchymal transition (EMT), invasion, and therapy resistance. Therapy-induced senescence (TIS) often leads to polyploidization and the emergence of polyploid giant cancer cells (PGCCs) that can escape arrest, regenerate proliferative progeny, and drive tumor relapses. Thus, senescence represents a biological paradox: a protective, transient process that maintains tissue integrity but, when unresolved, transforms into a driver of aging and malignancy. Understanding the molecular determinants, distinguishing beneficial from pathological senescence is crucial for developing targeted senotherapies.

The Glymphatic System and Meningeal Lymphatics: Current Understandings and Future Perspectives.

Hangzhe Sun, Haonan Fan, Yuhang Zhou +6 more

The central nervous system (CNS) maintains homeostasis and immune surveillance through a recently defined brain-wide clearance network: the glymphatic-lymphatic axis. This system couples the intramural glymphatic pathway, responsible for convective fluid transport and parenchymal waste removal, with the meningeal lymphatic vessels (MLVs), which serve as the critical efferent route to the peripheral immune system. This review delineates the structural and functional foundations of each component, their regulatory dynamics, including the roles of sleep and aging, and their synergistic interplay in maintaining fluid balance, clearing metabolic waste, and facilitating neuroimmune communication. Mounting evidence identifies the dysfunction of this integrated axis as a common pathological mechanism across a spectrum of neurological disorders. We highlight its pivotal role in three key paradigms: acute injury (stroke), chronic proteinopathy (Alzheimer's disease, AD), and autoimmune dysregulation (multiple sclerosis, MS), where impaired clearance and maladaptive immune responses are central, recurring themes. The review critically evaluates emerging translational strategies aimed at therapeutically modulating this axis, including pharmacological targets (VEGF-C, Piezo1 agonists), noninvasive neuromodulation (photo-biomodulation, PBM), and surgical interventions (lymphaticovenous anastomosis, LVA). This synthesis positions the glymphatic-lymphatic axis as a fundamental physiological network and a pivotal target for novel interventions, outlining key future research directions in neurology.

Acyl-CoA-binding protein (ACBP): a poor-prognosis biomarker in sepsis and a target for disease mitigation.

Flavia Lambertucci, Omar Motiño, Uxía Nogueira-Recalde +25 more

Sepsis remains a major clinical challenge, with high mortality and long-term disability despite current interventions. Here, we identify the tissue hormone acyl-CoA-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), as a biomarker and driver of poor outcome in sepsis. ACBP/DBI was elevated in the plasma of septic patients and associated with organ dysfunction and increased mortality. In murine models of endotoxemia, Escherichia coli infection, and polymicrobial sepsis, genetic deletion or antibody-mediated neutralization of ACBP/DBI conferred robust protection by dampening cytokine storm and preserving organ function. Across these three models, neutralization of ACBP/DBI with monoclonal antibodies restored thermoregulation and reduced mortality. Mechanistically, ACBP/DBI inhibition enhanced resilience to lipopolysaccharide-induced sterile inflammation and improved bacterial clearance by macrophages and granulocytes in vivo and in vitro. These effects were observed in monomicrobial infection models and confirmed by high-dimensional immunophenotyping in a polymicrobial sepsis model. Notably, ACBP/DBI inhibition could be favorably combined with glucocorticoids, enhancing survival and reversing histopathological, transcriptional or metabolic signatures of septic shock across heart, kidney, liver, lung, spleen and plasma. These findings position ACBP/DBI as a mechanistic amplifier of sepsis pathophysiology and propose its neutralization, alone or in combination with corticosteroids, as a promising therapeutic strategy to interrupt the fatal trajectory of septic shock.

Reprogramming aging astrocytes in Alzheimer's disease.

Maria Alfonso-Triguero, Amaia M Arranz

Alzheimer's disease typically unfolds within an aging brain, where astrocytic transcriptional programs are extensively remodeled. A recent study by Choi and colleagues shows that reinstating an aging-dependent Sox9 (SRY-box transcription factor 9)-MEGF10 (multiple EGF-like domains 10) axis restores amyloid clearance and preserves cognition in mouse models. These findings suggest that astrocyte dysfunction reflects destabilized, yet recoverable, homeostatic programs rather than irreversible degeneration.

Impairment of Macrophage Functions by the Senescence-Associated Secretory Phenotype of Vascular Smooth Muscle Cells-Brief Report.

Dimitrios Tsitsipatis, Tatiana Rodriguez Rivera, Mary Kaileh +6 more

This study aimed to determine the effect of senescent vascular smooth muscle cells (VSMCs) on foam cell formation and macrophage phagocytic activity in atherosclerotic conditions.

TFEB degradation is regulated by an IKK/β-TrCP2 phosphorylation-ubiquitination cascade.

Yan Xiong, Jaiprakash Sharma, Meggie N Young +9 more

Transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and cellular clearance pathways. TFEB activity is tightly controlled by multiple post-translational mechanisms, but the exact molecular mechanism controlling its stability has remained elusive. Here, we identify the IκB kinase (IKK) complex as a key regulator of TFEB protein stability through a phosphorylation-ubiquitination cascade. A high-content kinase inhibitor screen reveals that IKK inhibition increases TFEB protein levels, and genetic ablation of IKK components increases TFEB stability, upregulates lysosomal genes, and enhances lysosomal biogenesis and degradative capacity. Mechanistically, we show that IKK phosphorylates TFEB on a cluster of serine residues (423SPFPSLS429), generating a phosphodegron recognized by the E3 ligase β-TrCP2, which in turn targets TFEB for proteasomal degradation via ubiquitination of adjacent lysine residues (K430 and K431). Mutation of either the phosphosites or the ubiquitination sites stabilizes TFEB without impairing its ability to translocate to the nucleus, activate target gene expression, or promote tau clearance in a cell model of tauopathy. These findings establish IKK-β-TrCP2 as a core regulatory axis controlling TFEB protein turnover and levels and reveal a mechanistically distinct layer of TFEB regulation that may be leveraged to enhance lysosomal function in disease contexts.

Deconstructing senescence phenotypes in cells of the bone and bone marrow.

Lorenz C Hofbauer, Martina Rauner

Cellular senescence in osteogenic mesenchymal cells contributes to age-related bone loss. The bone marrow hosts myeloid cells, the precursors of immune cells, as well as mesenchymal cells, which give rise to osteoblasts and osteocytes. The senotype and senolytic response of bone marrow cells, particularly hematopoietic cells, in age-related bone loss is unclear. In this issue, Doolittle et al. showed that of all immune cells, myeloid cells had the strongest senescence profile, yet the relative level of senescence remained lower than that of mesenchymal stromal cells. Mesenchymal cells displayed a profound senotype, rendering them susceptible to senolytic clearance protecting against bone loss. By contrast, selective clearance of p16+ myeloid cells was not long-lasting and, hence, did not fully protect against age-related bone loss. These findings underscore the challenges of developing senolytic strategies for tissues with mixed senotypes, such as bone.

A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.

Farzaneh S Mirfakhar, Jacob A Marsh, Chihiro Sato +8 more

Tau accumulates in a group of neurodegenerative diseases known as tauopathies. A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the autophagy-lysosome pathway, but whether these defects are a cause or consequence of Tau accumulation remains unclear. Here we show that a disease-causing mutation in the MAPT gene, which encodes Tau, p.R406W, is sufficient to disrupt multiple steps of the autophagy-lysosome pathway in human neurons. Using Airyscan super-resolution imaging, we find that mutant Tau neurons accumulate Tau and phosphorylated Tau in dysfunctional lysosomes, exhibit reduced lysosome motility, impaired fusion of autophagosomes and lysosomes, and increased undegraded cellular cargo. Pharmacological enhancement of autophagy improves cargo clearance and lowers Tau levels, without restoring defects in lysosomal motility. Together, these findings demonstrate that mutant Tau directly perturbs cellular clearance pathways and suggest that boosting autophagy may help restore Tau homeostasis in tauopathies.

The Role of TFEB-Regulated Autophagy in Intervertebral Disc Degeneration and Its Therapeutic Potential.

Mengen Xue, Zhengfa Jiang, Zihao Wang +8 more

Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain, driven by nucleus pulposus cell (NPC) senescence, extracellular matrix imbalance, and chronic inflammation. Transcription Factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, has emerged as a pivotal player in degenerative diseases. By modulating autophagy-related genes, TFEB promotes the clearance of damaged components and maintains metabolic homeostasis in NPCs. Its dysfunction impairs autophagic flux, exacerbating cellular apoptosis, oxidative stress, and ECM degradation, thereby accelerating IVDD progression. Critically, this review is the first to systematically synthesize evidence positioning TFEB at the nexus of these pathological processes, establishing it as an integrative therapeutic target. We detail the molecular regulation of TFEB and its dysfunction in IVDD. Furthermore, we evaluate emerging TFEB-targeted strategies and discuss the key translational challenges. This work provides not only a mechanistic synthesis but also a forward-looking perspective on overcoming bottlenecks in TFEB-based therapy for IVDD.

Extracellular Protein Quality Control in Tau Pathology.

Prasun Kumar Bhunia, Deepanshu Verma, Priyanka Vimal +1 more

Aging is the primary risk factor for neurodegenerative diseases that are marked by the accumulation of misfolded and aggregated proteins, commonly known as proteinopathies. Among these, tauopathies are the disorders characterized by abnormal tau protein aggregation that are particularly significant in Alzheimer's Disease. Tau protein undergoes pathological post-translational modifications that promote its aggregation into neurofibrillary tangles, which disrupt neuronal function and cognitive decline. Tau can also spread between neurons via extracellular pathways in a prion-like manner, accelerating disease progression. Extracellular protein quality control (PQC) mechanisms modulate this process by balancing tau stability and clearance. However, age-related decline in these PQC systems enhances toxic tau assemblies, their extracellular accumulation and widespread dissemination. This review explores tau secretion, propagation, and extracellular protein quality control (PQC) in maintaining tau homeostasis, aiming to identify therapeutic strategies for tauopathies.

Intercompartmental communication in senescence.

Krystyna Mazan-Mamczarz, Eleanor J Wind, Jixiang Leng +1 more

Cellular senescence represents a response to sublethal damage, characterized by persistent growth arrest and a robust pro-inflammatory trait, the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in the body with age, promoting tissue dysfunction and age-related disease. In addition to profound reprogramming of gene expression patterns, senescent cells undergo broad remodeling of cellular compartments, including the plasma membrane, nucleus, endoplasmic reticulum (ER), Golgi apparatus, endolysosomal system, mitochondria, biomolecular condensates, and cytoskeleton. These changes alter the intracellular communication networks required for homeostasis. Here, we review how senescence alters (i) vesicular trafficking along secretory, endocytic, and autophagic routes, (ii) interorganelle contact sites such as those among mitochondria, ER, and lysosomes to modulate lipid and calcium exchange, and (iii) diffusion and transport of regulatory signals across the cytosol and membranes. We discuss how the impaired crosstalk among compartments increases ROS, exacerbates proteostatic stress, impairs clearance of damaged components, and activates p53/p21, p16/Rb, cGAS-STING, NF-κB, and mTOR pathways, enhancing apoptosis resistance and the SASP. Finally, we highlight emerging technologies to study the senescent organelle 'interactome' and identify therapeutic vulnerabilities in age-associated declines and diseases linked to senescence. Impact statement We synthesize evidence that cellular senescence arises not only from gene expression changes but also from disrupted interorganelle communication. We discuss defects in vesicle trafficking and organelle contact sites that redefine senescence as failure of the organellar interactome, highlighting future mechanistic work and therapeutic opportunities in age-related disease.

Large-scale bidirectional arrayed genetic screens identify OXR1 and EMC4 as modifiers of αSynuclein aggregation.

Sandesh Neupane, Lea Nikolić, Lorenzo Maraio +9 more

In Parkinson's disease and other synucleinopathies, αSynuclein (αSyn) misfolds and forms Ser129-phosphorylated aggregates (pSyn129) with the factors controlling this process largely unknown. Here, we used arrayed CRISPR-mediated gene activation and ablation to discover new pSyn129 modulators. Using quadruple-guide RNAs (qgRNAs) and Cas9, or an inactive Cas9 fused to a synthetic transactivator, we ablated 2304 and activated 2428 human genes related to mitochondria, trafficking, and motility functions in HEK293 cells. After exposure of cells to αSyn fibrils, pSyn129 signals were recorded by high-throughput fluorescence microscopy and aggregates were identified by image analysis. We found that pSyn129 was increased by activating the mitochondrial protein OXR1, which decreased ATP levels and altered the mitochondrial membrane potential. Instead, pSyn129 was reduced by ablation of the endoplasmic reticulum (ER)-associated protein EMC4, which enhanced ER-driven autophagic flux and lysosomal clearance. OXR1 activation preferentially modulated cellular reactions to fibrils derived from multiple system atrophy (MSA) patients, whereas EMC4 ablation broadly reduced pSyn129 across diverse αSyn polymorphs. These findings were confirmed in human iPSC-derived cortical and dopaminergic neurons, where OXR1 preferentially promoted somatic aggregation and EMC4 reduced both somatic and neuritic aggregates. These results uncover previously unrecognized roles for OXR1 and EMC4 in αSyn aggregation, thereby broadening our mechanistic understanding of synucleinopathies.

Cellular Senescence in Gastric Cancer: Molecular Mechanisms, Microenvironment Remodeling and Therapeutic Implications.

Zhiyuan Shi, Zhao Sun, Yuan Liu +6 more

Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide, with poor prognosis for advanced-stage patients. Therefore, in-depth exploration of the mechanisms underlying GC initiation and progression, as well as the development of novel therapeutic strategies, is of crucial importance. Cellular senescence is a stable cell cycle arrest program that plays a dual role in GC. It exerts tumor-suppressive effects via growth arrest but also promotes tumor progression and immune evasion by remodeling the tumor microenvironment (TME) through senescence-associated secretory phenotype (SASP). This review comprehensively elucidates the molecular mechanisms of cellular senescence in GC and the core regulatory networks involving gene regulation, epigenetic modifications, metabolic reprogramming, and cell cycle arrest. Additionally, the review highlights how senescent cells foster an immunosuppressive microenvironment via SASP, forming a self-reinforcing feed-forward loop. Regarding therapeutic strategies, we summarize potential approaches targeting cellular senescence, including senescence induction, senescent cell clearance, SASP modulation, and multi-target synergistic therapy by integrating epigenetic regulation, metabolic intervention, and immune microenvironment modulation. Despite progress, numerous challenges remain. Future studies should leverage multi-omics technologies, novel models' development, and large-scale clinical trials to advance the clinical translation of GC cellular senescence research, providing new insights for improving prognosis.