FOXO4-DRI

Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.

Ashish Sharma, Emiko Segawa, Xiaoying Chen +12 more

Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.

Lufei Chen, Xiaoling Lin, Mingzhi Fu +10 more

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.

Endometrial senescence: inevitability and conditional occurrence in female fertility.

Chunxue Niu, Xiuying Lin, Lei Liu +9 more

The endometrium is the primary site of embryo implantation. Cellular senescence within the endometrium can be broadly categorised into normal cyclical senescence and pathological excessive senescence. Normal cyclical senescence occurs as a normal component of the female reproductive cycle and contributes to endometrial receptivity for embryo implantation. In contrast, pathological excessive senescence arises in response to excessive external stimuli. This process may propagate between cells, impair immune-mediated clearance, and reduce the efficacy of senolytic therapies. This review aims to summarise the physiological and pathological endometrial cell senescence, as well as current therapeutic strategies targeting this process, thereby providing a theoretical framework and directions for future clinical research.

A PUFA-rich diet increases endogenous genotoxic stress and mitochondrial DNA damage in mice.

Masatomi Shimizu, Ayako Daizo, Kenichi Kawada +2 more

Substitution of dietary saturated fat with seed oils highly enriched in n-6 polyunsaturated fatty acids (PUFAs) has been advocated as healthy strategy to offset elevated cholesterol levels. However, both n-6 as well as n-3 PUFAs, considered essential because vertebrates lack the enzymatic apparatus for their de novo synthesis, are the main source of endogenous DNA damage during the aging process due to their high oxidizability. The membrane pacemaker theory of aging is an extension to the oxidative theory of aging and postulates that higher PUFA content in membrane lipids determines the lifespan of different species.

The oscillatory biology of sleep: Linkage to dementia.

Maiken Nedergaard

During wakefulness, neuromodulators operate largely independently to support behavior and cognition. By contrast, sleep reorganizes their activity into a coordinated brain rhythm. During sleep, the major neuromodulators-norepinephrine, acetylcholine, serotonin, and dopamine-exhibit synchronized fluctuations with a periodicity of ~50 seconds. These oscillations appear as recurrent bursts of fast (10 to 30 hertz) electroencephalography activity and are phase-coupled to cerebrospinal fluid flow. Neuromodulators are vasoactive agents and drive slow vasomotion, which provide the mechanical force that supports glymphatic clearance of metabolic waste. Disruption of neuromodulator signaling, as seen in psychiatric disorders, cardiovascular disease, aging, or with commonly prescribed drugs, impairs clearance of neurotoxic proteins, including amyloid-β and tau. Failure of this evolutionarily conserved brain rhythm may therefore represent a previously unrecognized mechanistic pathway linking diverse disorders with sleep disturbances to increased dementia risk.

Single-subject proteomic signatures in Alzheimer's disease reflect clinical phenotypes and distinguish asymptomatic from symptomatic cases.

Avijit Podder, Yi Juin Liew, Gregory A Cary +2 more

Alzheimer's disease (AD) exhibits considerable inter-individual variability in clinical presentation, neuropathological burden, and underlying molecular processes. Conventional cohort-based analyses of omics molecular data often mask individual-level heterogeneity, limiting insights into precision therapeutic strategies. To address this challenge, we developed INdividual-level DIfferential GenOmics (INDIGO), a computational framework that quantifies molecular deviations for each individual relative to healthy controls, enabling subject-specific profiling of disease-associated alterations in proteomic data, with a framework that is readily applicable to other omics modalities.

Symptom-Level Precision Neurology in Amyotrophic Lateral Sclerosis (ALS): Linking Microglial Pruning, Mitochondrial Nicotinamide Adenine Dinucleotide (NAD+) Compensation, and Autophagy Failure Across the Aging Spectrum.

Ngo Cheung

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurological disease with limited disease-modifying treatment options and, for many patients, a short survival window. The clinical course varies widely. Limb weakness, bulbar impairment, respiratory decline, fine-motor dysfunction, cognitive change, mood symptoms, and fatigue may each appear at different times and progress at different rates. This variability suggests that motor neuron loss alone may not fully explain the patient-level pattern of symptoms. This article is a narrative hypothesis framework, not a clinical guideline or a validated stratification tool. Established ALS biology, associative genomic findings, preclinical observations, computational predictions, and author-derived hypotheses are therefore separated throughout the article. This review brings together four interlinked studies by the current author as a primary hypothesis-generating corpus, which proposes that synaptic plasticity fragility may initiate a microglial pruning continuum shared by major depressive disorder and ALS, while ALS-specific progression may depend on mitochondrial stress, oxidized nicotinamide adenine dinucleotide (NAD+) compensation failure, and collapse of autophagy under aging-related limits. The model presented here maps symptom domains to vulnerable circuit compartments and separates three broad biological states: compensated plasticity, fragile plasticity, and network collapse. A compact mechanistic formulation is used to describe the balance between pruning pressure, glutamatergic burden, and aging stress on one side, and oxidative phosphorylation capacity, NAD+ reserve, and autophagic clearance on the other. The framework also incorporates opposing phosphoinositide 3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) pathway patterns that may distinguish ALS from frontotemporal dementia (FTD) within an aging context. The result is a falsifiable, biomarker-oriented hypothesis model for future studies, not an evidence-based diagnostic or therapeutic algorithm.

Applications of Mesenchymal Stromal Cells in Hematologic Disease: Advances, Challenges, and Bioengineering Strategies.

Yicheng Zhu, Chao Liu, Jing Yang

Mesenchymal stromal cells (MSCs) are multipotent cells of mesodermal origin capable of self-renewal and multilineage differentiation. Characterized by low immunogenicity and tropism toward injury sites, MSCs exhibit critical properties including hematopoietic support, immunomodulation, and tissue regeneration. These unique attributes position MSCs as promising therapeutic tools for hematologic diseases, where disruption of the bone marrow niche impairs normal hematopoiesis. Co-transplantation of MSCs with hematopoietic stem cells (HSCs) facilitates HSC homing to the bone marrow niche and significantly improves post-transplant hematopoietic reconstitution. Furthermore, MSCs show considerable therapeutic potential in both prophylaxis and management of graftversus- host disease (GVHD), a major complication of allogeneic transplantation. The therapeutic mechanisms of MSCs have evolved from an initial focus on engraftment to a broader understanding of their paracrine actions via the "hit-and-run" mechanism, wherein MSCs exert functions through secreted factors and extracellular vesicles before host clearance. Despite these advances, clinical translation faces significant challenges, including poor homing efficiency, cellular heterogeneity, culture-induced senescence, and vulnerability to inflammatory and oxidative stress. This review summarizes clinical applications of MSCs in aplastic anemia, leukemia, and co-transplantation with HSCs, while critically evaluating the balance between therapeutic efficacy and potential risks. Additionally, we discuss emerging bioengineering strategies designed to overcome current limitations and enhance MSC therapeutic potency for next-generation cell therapies in hematologic diseases.

Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.

Govindarajan Karthivashan, Shuai Wang, Qi Wu +6 more

Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.

ALDH2 alleviates diabetes-induced myocardial cell senescence and electrical remodeling by regulating SIRT1.

Lei Wang, Hui-Hui Wang, Qing Chen +19 more

There is a significant association between cardiomyocyte senescence and cardiac insufficiency. Senescent myocardial cells increase the susceptibility to cardiomyopathy and arrhythmia, while diabetes accelerates myocardial cell senescence. This study aims to explore whether ALDH2 can improve diabetes-induced myocardial cell senescence and electrical remodeling and reveal the underlying mechanism. In vivo, we found that ALDH2 overexpression effectively alleviated diabetes-induced cardiomyocyte senescence and the electrical remodeling of Nav1.5. Importantly, in vivo programmed electrical stimulation revealed that ALDH2 significantly reduced ventricular tachycardia (VT) susceptibility and duration in diabetic mice. In vitro, molecular docking confirmed the binding mode between ALDH2 and SIRT1. Using high glucose-induced H9C2 cardiomyocytes, we demonstrated that ALDH2 activation restored Nav1.5 protein expression and alleviated cellular senescence via SIRT1 upregulation. This protective mechanism is closely associated with SIRT1-mediated cellular ROS clearance and mitochondrial homeostasis. In conclusion, our study provides robust in vivo evidence that targeting the ALDH2/SIRT1 axis effectively prevents diabetic myocardial senescence and fatal electrical instability. These findings highlight a promising translational strategy to reduce the risk of malignant arrhythmias and improve cardiovascular health outcomes in diabetic patients.

Progress in research on the association between mesenchymal stem cell senescence and knee osteoarthritis.

Zhicheng Hu, Caixiang Xu, Shiwan Guo

Osteoarthritis (OA) is an age-related disease characterized by cartilage degeneration, subchondral bone remodeling, and chronic low-grade inflammation, with knee osteoarthritis (KOA) being a leading cause of functional impairment and reduced quality of life in middle-aged and elderly individuals. In recent years, advances in stem cell biology and aging research have highlighted the critical role of mesenchymal stem cells (MSCs) in maintaining joint homeostasis, regulating inflammatory responses, and mediating cartilage repair. Accumulating evidence indicates that reductions in MSC quantity and functional decline-particularly age-associated decreases in proliferative capacity, impaired differentiation potential, mitochondrial dysfunction, and activation of the senescence-associated secretory phenotype (SASP)-constitute key biological mechanisms driving KOA onset and progression.This review systematically summarizes the major molecular mechanisms underlying MSC senescence, including telomere shortening, DNA damage accumulation, mitochondrial dysregulation, and SASP activation, and emphasizes the roles of senescent MSCs in impaired cartilage regenerative capacity, disruption of extracellular matrix homeostasis, and imbalance in inflammatory and immune microenvironments. Additionally, we highlight recent research on potential interventions targeting MSC senescence, including senescent cell clearance, metabolic and mitochondrial restoration, MSC-derived exosome therapy, and advances in engineered culture and delivery technologies.In conclusion, MSC senescence represents not only a fundamental pathological basis for KOA development but also a critical target for future OA interventions, providing important theoretical and translational value for advancing regenerative medicine strategies toward clinical application.

Targeting microglia: A new strategy for the treatment of Alzheimer's disease.

Manyv Zheng, Mingjuan Yang, Wenya Su +2 more

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.

Chronic estrogen supplementation in the aging castrated male rat is not associated with renal injury or activation of the renin angiotensin system.

Jordan H Mallette, Breland F Crudup, Adrian Oudomrath Speyrer +4 more

The biological effects of chronic estrogen supplementation on renal function and injury with aging in men are unknown. Using an experimental model of feminizing hormone therapy (FHT) induced by 17β-estradiol (E2) (5 mg/kg, s.c.) supplementation plus castration (CTX) in the male Sprague Dawley rat starting at 13-15 months of age, equivalent to a late thirty- to forty-year-old man, we tested the hypothesis that FHT is associated with impaired renal function and renal injury with aging associated with activation of the renin angiotensin system (RAS). However, 24-hour creatinine excretion, plasma creatinine, and creatinine clearance did not differ in E2+CTX compared to Control by 22-24 months of age, or following 9 months of FHT. Lean mass was significantly reduced in E2+CTX versus Control, but creatinine clearance adjusted to lean mass did not differ. Serum cystatin C, a more reliable biomarker for renal function, was unchanged; urinary cystatin C was reduced, suggesting no renal impairment. However, cystatin C clearance was reduced in E2+CTX versus Control, suggesting decreased renal filtration. Proteinuria, urinary KIM-1 (a marker of proximal tubule injury), and glomerular injury score were significantly reduced in E2+CTX versus Control; however, albuminuria did not differ. Renal angiotensinogen mRNA expression was significantly decreased in E2C+TX, whereas urinary angiotensinogen, renal renin, and renal angiotensin type 1 receptor mRNA expression did not differ. Collectively, these results suggest that the biological effects of FHT in the aging male are not associated with increased renal injury or inappropriate activation of the RAS; whether renal function is altered remains unclear.

Bridging Trauma and Parkinson's Disease: Mechanisms, Models, and Biomarkers of Post-Traumatic Parkinsonism.

Singh Ankit Satyaprakash, Nitesh Kumar Gupta, Shekhar Singh +2 more

One of the most prevalent neurodegenerative diseases, Parkinson's disease (PD), is generally discussed in terms of aging, genetic predisposition, and environmental exposures. Nonetheless, there is growing evidence that both isolated severe traumatic events and repetitive mild traumatic brain injury may play a significant role in the development of parkinsonian features. This trauma-associated condition, known as Post-Traumatic Parkinsonism Syndrome (PTPS), is becoming more widely acknowledged as a clinically significant but underdiagnosed illness. The differences between PTPS and conditions like chronic traumatic encephalopathy (CTE) are often blurred because, in contrast to idiopathic PD, PTPS typically manifests after a specified latency period following head injury and is often accompanied by overlapping symptoms of cognitive, behavioral, and motor dysfunction. At the pathophysiological level, PTPS is defined by the combination of trauma-induced processes, such as neuroinflammation, axonal injury, and dysregulated acetylation pathways, with mechanisms known to be associated with PD, such as alpha-synuclein aggregation, dopaminergic neuronal loss, and impaired protein clearance. Today, experimental models demonstrate how trauma speeds up or even starts neurodegenerative cascades, providing a unique platform to investigate disease mechanisms outside of the traditional toxin-based paradigms of PD. The current understanding of PD, PTPS, and CTE is summarized in this review, with a focus on risk factors, comparative pathology, and experimental model translational insights. This review emphasizes the significance of acknowledging trauma as more than a trigger but rather as a potential contributor to long-term neurodegeneration and disability by presenting PTPS as a unique but related syndrome within the PD spectrum.

In vitro and in vivo activity of colistin-nitroxoline combination against polymyxin heteroresistant carbapenem-resistant Klebsiella pneumoniae.

Xin Chen, Jianping Jiang, Xiaogang Xu +3 more

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a critical global health threat, often causing life-threatening infections with limited therapeutic options. Polymyxins are often used as the last-line agent, but its efficacy is limited by heteroresistance-where resistant subpopulations emerge during treatment. To combat this, we evaluated the synergistic activity of colistin combined with nitroxoline against polymyxin heteroresistant (PHR) CRKP subpopulations.

Metabolic Transition Windows in Tissue Repair: Timing, Boundary Conditions and Resolution.

Fangyuan Zhu, Feixin Liang, Sijia Song

Regenerative repair is accompanied by extensive cellular remodeling, with metabolic reprogramming frequently observed across injury models. Glycolytic upregulation is commonly reported early after tissue damage, yet similar metabolic shifts have also been described in settings that progress toward functional regeneration or fibrotic remodeling. These observations indicate that pathway enrichment alone provides an incomplete explanation for divergent repair trajectories. Accumulating studies are consistent with a time-resolved perspective in which outcomes may depend on the onset, magnitude, and reversibility of metabolic remodeling, together with spatial and niche-derived boundary conditions. This review synthesizes recent work linking metabolic flux to chromatin regulation and cell-state plasticity. Metabolites such as acetyl-CoA, α-ketoglutarate, and lactate have been associated with chromatin remodeling and changes in epigenetic constraints in multiple contexts, although their necessity and directionality remain model dependent. We discuss evidence that immune microenvironments can shape metabolic boundary conditions by modulating oxygenation, inflammatory cues, and debris clearance, thereby influencing when reparative programs are engaged and whether tissues transition toward maturation and oxidative recovery. Comparative analysis across the heart, nervous system, lung, and liver supports the concept of organ-specific bottlenecks that may limit repair at distinct stages, including constrained entry into reparative states, impaired maintenance of rebuilding programs, or delayed resolution that coincides with persistent inflammation and scarring. We highlight methodological challenges that complicate causal interpretation, including reliance on transcript-level proxies and incomplete temporal sampling. We propose that advancing the field will require longitudinal and stage-resolved analyses coupled with functional repair endpoints, with explicit consideration of tissue microenvironmental context.

The Copper-Gut-Brain Axis: A Triple Inflammatory Pathway Driving Neuroinflammation in Alzheimer's Disease.

Ashwin Ambi

Serum copper increases progressively with normal aging, yet its downstream consequences for the gut microbiome and neuroinflammation remain unexplored. Gut microbiota dysbiosis and elevated lipopolysaccharide levels are established features of Alzheimer's disease, and growing evidence indicates that this dysbiosis drives neuroinflammatory disease progression. Yet the upstream trigger initiating this dysbiosis remains unknown. We propose that age-related copper dyshomeostasis serves as this missing trigger. The redox-active copper content of ceruloplasmin increases across the adult lifespan, and copper is selectively toxic to anaerobic bacteria, preferentially affecting butyrate-producing genera including Faecalibacterium, Roseburia, and Coprococcus while sparing copper-resistant species. This selective toxicity is supported by animal studies demonstrating copper-induced elimination of butyrate producers with reversible gut barrier damage and by Wilson's disease cohorts showing consistent depletion of butyrate-producing genera due to elevated copper levels. The resulting dysbiosis creates a triple inflammatory pathway: butyrate loss compromises gut barrier integrity and removes histone deacetylase-mediated suppression of neuroinflammation; the increase of Gram-negative bacteria elevates lipopolysaccharide translocation through the compromised barrier; and impaired blood-brain barrier integrity reduces amyloid-β clearance. These three insults trigger microglial activation through NF-κB signaling, creating a 'triple hit' on a single transcription factor that may explain the magnitude of neuroinflammatory effects observed in Alzheimer's disease. This mechanism explains the increased acetate/butyrate ratio recently identified as a biomarker distinguishing Alzheimer's-related from non-Alzheimer's cognitive impairment (AUC 0.951), since copper disrupts microbial metabolic cross-feeding networks that convert acetate to butyrate. We present specific, falsifiable predictions that can be tested in human cohorts and propose copper as a novel upstream therapeutic target for Alzheimer's disease prevention.

Stagnation and Progression: How Glymphatic Failure Promotes Meningioma Malignancy in Aging.

Wenfei Zhou, Naili Wei, Feng Xu +13 more

Meningiomas in the elderly present a clinical paradox: despite typically benign histology, they frequently manifest disproportionate peritumoral brain edema (PTBE) and aggressive behavior. Traditional hormonal hypotheses fail to explain this age-specific malignancy. This review articulates a "Neuro-Glymphatic-Tumor Axis" as a working hypothesis, proposing that the senescent collapse of brain clearance infrastructure, rather than tumor genetics alone, may be a key driver of this progression. Specifically, the loss of astrocytic aquaporin-4 (AQP4) polarity and the atrophy of meningeal lymphatic vessels are hypothesized to create a critical "hydrodynamic mismatch." This systemic failure may trap oncogenic toxins, specifically HMGB1 and S100A4, potentially activating RAGE signaling, while simultaneously blocking antigen drainage, which could induce a state of "immunological ignorance." Consequently, the tumor microenvironment may become physically congested and immunologically suppressed. Translating this framework into practice, we suggest that assessing "glymphatic frailty" via functional MRI and exploring microenvironment-targeted strategies, including lymphatic-sparing surgery and AQP4 modulation, represent promising future directions for dismantling the cycle of edema and recurrence in the vulnerable geriatric population.

Deep Venous Perivascular Space Dysfunction Reflects Glymphatic Aging and Predicts Cognitive Vulnerability: In Vivo Human Evidence.

Kemeng Zhang, Ying Zhou, Yifei Li +4 more

Impaired glymphatic clearance has been recognized as a fundamental mechanism of cognitive decline. While models suggest cerebrospinal fluid influx along arterial perivascular spaces (aPVS) and efflux along venous PVS (vPVS), their differential roles in humans are unclear. We aimed to visualize directional glymphatic flow in vivo, classify human PVS functionally and determine their associations with cognition. This study included 91 patients undergoing intrathecal gadodiamide with serial MRI at baseline, 4.5 hours, 15 hours and 39 hours post-injection. PVS showing early (4.5h) and delayed (39h) enhancement peaks were defined as aPVS and vPVS, respectively. Among 742 basal ganglia (BG) and 1380 centrum semiovale (CSO) PVS analyzed, 10.4% and 21.6% were aPVS, while 62.7% and 52.0% were vPVS, respectively. BG-vPVS burden correlated with age (r=0.275, p<0.001) and hypertension. Among 60 patients with cognitive assessment (telephone Montreal Cognitive Assessment, T-MoCA) data, only BG-vPVS burden independently correlated with lower scores after adjusting for age and education (β=-0.16, p=0.041). This study provided direct in vivo MRI evidence of glymphatic flow within human PVS. We introduced a novel functional classification method to differentiate arterial from venous PVS, finding their different role in cognitive impairment, which may represent a potential target for therapeutic intervention.

Cerebrovascular-CSF coupling measured by broadband near-infrared spectroscopy as a physiological marker of brain aging and Alzheimer's disease.

Fiza Saeed, Kathy L Siepker, Soeun Jang +2 more

Alzheimer's disease (AD) is strongly associated with cerebrovascular dysfunction and impaired glymphatic clearance. These dysfunctions may precede, contribute to, and interact bidirectionally with AD pathology, highlighting the importance of identifying physiological markers for the early detection of AD. Noninvasive approaches for assessing these processes and identifying early biomarkers remain limited. Cerebrospinal fluid (CSF) plays a central role in clearing neurotoxins from the brain, but current methods for quantifying CSF dynamics are invasive, costly, and not well suited for early detection of AD.

Multimodal Free-Water Imaging Links Cardiometabolic Risk to Periarterial Dysfunction and Amyloid Accumulation in Early Alzheimer's.

Yaqiong Chai, Hedong Zhang, Andrew S Kim +17 more

The brain's waste-clearance (glymphatic) system removes metabolic byproducts via periarterial influx, interstitial exchange, and perivenous efflux. Although dysfunction is implicated in Alzheimer's disease (AD), current imaging markers emphasize perivenous changes and may overlook earlier periarterial impairment. We developed a diffusion MRI framework to quantify periarterial fluid mobility, white matter free water, and perivenous integrity, and applied it to 546 cognitively normal adults (HCP-Aging) and 173 participants across the AD spectrum (ADNI). Periarterial mobility was reduced with higher cardiometabolic risk and amyloid positivity, particularly in AD-vulnerable regions. Free water increased with aging and metabolic burden, whereas perivenous dysfunction was most pronounced in AD. Combined measures predicted amyloid positivity and cognitive impairment (AUC = 0.82). Mediation analyses showed that blood pressure influenced cognition through periarterial dysfunction and amyloid burden. These findings support a staged, compartment-specific trajectory of glymphatic dysfunction, with early periarterial impairment representing a potential biomarker and therapeutic target.

An agent-based model suggests how senescent cell behavior and matrix mechanics drive pulmonary fibrosis in aged mice.

Mackenzie L Skelton, Julie Leonard-Duke, Leilani R Astrab +5 more

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease of aging, driven by dysregulated fibroblast activation and accompanied by collagen accumulation in the lung interstitium, resulting in tissue stiffening. While the accumulation of senescent cells has been increasingly implicated in IPF pathogenesis, understanding the reciprocal dynamics of senescent fibroblast levels and evolving tissue mechanics is difficult to achieve with experimental approaches alone. To address this limitation, we developed an agent-based model (ABM) of fibroblast activation in the lung that couples cell behavior to the dynamic mechanical changes accompanying fibrosis. This model was parameterized entirely from experimental data in young mice to enable robust validation and then adapted to fit aged mouse biology for additional validation. Both young and aged models accurately reflected changes in collagen accumulation and stiffness burden of experimental systems. We then incorporated senescent cell behavior into the aged model to investigate how senescent cell burden influences fibrosis progression and how cell-cell interactions drive senescent cell accumulation. These simulations identified a unique role for juxtacrine-mediated contact between non-senescent and senescent fibroblasts in expanding the total senescent cell burden. Our ABM also revealed that the timing of immune-mediated senescent cell clearance critically regulates fibrotic outcomes. Together, this ABM provides useful insights into how the interrelated dynamics of tissue mechanics and senescent fibroblasts drive fibrosis progression.

Fabrication of fusogenic and magnet-responsive cells for transplantation of an intact mitochondrial network.

Liqun Xu, Xiao Li, Xing Fan +10 more

Mitochondrial transplantation is a promising treatment for many diseases associated with mitochondrial defects or aging; however, a reliable method for mitochondrial transfer remains urgently needed. In this study, we assemble fusogenic and magnet-responsive cells (FMRCs), which are enucleated stem cells loaded with Fe 3O 4 nanoparticles and further incorporated fusogenic vesicular stomatitis virus glycoprotein G (VSV-G). Mitochondrial transplantation from FMRCs via fusion in the presence of a magnetic force restores normal mitotic activity, mitochondrial membrane potential, ROS levels and ATP production in cells subjected to partial mtDNA depletion or in cybrids harboring mtDNA with a 4977-bp deletion. SNP tracing and qPCR analysis of the mitochondrial and nuclear genomes unequivocally demonstrate that exogenous mitochondria are able to reside stably and predominately. Mitochondrial transplantation stimulate autophagy and thus the clearance of defective endogenous counterparts, resulting in lower mtDNA heteroplasmy. These results suggest that FMRCs are excellent vehicles for mitochondrial transplantation and could be used for the treatment of aging and mitochondria-associated diseases.

Hydrogen reshapes the senescent microenvironment of callus to enhance the healing of anti-osteoporotic-drug-induced atypical femoral fracture.

Yuanming An, Haozhi Zhang, Yuantao Zhang +10 more

Long-term bisphosphonates (BPs) are widely used to treat osteoporosis, however, they are paradoxically associated with the development of atypical femoral fractures (AFFs), which often characterized by impaired healing. In this study, we induced an AFF model using zoledronate (ZOL) administration in ovariectomized (OVX) osteoporotic rats, following a unilateral femoral fracture. Here we identified that a local pro-senescent microenvironment causes persistent inflammation and impairs effective regeneration in rat AFFs. Molecular hydrogen has demonstrated anti-senescence and anti-inflammatory properties, yet its effects on AFF healing remain unexplored. Therefore, we treated the AFF rats with hydrogen rich water (HRW). The outcomes were assessed by radiographs, histology, micro-CT, and biomechanical tests. The fracture microenvironment was analyzed based on the indicators of senescence, fibrosis, macrophage polarization, cytokine expression, and angiogenesis. We found that HRW significantly promoted callus bridging and resolved the non-union gap in ZOL-induced AFFs, whereas the ZOL group exhibited persistent fibrous tissue. Micro-CT and biomechanical tests confirmed that HRW did not compromise the mechanical strength of the bone mass elevated by BPs. Instead, HRW specifically attenuated the local senescent microenvironment, with a reduction in both SA-β-gal activity and the expression of p16, p21 within the fracture gap. This was accompanied by clearance of pathological fibroblasts, a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages, a rebalanced cytokine profile, and restored formation of osteogenesis-coupled type-H vessels. Our findings confirm that molecular hydrogen facilitates AFFs healing by locally reversing the senescent microenvironment, rather than boosting systemic bone formation. This creates a favorable niche for callus bridging, representing a novel therapeutic strategy for fracture delayed union or non-union.

Efferocytosis: Signaling Pathways and New Therapeutic Strategies for Diseases.

Lei Wang, Jingjing Ge, Zehua Wang +4 more

Efferocytosis-the phagocytic clearance of apoptotic cells (ACs)-is essential for maintaining tissue homeostasis, immune tolerance, and inflammation resolution. Beyond classic receptor-mediated recognition, this process drives phagocyte metabolic reprogramming to actively facilitate tissue repair. Consequently, defective efferocytosis serves as a core pathogenic mechanism across major human diseases. This review outlines the molecular and metabolic foundations of efferocytosis and defines four universal hallmarks of its dysfunction: senescence-driven impairment, unresolved inflammation, loss of immune tolerance, and fibrotic tissue repair. Subsequent sections explore how these defects manifest in cardiovascular, autoimmune, and neurodegenerative conditions, as well as cancer. Because efferocytosis exhibits a dual pathophysiological nature, therapeutic interventions must be highly disease-specific. Enhancing apoptotic clearance can effectively resolve chronic inflammatory and fibrotic conditions. Conversely, because tumors hijack these same pathways to build immunosuppressive microenvironments, inhibiting efferocytosis remains a critical strategy in oncology. The synthesis of these divergent roles informs a "context-dependent directionality" framework to guide the clinical translation of efferocytosis-targeted precision therapies.

Eugenol from Syzygium aromaticum enhances longevity and proteostasis in aged yeast.

Suchanya Suesattayapirom, Tachaporn Kanhachai, Anjana Puttapong +5 more

Clove (Syzygium aromaticum) extracts promote longevity in several model systems, yet the underlying molecular mechanisms responsible for the pro-longevity remain poorly defined. This study utilized a Saccharomyces cerevisiae model to investigate how clove extracts modulate two primary hallmarks of cellular aging: oxidative damage and the decline of protein quality control systems. Clove extracts promoted increased chronological lifespan (CLS) of yeast cells. The change in longevity was associated with a reduction in both reactive oxygen species (ROS) levels and increased resistance to oxidant and thermal challenges. The appearance of protein aggregates was also limited with treatment with clove extract and is likely linked to induction of the autophagy pathway. Deletion of RAS2 abrogated the enhanced CLS from clove extracts. This observation suggests that the ability of clove extracts to extend the lifespan of S. cerevisiae is dependent on the Ras/PKA (Protein Kinase A) signaling pathway.These results indicate that the enhanced CLS from clove extracts are mediated through improving the maintenance of proteostasis rather than general antioxidant activity. Chemical profiling and comparative bioassays of major constituents identified eugenol as the principal bioactive compound, which successfully replicated the anti-aging and stress-reducing properties of clove extract. Our findings demonstrate that clove extracts, through the bioactive compound eugenol, promote survival in aged cells through reducing oxidative stress and damage and improving the clearance of aggregated proteins to limit proteotoxicity.

Stereoselective Targeting with Chiral Nanomaterials: A Strategy for Precision Therapy in Neurodegenerative Diseases.

Ruhui Luo, Yaqing Zhang, Xiner Tan +1 more

The challenge in treating neurodegenerative diseases (NDs) lies in the complexity of their pathological mechanisms. Strategies capable of synergistically regulating multiple pathological features are crucial for treating NDs. Chiral nanomaterials (CNMs), including chiral nanoparticles (CNPs) and chiral nanoassemblies (CAMs), offer a unique platform for achieving such precise multitarget regulation because of their stereoselective interactions. Strategies for synthesizing CNMs are outlined in this review, and an in-depth analysis of their core biological mechanisms for treating NDs-inhibiting and clearing pathological proteins, enhancing synaptic plasticity, alleviating neuroinflammation, selectively eliminating senescent cells and promoting the differentiation of neural stem cells-is provided. Optimization of these functions through internal chiral design and external physical field modulation is explored. Finally, we propose forward-looking concepts such as "stage-optimized chiral nanomedicines" and "intelligently responsive chiral nanomaterials" to provide guidance for next-generation precision nanomedicine for NDs. STATEMENT OF SIGNIFICANCE: The key challenge in treating neurodegenerative diseases (NDs) lies in the precise identification and coordinated regulation of multi-target pathological processes. In recent years, chiral nanomaterials (CNMs), including chiral nanoparticles (CNPs) and chiral nanoassemblies (CAMs), have emerged as innovative tools for NDs intervention owing to their unique stereoselective recognition capabilities. This review systematically categorizes CNMs and their synthesis strategies, and focuses on elucidating their core biological mechanisms, including the inhibition and clearance of pathological proteins, enhancement of synaptic plasticity, alleviation of neuroinflammation, selective elimination of senescent cells, and promotion of neural stem cell differentiation. Furthermore, strategies to optimize their functionality through internal chiral structure design and external physical field modulation are explored. Collectively, this review aims to systematically elucidate the biological mechanisms and material properties of CNMs in NDs therapy, providing a theoretical foundation and guidance for the rational design and construction of next-generation neurorepair materials.

Superoxide dismutase in intervertebral disc degeneration: from pathophysiological mechanism to therapeutic strategies.

Huan Liu, Fengguang Yang, Guangzhi Zhang +4 more

Reactive oxygen species (ROS) induce inflammation, senescence and various forms of cell death in nucleus pulposus cells. By promoting these reactions and their interplay, ROS significantly accelerate intervertebral disc degeneration (IDD). Conventional surgical interventions and analgesics can alleviate symptoms but fail to halt the disease progression mechanistically. Eliminating ROS may serve as a fundamental therapeutic approach to mitigate IDD. Within the endogenous antioxidant defense system for scavenging ROS, superoxide dismutase (SOD) serves as the first line of defense, playing an irreplaceable role in initiating the clearance of reactive species. Furthermore, transcriptomics and single-cell sequencing analyses have identified SOD as a key gene in nucleus pulposus tissue degeneration, underscoring its unique value in the research of antioxidant therapies for IDD. Recently, a range of SOD-centered therapeutic strategies, including the enhancement of endogenous SOD via drugs, hormones, herbal medicines, exosomes, genetically engineered stem cells, in addition to the use of exogenous SOD nanozymes have been explored. Despite these advancements, a comprehensive overview of these emerging approaches remains elusive. This review details how ROS contribute to IDD and critically assesses current and future SOD-centered therapeutic strategies, providing valuable insights for clinical practice and research directions.

Health-related quality of life domains relevant to people in Europe undergoing cancer treatment: a systematic review of qualitative research.

Catalina Lizano-Barrantes, Clara Amat-Fernandez, Olatz Garin +76 more

To identify and synthesize evidence from European qualitative studies on cancer-related quality of life outcomes, needs, experiences, preferences, and concerns of people undergoing cancer treatment in the last decade.

Corpora amylacea and glymphatic system in temporal lobe epilepsy patients: Clinicopathological correlation.

Dalila Biancheri, Laura Rossini, Cinzia Cagnoli +12 more

Corpora amylacea (CA), now called wasteosomes, are basophilic inclusions associated with aging, neurodegeneration, and impaired glymphatic waste clearance. Their presence is well described in temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and related to hippocampal neuronal loss and longer epilepsy duration. Here, we assessed CA deposition in TLE patients submitted to epilepsy surgery with any histological diagnosis and explored its relationship with clinical and neuropsychological variables. Histological signs of the glymphatic system were evaluated.

Antibodies targeting amyloid-β and Tau oligomers in Alzheimer's disease.

Subashchandrabose Chinnathambi, Nagaraj Rangappa, Madhura Chandrashekar

Alzheimer's disease is a leading neurodegenerative disorder, is characterized by cognitive decline linked to amyloid-beta plaques and Tau tangles. These pathological aggregates disrupt the neuronal communication, induce neuroinflammation, and contribute to synaptic dysfunction. Genetic mutations, aging, environmental and lifestyle factors exacerbate these mechanisms, promoting neurotoxicity. Advances in immunotherapy have targeted Aβ and Tau oligomers using several monoclonal antibodies and Tau-specific antibodies. These therapies aim to neutralize toxic aggregates, facilitate clearance, and slow cognitive decline. Dual-targeting approaches, such as bispecific antibodies, address both Aβ and Tau, enhancing therapeutic efficacy. Despite challenges-like limited blood-brain barrier penetration, off-target effects, and high production costs, innovations in nanobody technology and personalized medicine are the key players. Artificial intelligence-driven antibody design further accelerates development, offering hope for transformative Alzheimer's disease treatments. Future research focuses on optimizing safety and efficacy, paving the way for comprehensive management of this devastating disease.

The effects of time constraints on electrocortical dynamics underlying obstacle avoidance while walking.

Marco A Bühler, Sylvain Baillet, Bradford J McFadyen +2 more

A growing body of literature has characterized the extensive and widespread engagement of cortical resources during the execution of locomotor adaptations. However, evidence suggests that the extent of cortical regulation involved in such adaptations is modulated by the available time to respond. In this study, a treadmill-based virtual reality paradigm was used to examine the electrocortical oscillations associated with obstacle avoidance under short versus long available response times (ARTs). Electroencephalography data were recorded from healthy young adults as they stepped over virtual obstacles. These obstacles were presented in far space, allowing either a short (1.5 sec) or long (4 sec) ART between their presentation and clearance. Data were parsed with independent component analysis and clustered within the prefrontal, sensorimotor, parietal and occipital regions. Distinct spectral signatures were observed across all cortical regions, characterized by transient synchronizations shortly after obstacle presentation and immediately prior to clearance. Compared to the long ART condition, the short ART condition elicited stronger prefrontal theta, alpha, and beta synchronizations. During clearance, long ARTs were associated with a sensorimotor alpha desynchronization during obstacle clearance; however, such desynchronization was largely absent under short ART. Taken together, these findings suggest that tighter temporal constraints during obstacle avoidance enhance prefrontal involvement and decrease sensorimotor network activation. Such time-dependent cortical dynamics offer new insights into the neural mechanisms underlying locomotor adjustments that can inform our understanding of locomotor deficits in aging and neurological disorders.

Mechanical aging of tire microplastics enhances the bioavailability of pre-adsorbed 17β‑estradiol in goldfish.

Wenwen Song, Yiyu Wu, Zhuanxi Luo +3 more

Tire microplastics (TMPs) are emerging contaminants in aquatic environments, posing ecological risks from both their ingredients and adsorbed pollutants. However, the transformation of TMPs by mechanical forces on wet-road surfaces and its effects on the carrier behavior of TMPs remain poorly understood. Here, we employed wet ball-milling to simulate mechanical TMP aging after rainfall by repeated TMP-road surface friction. The mechanical aging significantly increased the proportion of fine particles (1-10 μm) from 6.4% to 73.1%, accompanied by a change from dense, compact structures into loosely aggregated particles. In vitro desorption experiments showed that the aging enhanced the release of 14C-labeled 17β-estradiol (E2) pre-adsorbed onto the TMPs in simulated fish digestive fluids. This enhancement was likely due to shortened intraparticle diffusion pathways, leading to increased bioavailability. Goldfish exposure experiments revealed that the aged TMPs modulated the absorption, distribution, and clearance of E2 in vivo, promoting its intestinal release while delaying its hepatic accumulation, thereby altering the temporal response of the estrogen-responsive biomarker vitellogenin. Our findings indicate that mechanical aging under wet-road conditions not only refines TMP particles and alters their structure, but also increases their environmental risks as carriers of low-molecular-weight organic pollutants.

Natural killer cell immunotherapy reverses lung fibrosis by eliminating senescent fibroblasts.

Wolfgang Merkt, Lea Rodon, Franca S Deicher +29 more

Impaired immune clearance of senescent fibroblasts is a putative driver of pulmonary fibrosis. Exhausted natural killer (NK) cells have been implicated in this process, yet the underlying immune evasion mechanisms remain poorly understood. Using single-cell RNA sequencing (scRNA-seq) and spectral flow cytometry, we identified natural killer group 2 member A (NKG2A) as the predominant inhibitory checkpoint receptor expressed on NK cells in fibrotic lung diseases. Mechanistic in vitro coculture studies showed that NK cell suppression was mediated by senescent fibroblasts expressing human leukocyte antigen-E (HLA-E), the high-affinity ligand for NKG2A. scRNA-seq analysis of lungs from patients with idiopathic pulmonary fibrosis (IPF) further identified selective HLA-E expression in senescent HAS1+ fibroblast subsets. Further, spatial transcriptomics and multiplex immunofluorescence of patient lungs demonstrated that HLA-E+ fibroblasts were positioned at the periphery of fibroblast foci adjacent to NKG2A+ NK cells, establishing an immune-privileged niche. In contrast, extracellular matrix-producing myofibroblasts at the core of fibrotic foci lacked HLA-E and exhibited minimal NK engagement. In vivo, therapeutic blockade of NKG2A restored NK cell function, promoted clearance of senescent fibroblasts, and promoted fibrosis resolution in the bleomycin-induced mouse model. Monalizumab, a clinical-grade NKG2A inhibitor, reactivated patient-derived NK cells and enhanced lysis of human senescent fibroblasts in vitro. Together, these findings uncover a spatially restricted immune checkpoint axis that allows senescent fibroblasts to evade immune NK surveillance. Targeting the HLA-E/NKG2A axis represents a promising therapeutic strategy to restore NK cell-mediated immune clearance of senescent fibroblasts and reverse pulmonary fibrosis.

Phagocytosis deficient glia display phagosome processing defects and macrophage recruitment to the brain of adult Drosophila melanogaster.

Guangmei Liu, Iqra Amin, Cheng Yang Shi +1 more

Efficient clearance of dying cells is essential for brain homeostasis, yet how partial defects in phagocytic processing affect neuroimmune interactions during aging remains unclear. In the adult Drosophila brain, glia function as professional phagocytes through the conserved engulfment receptor Draper (Drpr). Here, we show that glial loss of Drpr does not completely eliminate phagocytosis but instead leads to persistent, age-dependent inefficiency in corpse degradation. Using a genetically encoded pH-sensitive reporter to visualize acidified phagocytic compartments, we find that drpr -deficient glia retain residual engulfment activity but progressively accumulate enlarged, incompletely degraded phagocytic cargo. This chronic clearance defect coincides with altered immune dynamics at the central nervous system periphery, including increased recruitment and adhesion of peripheral hemocytes at the blood-brain barrier (BBB), without overt BBB disruption. Notably, hemocytes at the brain surface can phagocytose glial material in a Drpr-dependent manner, revealing a form of barrier-associated "border clearance". Together, these findings demonstrate that inefficient corpse degradation is sufficient to reshape neuroimmune interactions during aging.

The Impact of Alternate-Day Fasting on the Salivary Gland Ductal Compartments and the Differentiation Potential of Keratin 5+ Salivary Gland Progenitor Cells in an Induced Mouse Model of Sjögren's-like Hyposalivation.

Dongfang Li, Shoko Onodera, Qing Yu +1 more

Intermittent fasting confers protection in diverse diseases through various mechanisms, including the clearance of senescent and pathogenic cells, modulation of tissue inflammation and enhancement of stem/progenitor cell niche and functionality. Our previous study demonstrated the beneficial impact of alternate-day fasting (ADF) on xerostomia and sialadenitis, along with an improvement in salivary gland ductal compartments, where salivary gland progenitor cells reside, in non-obese diabetic mice, a spontaneous model of Sjögren's syndrome (SS). In the present study, we induced SS-associated hyposalivation in KRT5CreERT2; R26tdTomato lineage tracing mice by immunizing them with submandibular gland proteins from wild-type C57BL/6 mice. ADF alleviated salivary gland hypofunction, which was accompanied by decreased expression of the senescent cell marker p16INK4a, reduced protein levels of anti-apoptotic proteins BCL-2, BCL-XL, and MCL-1, and attenuated NLRP3 inflammasome activity in the submandibular glands, particularly within the ductal compartments, of this inducible model. Furthermore, immunofluorescence staining of submandibular gland sections revealed the expression of the acinar cell marker aquaporin 5 in a small subset of Keratin 5+ cells in 2 of 9 mice that were subjected to ADF, whereas no such cells were detected in the control mice. Taken together, these findings indicate that ADF favorably modulates the salivary gland progenitor cell niche, potentially by promoting apoptosis-mediated senescent cell clearance, suppressing NLRP3 inflammasome signaling, and promoting Keratin 5+ progenitor cell-derived acinar cell replenishment, thereby contributing to the structural and functional restoration of damaged salivary glands in autoimmune exocrinopathy.

Clinical impact of potential drug-drug interactions between midostaurin and posaconazole in FLT3-mutated AML.

Carolin S Joisten, Sibylle C Mellinghoff, Danila Seidel +9 more

To determine midostaurin and posaconazole plasma concentrations and investigate adverse events (AEs) resembling drug-drug interactions (DDI) when both drugs were administered concomitantly during induction chemotherapy for acute myeloid leukemia (AML). Patients with FLT3-mutated AML who received midostaurin and posaconazole concomitantly between May 2019 and December 2022 were included and followed up to March 2023. Twice-weekly trough levels for midostaurin and posaconazole were measured with validated liquid chromatography-tandem mass spectrometry methods. Potential DDIs were independently reviewed by two physicians and attributed using the Drug Interaction Probability Scale (DIPS). Population pharmacokinetics analysis was done via nonlinear mixed-effect modeling. In 29 patients, concentrations ranged from 0.6 to 24.5 mg/L for midostaurin and from <30 to 2,572 µg/L for posaconazole. A total of 375 AEs in 66 midostaurin cycles, with 280 AEs classified as grade ≥3, were recorded. Probable DDI with a DIPS score of ≥5 was attributed in 14/375 AEs; no highly probable AEs were registered. Eight AEs led to dose modification or discontinuation of midostaurin in seven patients. Clearance for midostaurin during co-administration with posaconazole was 0.52 L/h (95% CI, 0.42-0.62 L/h). A breakthrough fungal infection was recorded in eight patients (27.5%). DDI of midostaurin and posaconazole is clinically meaningful but infrequent. High inter- and intra-individual variabilities of midostaurin and posaconazole plasma exposure were observed. Midostaurin clearance was delayed during co-administration. Midostaurin therapeutic drug monitoring may serve for decision-making when DDI with CYP3A4 inhibitors is suspected.

Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.

Xiaoyang Lu, Yiling Jiang, Xiuqing Lin +3 more

Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.

Modulating hepatic stellate cell senescence: A promising therapeutic strategy for liver fibrosis.

Muthusethupathi Sharmila, Karthik Shree Harini, Devaraj Ezhilarasan

Fibrosis is characterized by the abnormal deposition of extracellular matrix (ECM) components in liver tissue following chronic liver injury, ultimately leading to hepatic cirrhosis. Following liver damage, hepatic stellate cells (HSCs) undergo transition from a quiescent to an activated phenotype which differentiate into proliferative, fibrogenic, and contractile myofibroblasts. The activated HSCs act as the primary source of collagen in the injured liver, promoting scar formation and fibrogenesis while reducing ECM degradation. Therefore, potential therapeutic strategies for liver fibrosis include inhibiting HSC activation, proliferation, and function, as well as promoting their clearance through autophagy, pro-apoptotic agents, and senescence inducers. In recent years, the induction of HSC senescence has emerged as a promising therapeutic approach to halt fibrosis progression. This review provided a comprehensive analysis of the fundamental role of the senescence-associated secretory phenotype and its regulatory pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes, Notch signaling, nuclear factor kappa B, and mechanistic target of rapamycin complexes. This review also discussed each of these pathways in terms of their influence on the senescence behaviour of HSCs and their interactions within the fibrotic hepatic microenvironment. Recent advancements in identifying senescence markers, such as p21, β-galactosidase, interleukin-6, and urokinase plasminogen activator receptor, offer promising opportunities for targeted therapeutic interventions. Consequently, the strategic targeting of HSC senescence emerges as a compelling therapeutic approach for liver fibrosis, with the potential not only to halt disease progression but also to promote essential tissue remodeling processes.

Immunotherapy for Senescent Cell Clearance: Hallmarks, Strategies and Translational Challenges.

Wenjie Zhang, Shihong Chen, Xianghua Zhuang

Cellular senescence, a complex multifactorial process, is involved in the pathophysiology of various age-related diseases, such as cardiovascular disease and neurodegenerative disorders. Traditional interventions targeting single mechanisms yield limited efficacy. As a core hallmark and driver of aging, immunosenescence provides a critical target for precision interventions. This systematic review examines the hallmarks of aging, including cellular damage, epigenetic abnormalities, and immunosenescence. It highlights immunotherapy strategies targeting senescent cells, including CAR-T/NK cell therapies, vaccines, and immune checkpoint blockade. These approaches have demonstrated significant efficacy in animal models by eliminating senescent cells and improving senescence phenotypes. Simultaneously, it analyzes current challenges such as insufficient target specificity, safety and cost concerns in cell therapies, and species differences. It also explores future directions including multi-target synergistic strategies, AI-assisted target screening, and the integration of precision medicine technologies. Immunotherapy offers a revolutionary paradigm for aging intervention, holding promise to extend healthy lifespan by regulating the immune system. However, further breakthroughs are needed for its clinical translation.

Senescent cells in systemic aging: SASP heterogeneity, immune escape, and endocrine modulation.

Louay Abo Qoura, Alexey V Churov, O N Maltseva +2 more

Aging is characterized by progressive loss of physiological resilience accompanied by increased susceptibility to chronic diseases. Among the interconnected hallmarks of aging, cellular senescence has emerged as a central driver of systemic inflammation through the senescence-associated secretory phenotype (SASP). Senescent cells accumulate across multiple tissues with advancing age and secrete complex mixtures of cytokines, growth factors, and proteases that reshape tissue microenvironments and propagate inflammatory signaling locally and systemically. Increasing evidence indicates that SASP composition is highly heterogeneous and depends on cell lineage, metabolic state, and the nature of the senescence-inducing stressor. Recent discoveries further demonstrate that inflammatory signaling in senescent cells is sustained by multiple nucleic acid-sensing pathways, including both cGAS-STING-dependent DNA sensing and mitochondrial RNA-mediated activation of RIG-I-like receptors. Concurrently, senescent cells deploy immune-evasion mechanisms that limit clearance by cytotoxic lymphocytes and natural killer cells, facilitating their persistence within aging tissues. Accumulation of senescent cells therefore represents a critical mechanistic link between molecular damage and the systemic inflammatory state known as inflammaging. This review synthesizes current understanding of tissue-specific SASP programs across immune, vascular, metabolic, hepatic, and neural systems. Particular emphasis is placed on mechanisms that amplify local senescence into organism-wide inflammation, including endocrine signaling, extracellular vesicle trafficking, and sex-dependent modulation of senescence pathways.

The common pathological network of inflammation, extracellular matrix imbalance, and senescence in intervertebral disc degeneration and osteoarthritis.

Wenbo Xie, Chao Song, Lei Yang +5 more

As representatives of degenerative orthopedic diseases, intervertebral disc degenerative disease (IVDD) and osteoarthritis (OA) involve the spine and peripheral articular cartilage, respectively. Their comorbidity rate in individuals over 60 years exceeds 40%, suggesting overlapping pathological and physiological features. Age-related "inflammaging" and cellular senescence, obesity-mediated mechanical load and metabolic disorders, and genetic/epigenetic abnormalities (e.g., COL2A1, ADAMTS5) constitute a shared risk factor network. Extracellular matrix (ECM) imbalance is a core initiating event: the MMPs/ADAMTS enzyme system, together with inflammatory cytokines such as IL-1β and TNF-α, drives excessive degradation of type II collagen and aggrecan, forming a "degradation-inflammation" positive feedback loop. In the chronic inflammatory microenvironment, damage-associated molecules activate TLR/NLRP3 pathways, triggering M1 macrophage polarization and Th17 cell infiltration, further disrupting ECM and inducing cell apoptosis. Cellular senescence releases pro-inflammatory mediators and degradation enzymes via the senescence-associated secretory phenotype (SASP). Abnormal mechanical loading exacerbates mechanobiological dysregulation through the integrin-YAP/TAZ signaling axis, while hypoxia/acidification-induced mitochondrial dysfunction creates a "mechanical-metabolic" double hit. Innate and adaptive immune cells recognize degenerated fragments and amplify local tissue damage. The interweaving of these mechanisms contributes to the comorbid progression of IVDD and OA through mechanical conduction, inflammatory diffusion, and neural sensitization. Importantly, we also discuss key differences between the two diseases, including the avascular nature of the intervertebral disc, the distinct roles of nutrient supply and disc herniation subtypes, and the etiological heterogeneity of OA across different joints. Future research should move beyond single-disease frameworks, analyze multi-tissue interactions from a systemic degeneration perspective, and develop combined strategies targeting senescent cell clearance, inflammatory blockade, and ECM repair. The concept of "spine-joint integrated diagnosis" - defined as concurrent evaluation of spinal and peripheral joint degeneration - is proposed to guide integrated management and improve clinical outcomes in comorbid patients.

Age- and sex-related glymphatic differences and hemispheric asymmetry in healthy adults at 7.0T magnetic resonance imaging.

Yumei Yue, Xiaocui Tang, Ting Shen +5 more

The glymphatic system plays a critical role in cerebral waste clearance and has been implicated in neurodegenerative and cerebrovascular disorders. However, normative variations in glymphatic structure and function across age, sex, and hemispheric organization in healthy adults remain incompletely characterized.

In Situ Engineered "Cascade-Amplified" Drug-Loaded Vesicles for Enhanced Cancer Stem Cell Therapy.

Tiantian Zhang, YuanYuan Wei, Zimai Liu +9 more

Cancer stem cells (CSCs) characterized by the capacity of self-renewal and drug resistance, are a major cause of tumour recurrence and metastasis. However, CSCs are mainly localized in the deep and hypoxic regions of the tumour microenvironment that hinder drug penetration. Furthermore, their overexpression of the CD24/Siglec10 immune checkpoint axis markedly suppresses immune clearance, severely limiting the efficacy of current therapeutic strategies. To address this challenge, this study developed an in situ engineered "cascade-amplified" drug-loaded vesicle delivery system, aiming to achieve deep drug delivery into CSC-enriched regions and enhance anti-tumour immune responses. Based on a biomimetic "core-shell" nanoplatform (siXkr8/Dox@PMLC), this system initiates a cascade within the TME where Doxorubicin (Dox) induces tumour cells to generate drug-loaded apoptotic bodies (ApoBDs). These ApoBDs serve as primary vesicles that, upon uptake by adjacent tumour cells, trigger secondary apoptosis, establishing a "cascade-amplified" cycle of enhanced drug delivery. Meanwhile, the silencing of the phospholipid scramblase Xkr8 via siRNA inhibits phosphatidylserine (PS) exposure on the surface of ApoBDs, thereby preventing their recognition and clearance by M2-type macrophages and facilitating immune phenotype remodelling. Furthermore, through targeted blockade of the CD24/Siglec-10 immune axis, the nanoplatform enhances macrophage-mediated phagocytosis of CSCs. In summary, this strategy achieves deep eradication of CSCs and synergistically enhances anti-tumour immunotherapy, demonstrating significant translational potential.

FMO1 disrupts mitochondrial functional homeostasis through ROS-mediated mechanisms to drive chondrocyte senescence and hypertrophy.

Ruohui Tang, Debin Guo, Shidan Li +6 more

The induced membrane technique is a clinical strategy for managing large bone defects, which relies on endochondral ossification. However, the metabolic mechanisms regulating this process remain largely uncharacterized. We utilized scRNA-seq to analyze chondro-osseous dynamics during membrane-induced osteogenesis, with a specific focus on the role of FMO1.

Dual-system engineered bacteria and dendritic cells enable precise intratumoral IL-12 delivery and potent antitumor immunity.

Yuan Deng, Heng Liang, Arabella H Wan +17 more

Interleukin-12 (IL-12) potently stimulates antitumor immunity, but its clinical use is limited by systemic toxicity and poor spatial control. Here, we develop a dual-engineered delivery system that combines Escherichia coli Nissle 1917 (EcN) programmed for hypoxia- and quorum-sensing-regulated IL-12 expression with engineered dendritic cells (eDCs) that facilitate bacterial delivery and immune support. In murine colorectal cancer and liver metastasis models, eDC-EcN-IL12-QS preferentially localizes to tumors, increases intratumoral IL-12 and IFN- γ levels, enhances dendritic cell activation and CD8+ T cell infiltration, and suppresses tumor growth and metastatic burden. The system also prolongs survival and remains controllable by antibiotic-mediated clearance. These findings support a programmable microbial-cellular strategy for localized cytokine delivery and immune activation in immunologically cold tumors.

Using iPSC models to examine neuron-glia interactions in neurodegenerative diseases.

Dianne M Lopez, Lois K Keavey, Kathryn R Bowles

Neurodegenerative diseases remain without effective or accessible treatments and interventions, despite their increasing global burden. Clinically, these disorders are characterised by progressive cognitive decline, behavioural changes, and loss of motor function, all of which are associated with neuronal and synaptic loss or dysfunction. Although traditionally viewed as neuron-centric, it is becoming increasingly clear that glial cells play critical roles in maintaining and regulating neuronal and synaptic health. Mounting evidence implicates glial dysregulation in both the onset and progression of neurodegenerative diseases through mechanisms such as aberrant synaptic engulfment and protein clearance, impaired homeostatic support, metabolic dysfunction, chronic inflammation, transmission of pathogenic proteins, and cellular senescence. Elucidating how disruptions in neuron-glia interactions contribute to neuronal dysfunction is therefore essential for developing effective therapies. Induced pluripotent stem cell (iPSC)-based models provide a powerful platform to investigate these interactions in human-relevant systems. Here, we will discuss recent insights into the mechanisms contributing to neurodegenerative disease that have been gained specifically from modelling neuron-glia interactions in human iPSCs.

Secretory form of viral protease NIa ameliorates amyloid-β pathology and cognitive deficits in a mouse model of Alzheimer's disease.

Euy Jun Park, Bo-Ram Mun, Sung Yoon Kim +4 more

Alzheimer's disease (AD), the leading cause of dementia, is characterized by extracellular amyloid-β (Aβ) accumulation. Immunotherapies targeting Aβ clearance show promise, highlighting the therapeutic value of enhancing Aβ removal. We previously identified that nuclear inclusion a (NIa), a plant viral protease, fortuitously cleaves Aβ with strict sequence specificity. Here, we engineered a secretory form, SecNIa, to degrade extracellular Aβ. SecNIa was efficiently secreted from transfected cells while retaining potent Aβ-cleaving activity. Adeno-associated virus (AAV)-mediated delivery of SecNIa into 5xFAD mice resulted in robust hippocampal expression and cerebrospinal fluid secretion. SecNIa expression significantly reduced soluble and insoluble Aβ, decreased hippocampal plaques, and improved cognition, fully normalizing recognition memory and enhancing spatial learning. These findings establish SecNIa as a promising therapeutic strategy to directly target pathogenic extracellular Aβ in AD.

Trehalase-trehalose axis in the human brain: A potential modulator of neuroprotection and neurodegeneration.

Kalle Keisu, Arttu Autio-Kimura, Johanna Mappes +1 more

Trehalase, the primary enzyme responsible for the degradation of gastrointestinal trehalose ("mushroom sugar"), is well-characterised in the human gut, but has not been conclusively identified in the human brain. Trehalose itself has shown promise in neuroprotection through diverse molecular mechanisms, including the autophagy-driven clearance of cellular debris and neurotoxic aggregates. However, the mechanisms activating trehalose and its integration into human central nervous system processes remain elusive. To investigate the modulatory role of trehalase in the trehalose-mediated neuroprotection, we analysed two independent RNA-seq datasets derived from post-mortem human brain tissue. Hypothesis testing of age- and multiple sclerosis-associated changes in trehalase gene expression revealed significant decrease in both aged donors and patients with multiple sclerosis compared to controls. Differential gene correlation analysis combined with pathway enrichment showed that trehalase-associated gene networks shift according to bimodal age segmentation, implicating pathways related to autophagy, mitophagy, oxidative phosphorylation, and neurodegeneration. Moreover, trehalase expression correlated positively with oligodendrocyte proportions in many brain regions and negatively with neuronal proportions in the hippocampus, suggesting cell-type-specificity. A robust positive association with sirtuin 1 expression further links trehalase to established neuroprotection. These results provide the first direct evidence of trehalase expression in the human brain and suggest that the trehalase-trehalose axis may function as a mediator of cellular homeostasis and neuroprotection in neurons and glia. Our results position trehalase as a candidate biomarker and modulator of trehalose-linked pathways in ageing and neurodegeneration, warranting future studies integrating both trehalase and trehalose profiling in paired samples.

Cellular senescence: from pathogenic mechanisms to precision anti-aging interventions.

Jian Deng, Ruipu Sun, Zhiyong Bai +3 more

For decades, research on cellular senescence has predominantly focused on the static identification of senescent cells using markers such as p16 and β-galactosidase, largely overlooking their functional heterogeneity across spatiotemporal dimensions. Accumulating evidence reveals that senescent cells are not merely deleterious pathological byproducts; rather, a subset plays indispensable physiological roles in embryonic development, wound healing, and the maintenance of tissue homeostasis. Based on these insights, this review summarizes the induction mechanisms of cellular senescence and the subsequent evolution of their functional phenotypes across diverse tissues. Consequently, we propose a novel paradigm for senescence management centered on "prevention first, followed by precision intervention." This strategy involves, on one hand, mitigating environmental stressors and optimizing metabolism to intercept the onset of detrimental senescence at its source. On the other hand, it advocates for the functional profiling of existing senescent populations via single-cell omics and lineage tracing, enabling the targeted clearance of "maladaptive" components that drive pathological phenotypes while preserving "beneficial" elements essential for physiological stability. Such a systematic intervention, grounded in the classification of induction factors and functional subtypes, offers a safer and more efficacious trajectory for the prevention of age-related diseases and the extension of healthspan.

Host immunosenescence compromises Mycobacterium tuberculosis clearance.

Falak Pahwa, Shweta Chaudhary, Ashish Gupta +2 more

Immunosenescence increases susceptibility to infectious diseases like tuberculosis (TB) in older adults (≥60 years) and hinder effective containment of Mycobacterium tuberculosis (Mtb) during therapeutic intervention. A comprehensive understanding of the cellular and molecular changes underlying age-associated immune alterations may inform development of strategies to improve treatment outcomes. Here, we monitored the immunopathology, frequency, and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with Mtb H37Rv and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks post infection, mycobacterial load in tissues (lung, spleen, and liver) of old (17-19 months; M) and aged (31M) C57BL/6 mice was similar to that of young (2-4M) mice. However, at two weeks post-treatment, older mice showed a slower rate of Mtb clearance in the lungs. Mtb-infected old mice had higher splenic T-follicular cytotoxic (TFC)-like cells, and proteomic analysis of flow-sorted CD4+CD44+ T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase, and prostaglandin E synthase), suggesting impaired mitochondrial function. Collectively, these findings suggest that age-associated immune alterations may disrupt immunometabolic pathways, thereby contributing to the delayed Mtb clearance. Targeting immunometabolic dysfunction therefore represents a promising strategy to enhance TB treatment efficacy and reduce disease burden in older populations.

Engulfment by brain macrophages in a short-lived vertebrate.

Rahul Nagvekar, Angela N Pogson, Prateek R Kalakuntla +20 more

Engulfment by macrophages is critical for waste clearance in the vertebrate brain. Understanding clearance mechanisms may open new therapeutic possibilities to counter brain aging and neurodegenerative diseases. However, few in vivo models exist to study engulfment in the brain and characterize this process during aging and across species. Here we present a genetic model for secretion of a fluorescent protein by neurons in the brain of the African turquoise killifish, the shortest-lived vertebrate that can be bred in captivity. We use this model to identify a population of brain macrophages in the killifish responsible for engulfment of material from the brain extracellular space. Intriguingly, many of these cells bear similarities to mammalian border-associated and monocyte-derived macrophages, rare subsets of macrophages in mouse and human brains noted for their engulfment capabilities. We also find that in our model, killifish brain macrophages decline in engulfment capacity with age. This work highlights how vertebrate brain macrophages, particularly those at brain border regions, can play a critical role in clearance and provides an opportunity to test interventions that can boost engulfment by these macrophages to promote brain resilience in old age and disease.

Mapping cardiac and respiratory pulsations simultaneously with functional connectivity in the rat brain using zero echo time fMRI.

Ekaterina Paasonen, Petteri Stenroos, Antonio Caulin Atienzar +8 more

Vascular pulsations are increasingly recognized as key contributors to cerebral perfusion and brain clearance mechanisms, with alterations linked to aging and neurodegenerative diseases. However, capturing fast physiological dynamics in preclinical models remains technically challenging due to high cardiac frequencies and small brain size. Here, we investigated the feasibility of zero echo time (ZTE) functional MRI (fMRI) to capture cardiac- and respiration-related pulsations across multiple temporal scales in the rat brain under isoflurane anesthesia. We used retrospective binning to assess cardiac- and respiration-related pulsations. Cardiovascular state was modulated with medetomidine, and functional connectivity analyses were performed to evaluate slower neural dynamics. ZTE fMRI robustly detected physiological pulsations across the brain, achieving effective temporal resolution of 8 ms, with the strongest signals observed in large arteries, consistent with an inflow‑based contrast mechanism. Cardiac pulsation amplitudes increased significantly under combined medetomidine-isoflurane anesthesia, whereas respiration‑related pulsations remained stable. Functional connectivity decreased under combined anesthesia, confirming ZTE fMRI sensitivity to slower neural dynamics. ZTE fMRI enables simultaneous assessment of cerebrovascular pulsatility and functional connectivity, providing a powerful tool for studying physiological brain dynamics in vivo.

The emerging role and therapeutic targeting of autophagy-lysosome pathway in the pathogenesis of Parkinson's disease.

Takahiro Shimizu, Sanem Isik, Nitika Kamath +1 more

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss and the accumulation of misfolded α-synuclein, yet the underlying mechanisms remain incompletely understood. Over the past two decades, genetic discoveries have highlighted the convergence of multiple familial PD genes on the autophagy-lysosome pathway (ALP), a key cellular system responsible for the degradation and recycling of intracellular components. Recent studies have further revealed that components of the ALP not only mediate the clearance of α-synuclein aggregates but also, under certain pathological conditions, contribute to their propagation via lysosomal exocytosis or secretory autophagy. The precise functions of autophagy are highly context-dependent, with neuronal and glial cells exhibiting distinct ALP dynamics that shift with development, stress, and aging. In this review, we summarize current knowledge on the physiological regulation of autophagy in the brain and critically examine its involvement in PD pathogenesis, incorporating mechanistic insights from familial models and emerging evidence from sporadic PD. We also explore translational implications, focusing on efforts to identify ALP-related biomarkers in cerebrospinal fluid and urine, and on the therapeutic potential of modulating ALP activity. Although the causality between ALP dysfunction and PD remains elusive, mounting evidence supports its contribution to disease progression, particularly through impaired lysosomal homeostasis and disrupted intracellular trafficking. Future research should aim to define cell type-specific ALP alterations, clarify the bidirectional interactions between α-synuclein and autophagic machinery, and develop in vivo tools to monitor autophagy activity and secretory signatures. A deeper understanding of these processes will be crucial for refining PD models, discovering robust fluid biomarkers, and designing targeted therapies capable of modifying disease trajectory.

Retraction notice to "Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome" [Biomedicine & Pharmacotherapy 174 (2024) 116447].

Ye Gao, Fei Cao, Xinyi Tian +12 more

Hepatic expression of APOE3 Christchurch mitigates APOE4-related Alzheimer's disease pathologies in mice.

Jin-Yi Tang, Qi Tan, Zhong-Yuan Yu +10 more

The ε4 allele of apolipoprotein E (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and exacerbates AD-related pathologies. Identifying strategies to mitigate the pathogenic effects of APOE4 remains a critical challenge in the field of AD research. The rare APOE3 Christchurch (APOE3Ch) variant has been suggested to be potentially protective against AD. Our study investigated whether hepatic expression of APOE3Ch could mitigate APOE4-associated AD pathologies. We successfully delivered APOE3Ch or APOE3 into the liver by adeno-associated virus in APP/PS1 mice expressing human APOE4. We observed that hepatic APOE3Ch delivery reduced amyloid-β (Aβ) burden in the brain. Hepatic APOE3Ch expression attenuated neuroinflammation, neurodegeneration, and cognitive impairments. Mechanistically, APOE3Ch expression increased the capacity of Aβ clearance by monocytes and hepatocytes. Our findings demonstrate that hepatic APOE3Ch expression attenuates AD-type pathologies in APOE4-expressing APP/PS1 mice, highlighting liver-directed APOE3Ch gene transfer as a promising therapeutic strategy for APOE4-associated AD.

Paeonol mitigates age-related osteoporosis via mitophagy-mediated NLRP3 inflammasome inhibition.

Jingliang Gu, Min Ma, Laiya Lu +4 more

Age-related osteoporosis, a progressive skeletal disorder inherent to aging, is pathologically defined by diminished bone mass and deteriorated bone microarchitecture, resulting in heightened skeletal fragility. Despite extensive research, effective therapeutic interventions for age-associated bone loss remain limited. Accumulating evidence indicates that aging-induced immune dysregulation contributes significantly to chronic low-grade inflammation, thereby exacerbating osteoporotic progression. In this study, we identify Paeonol (PAE) as a potent mitigator of senile osteoporosis, acting through the modulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome/mitophagy axis. We demonstrate that PAE ameliorates aging-induced bone loss in the NLRP3 inflammasome-dependent manner by enhancing mitophagic flux. Specifically, PAE facilitates the clearance of dysfunctional mitochondria, thereby suppressing NLRP3 inflammasome activation and subsequent inflammatory responses. Notably, pharmacological or genetic inhibition of mitophagy abrogates the protective effects of PAE, as evidenced by the attenuated suppression of NLRP3 inflammasome activation and the diminished preservation of bone mass in aged murine models. These findings highlight the critical interplay between mitophagy and NLRP3 inflammasome in age-related bone loss and suggest that PAE-mediated enhancement of mitochondrial quality control represents a promising therapeutic strategy for osteoporosis management.

Physical Therapy Intervention With Hippotherapy (HPOT) Affects Balance Control in the Elderly: A Randomized Controlled Trial.

Bita Bahrami Gholami, Ali Fatahi, Neda Boroushak +1 more

Aging is characterized by a decline in functional abilities, strength, balance, flexibility, agility, and coordination due to neurological and muscular changes. Hippotherapy (HPOT) has been recognized for its physical and psychological benefits for older adults. Hence, this study aimed to investigate the effects of hippotherapy on balance in elderly individuals. The novelty lies in using the Biodex Balance System SD for dynamic balance assessment in healthy elderly without neurological disorders.

Cellular senescence in skeletal muscle regeneration.

Xingyuan Liu, Huating Wang

Skeletal muscle possesses a remarkable capacity for regeneration, driven by the activation and proliferation of Pax7-positive muscle stem cells within a dynamic niche that includes immune cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and neural elements. Cellular senescence, a stress-induced program featuring stable cell-cycle arrest and the senescence-associated secretory phenotype (SASP), has emerged as a critical yet paradoxical regulator of this process. Accumulating evidence indicates that transient senescence, particularly in FAPs, macrophages, and other niche cells during acute muscle injury, plays a beneficial role in supporting muscle regeneration. These senescent cells promote cellular plasticity, enhance myoblast differentiation, facilitate phagocytic clearance of debris, and modulate inflammation and repair via timely SASP factor secretion. However, conflicting findings suggest that senescent cells exert detrimental effects, impairing regeneration by establishing a sustained pro-inflammatory and pro-fibrotic niche, especially when senescence persists in aged or dystrophic muscle. This review synthesizes the complex and contradictory roles of cellular senescence in skeletal muscle regeneration, underscores the distinction between transient pro-regenerative and persistent deleterious senescence, highlights the importance of cell-type-specific contributions, and emphasizes the need for precise characterization of senescent cell dynamics and fate. Resolving these discrepancies will be critical for developing targeted senotherapeutic strategies to enhance muscle regeneration in aging and degenerative diseases.

Targeting senescence mitigates the deleterious effects of midlife obesity on neurovascular function by partially restoring blood-brain barrier integrity and neurovascular coupling.

Sharon Negri, Madison Milan, Rakesh Rudraboina +17 more

Midlife obesity is a major risk factor for vascular cognitive impairment (VCI) and dementia, but the cellular mechanisms linking obesity to brain microvascular dysfunction remain unclear. Here, we show that high-fat diet (HFD)-induced obesity accelerates cellular senescence within the neurovascular unit (NVU), resulting in structural and functional microcirculatory deficits. Combining multimodal in vivo longitudinal imaging with single-cell RNA sequencing, we identify a senescence-associated transcriptional program in endothelial cells and neurons, coinciding with reduced brain microvascular density, impaired neurovascular coupling (NVC), and disruption of blood-brain barrier (BBB) integrity. These vascular abnormalities associate with cognitive decline in behavioral assays. Transcriptomic profiling further revealed cell-type-specific senescence signatures, including dysregulation of angiogenic, mitochondrial, and inflammatory pathways, which were alleviated by senescent-cell clearance. Notably, clearing p16+ senescent cells partially restored BBB integrity, improved NVC responses, and reduced neuroinflammation. Together, these findings identify cellular senescence as a mechanistic driver of midlife obesity-induced cerebrovascular and cognitive dysfunction and provide proof-of-concept that senescence-targeted therapies may preserve brain health in individuals with midlife obesity who are at risk for dementia.

Translational nanomedicine strategies for selective senescent cell clearance in aging and age-related diseases: a critical review.

Dilpreet Singh, Sankha Bhattacharya

Aging is driven by progressive cellular damage, dysfunction, and senescence, a therapeutically actionable contributor to chronic inflammation, tissue degeneration, and age-related disease. However, senolytic and senomorphic translation remains constrained by senescent-cell heterogeneity, narrow therapeutic windows, inconsistent exposure, limited tissue penetration, uncertain nanoparticle accumulation in poorly perfused aged organs, and the absence of definitive clinical efficacy. Nanomedicine should therefore be viewed not as generic drug packaging, but as a strategy to improve the senolytic index through controlled exposure, multi-step selectivity, intracellular delivery, and context-responsive release. This review critically evaluates lipid-based, polymeric, hybrid, and biomimetic nanoplatforms by asking whether they improve target engagement, functional recovery, and safety over free drugs, rather than merely increasing encapsulation efficiency or in vitro cytotoxicity. Emphasis is placed on assay-aware interpretation of quantitative claims, limitations of single-marker targeting, variability of EPR-like behavior in aging tissues, manufacturability, and regulatory readiness. Overall, nanomedicine-based senotherapy is highly promising but not yet clinically de-risked; meaningful progress will require disciplined biology-to-design integration, human-tissue validation, and rigorous benchmarking against clinically relevant outcomes.

Research Hotspots and Emerging Frontiers in Ovarian Aging: A Bibliometric Analysis (2006-2025).

Qingquan Gong, Wenhong Ma, Chao Yang +4 more

Ovarian aging has a critical impact on women's fertility and overall health. This study uses bibliometric methods to analyze the current state of research in the field of natural ovarian aging and to identify emerging trends.

Ultraviolet irradiation-induced enhancement of inflammatory potential of polystyrene nano- and microplastics and effects of dispersion on lung clearance.

Yeonjeong Ha, Jun Hui Jeon, Eunsol Bae +7 more

Microplastics are pervasive environmental pollutants that pose potential risks to human health, particularly through inhalation. Despite growing concerns, limited data exist on how environmental aging, such as ultraviolet (UV) irradiation, affects the pulmonary toxicity of inhaled nano- and microplastics. This study evaluated the influence of UV-driven surface oxidation on the inflammatory potential and lung clearance kinetics of polystyrene (PS) particles. Spherical PS particles (50, 200, and 400 nm) were synthesized, selectively oxidized by UV irradiation, and thoroughly characterized for surface chemistry and intrinsic reactive oxygen species (ROS) generation.

Vascular Aging.

Ruoqi Wang, Stephen Y Chan, Toren Finkel

Vascular aging is a central determinant of healthy life span, not only influencing the susceptibility to cardiovascular diseases but also shaping the risk of systemic decline across multiple organs. It is driven by a variety of age-related factors, including cellular senescence, chronic inflammation, loss of proteostasis, mitochondrial dysfunction, genomic instability, epigenetic remodeling, and stem cell exhaustion. These processes interact with the unique mechanical and metabolic environment of the vasculature to create a distinctive pathological trajectory, manifested in part as arterial stiffening, impaired barrier integrity, and dysregulated vasomotor control. Recent advances in single-cell omics and cross-organ molecular clocks have revealed the heterogeneity and organ specificity of aging, underscoring the need for integrative frameworks that connect vascular biology with overall health. Meanwhile, the development of diverse therapeutic strategies-ranging from senolytic and immune-mediated clearance to metabolic and mitochondrial interventions-highlights the translational potential of targeting the aging vasculature. Looking ahead, multimodal biomarkers and precision medicine may transform vascular aging from an inevitable process into a modifiable determinant of health span.

Bacterial Extracellular Vesicles in Aging: Mechanisms and Therapeutic Prospects.

Junfei Tan, Muhammad Zubair, Lin Zhang +5 more

Bacterial extracellular vesicles (bEVs) are increasingly recognized as critical mediators of gut-host interactions; however, their specific role in the aging process remains obscured by fragmented data and disease-specific silos. Current understanding lacks a cohesive mechanism that explains how age-related physiological changes transform bEVs from commensal signals into systemic drivers of pathology. This review synthesizes disparate findings to elucidate a synergistic mechanism: aging compromises intestinal barrier integrity, facilitating bEV translocation, while simultaneously impairing immune clearance capabilities (e.g. loss of Vsig4+ Kupffer cells), leading to their toxic accumulation. We resolve conflicting reports on bEV functionality-such as the paradoxical pro-calcific effects of Lactobacillus rhamnosus GG-derived vesicles in chronic kidney disease-by contextualizing them within the host's aging microenvironment. Beyond mapping these interactions across the gut-brain, metabolic, cardiovascular, and bone axes, we identify specific cargo molecules, such as lipopolysaccharide (LPS), curli, and bacterial DNA, that fuel inflammaging. However, translating these insights into therapeutic applications faces significant challenges, including methodological heterogeneity in isolation protocols and unresolved immunogenicity risks. By outlining a strategic roadmap for standardization and rigorous clinical validation, this study redefines bEVs not merely as biomarkers but as actionable targets for delaying aging and mitigating age-related diseases.

Altered cerebrospinal fluid-based clearance mechanisms in aging autistic adults.

Danielle Christensen, Giuseppe Barisano, Bradley J Wilkes +8 more

Autistic adults demonstrate a 4-6-fold increased risk of unspecified dementia compared with the general population; however, the neurobiological substrates underlying this elevated risk remain unexplored. Alterations in cerebrospinal fluid-based mechanisms involved in brain metabolic waste clearance may represent a shared neuropathological pathway between autism spectrum disorder and dementia. Specifically, developmental deviations in cerebrospinal fluid-related imaging markers have been consistently reported in autistic infants, children, and adolescents, and brain amyloid and other metabolic waste accumulation is a hallmark of Alzheimer's disease and related dementias. Despite this overlap, cerebrospinal fluid-based regulatory mechanisms have not been systematically examined in ageing autistic adults. Here, we used a multimodal magnetic resonance imaging approach to quantify structural and diffusion-based markers of cerebrospinal fluid regulation in middle-aged and older autistic adults compared with matched controls.

A composite measure of cerebral small vessel disease predicts cognitive change after stroke.

Mahir H Khan, Stuti Chakraborty, Octavio Marin-Pardo +15 more

Post-stroke cognitive recovery is difficult to predict using focal lesion characteristics alone. The brain's capacity to maintain cognitive function depends also on structural integrity of the whole brain. One way to measure brain health is through the severity of cerebral small vessel disease (CSVD) markers, which reflect aging-related pathologies that erode structural integrity. Here, we propose a composite measure of CSVD (cCSVD) integrating three independently validated biomarkers automatically quantified using T1-weighted MRIs: white matter hyperintensity volume (WMH; representing vascular injury), perivascular space count (PVS; putative glymphatic clearance), and brain-predicted age difference (brain-PAD; structural atrophy). We hypothesize that cCSVD, which captures the shared variance across these CSVD biomarkers, will be a robust indicator of whole-brain structural integrity and predict cognitive changes 3 months after stroke. We analyzed 65 early subacute stroke survivors with assessments within 21 days (baseline) and at 90 days (follow-up) post-stroke. WMH volume, PVS count, and brain-PAD were quantified from baseline T1-weighted MRIs, and then residualized for age, sex, days since stroke, and intracranial volume. Principal component analysis (PCA) of the residualized biomarkers was used to derive cCSVD. Beta regression with stability selection using LASSO was used to model three outcomes: baseline Montreal Cognitive Assessment (MoCA) scores, follow-up MoCA scores, and longitudinal change (follow-up score adjusted for baseline score). Logistic regression was used to test if baseline cCSVD predicted improvement in those with baseline cognitive impairment (MoCA < 26). The PCA revealed that the first principal component (PC1) explained 43.1% of the total variance among WMH volume, PVS count, and brain-PAD. The three biomarkers contributed nearly equally to PC1, which was subsequently used as the baseline cCSVD score. Lower baseline cCSVD was significantly associated with better MoCA scores at follow-up (β = -0.19, p = 0.009), even after adjusting for baseline MoCA (β = -0.12, p = 0.042), and, importantly, outperformed all individual biomarkers. Furthermore, lower cCSVD at baseline significantly increased the likelihood of improving to cognitively unimpaired status at three months (OR = 0.34, p = 0.036), independent of age and education. The composite CSVD captures the additive impact of vascular injury, glymphatic dysfunction, and structural atrophy on recovery in a way that individual measures do not. cCSVD accounts for shared variance across these domains, reflecting a patient's latent capacity for cognitive recovery, where relative integrity in one CSVD domain may mitigate effects of another. This automated, T1-based framework offers a scalable tool for predicting post-stroke recovery.

The Role of Cellular Senescence in Obstructive Airway Diseases: From Mechanisms to Therapeutic Targets.

Argyro Vrouvaki, Marina Moustaka Christodoulou, Georgios Hillas +2 more

Cellular senescence is a stress-induced type of irreversible cell cycle arrest, driven by telomere attrition, oxidative stress, DNA damage, mitochondrial dysfunction, oncogene activation, and chronic inflammation. Senescent cells remain metabolically active, secreting cytokines, chemokines, growth factors, matrix metalloproteinases, extracellular vesicles and oxidative mediators, comprising a senescence-associated secretory phenotype (SASP) that affects the tissue microenvironment. With aging, impaired immune clearance results in senescent cell accumulation, promoting inflammation, immunosuppression and fibrosis. Emerging evidence implicates cellular senescence in obstructive airway diseases, reflecting the lung's continuous exposure to environmental and oxidative insults, and several pathways, including DNA damage response and p53/p21 and p16INK4a signaling, telomere dysfunction, reactive oxygen species production, and mitochondrial defects, integrate stress signals to enforce senescence. In chronic obstructive pulmonary disease, a SASP-associated inflammatory milieu supports stress-induced tissue injury, while uncertainty still exists about the effects of chronic SASP on tumor suppression versus tumor promotion. In asthma, senescence processes have been associated with both Type(T)2-high and T2-low endotypes, underlying the interplay between environmental exposures, airway epithelial dysfunction and induced senescence mechanisms. Finally, in bronchiectasis, the neutrophilic, dysbiotic airway environment links dysregulated senescence with disease persistence and progression. Conventional therapies, antioxidants, serine protease inhibitors and novel senotherapeutic strategies represent promising approaches for therapeutic interventions.

Association between epilepsy duration and glymphatic dysfunction assessed by DTI-ALPS: A systematic review and meta-analysis.

Su Ji Lee, Soomi Cho, Hui Jin Shin +2 more

To systematically evaluate whether epilepsy duration is associated with glymphatic dysfunction as measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS).

Combination of Ophiopogonin D, Ginsenoside Rg1, and Ginsenoside Rg3 ameliorates idiopathic pulmonary fibrosis via inhibiting type 2 alveolar epithelial cell senescence and epithelial-mesenchymal transition.

Jiang Zhu, Kai Gong, Mengzhen Xu +7 more

Idiopathic pulmonary fibrosis (IPF) represents a chronic, non-reversible, and irreversible interstitial lung disease with the lack of curative interventions and a poor prognosis; identifying safe and effective therapeutic agents is of paramount importance. The Ophiopogon-Ginseng herb pair, a classical traditional Chinese medicine (TCM), exerts Qi-replenishing and Yin-nourishing effects. Its active constituents Ophiopogonin D (OP-D), Ginsenoside Rg1 (Rg1), and Ginsenoside Rg3 (Rg3) have individual anti-fibrotic potential, while their synergistic effects in IPF remain to be elucidated. This study aimed to explore how OP-D-Rg1-Rg3 attenuates IPF and to clarify its possible molecular mechanisms. Bleomycin (BLM)-induced cellular senescence and transforming growth factor-β1 (TGF-β1) induce epithelial-mesenchymal transition (EMT) in A549 cells. MTT assay and RSM determined the optimal combination ratio. Cellular senescence and EMT were assessed by SA-β-Gal staining, RT-qPCR, WB, and ELISA. An IPF mouse model was established by intratracheal BLM administration, followed by treatment with the optimized OP-D-Rg1-Rg3 combination, pirfenidone (PFD), or saline for 21 days. Pulmonary structural alterations and molecular changes were then evaluated by micro-CT, HE, Masson, and molecular analyses. The results showed that the synergistic OP-D-Rg1-Rg3 combination markedly attenuated A549 cell senescence, as evidenced by reduced SA-β-Gal activity and decreased expression of p53, p21, p16, and TGF-β1-induced EMT (upregulated E-cadherin, downregulated vimentin, fibronectin, Col-I). In vivo, the combination alleviated AEC2s senescence and pulmonary EMT, improved mouse body weight and lung morphology, reduced histopathological damage, and attenuated IPF. In conclusion, the OP-D-Rg1-Rg3 combination ameliorates IPF by inhibiting AEC2s senescence and EMT, highlighting promising clinical application prospects for IPF treatment.

Optimizing Georgia's public health workforce: a study on demographics, engagement, and capacity building.

Smriti Ridhi, Binita Adhikari, Ekaterine Cherkezishvili +4 more

A well-functioning public health system relies on a robust workforce. Comprehensive data on the workforce, such as number, distribution, and key characteristics, are crucial for evidence-based workforce planning and development. However, few comprehensive public health workforce assessments exist, especially in low- and middle-income countries. Public health reforms over the years and needs identified during the COVID-19 pandemic prompted this assessment in Georgia.

Senescence dynamics define therapeutic windows for Duchenne muscular dystrophy in DBA/2-mdx mice.

Aina Calls-Cobos, Aida Beà Tàrrega, Andrés Cisneros +17 more

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder marked by progressive muscle degeneration and regeneration, inflammation and fibrosis. Cellular senescence has emerged as a potential driver of chronic muscle damage, yet its temporal dynamics and therapeutic relevance remain unclear.

The central role of macrophages in skeletal muscle regeneration: Phenotypic Polarization, metabolic reprogramming, and therapeutic prospects.

Ruiqi Liu, Yuntian Shen, Yutong Wei +5 more

Macrophages are central regulators of skeletal muscle regeneration, dynamically transitioning from pro-inflammatory (M1-like) to reparative (M2-like) phenotypes to coordinate debris clearance, inflammation modulation, satellite cell activation, and tissue remodeling. This review details the underlying molecular mechanisms, focusing on metabolic reprogramming, such as the shift to oxidative phosphorylation and key roles of AMPK, lactate, and glutamine metabolism. It further examines the transcriptional networks (e.g., PPARγ, Nfix) and multicellular crosstalk that shape the regenerative niche. We analyze macrophage dysfunction in pathological contexts: aging-related impairments in dynamics and metabolism that hinder repair, and in Duchenne Muscular Dystrophy (DMD), where sustained inflammation and trained immunity drive fibrosis. Current challenges include deciphering macrophage heterogeneity beyond the M1-like/M2-like paradigm and bridging translational gaps between models and human disease. The review outlines therapeutic strategies to reprogram macrophage function, spanning pharmacological agents (AMPK/PPARγ agonists, cytokine/chemokine modulation), nanotechnology, cell therapies (e.g., exosomes), and physical interventions. A key feature is the integration of molecular docking analyses, revealing structural interactions between compounds (e.g., AICAR, Cenicriviroc) and targets like AMPK, PPARγ, CCR2, and CCR5. This provides a structural pharmacology foundation for developing targeted immunometabolic therapies to restore muscle regeneration in injury and degenerative diseases.

Meeting report: Translating exercise research in dystrophinopathy to the clinic.

Donovan J Lott, Tina Duong, Rachel Schrader +2 more

To integrate current evidence and expert consensus on safe, effective exercise prescription in Duchenne and Becker muscular dystrophy (DMD/BMD), translating key pathophysiological principles into practical clinical guidance.

Aging-Associated CCL8+ Senescent Macrophages Recruit CCR1+ Neutrophils to Promote NETs Formation and Impair Meningeal Lymphatic Drainage.

Ye Yuan, Ruoli Wang, Qiuguang He +11 more

Meningeal lymphatic vessels (mLVs) are essential for central nervous system (CNS) waste clearance and brain homeostasis, yet their functional decline during aging remains poorly understood. Here, through integrated single-cell and bulk transcriptomic analyses, we identify a distinct macrophage subset characterized by high CCL8 expression (CCL8⁺ macrophages) that accumulates in aged meninges and exhibits a pronounced senescence-associated secretory phenotype (SASP). Trajectory analysis positions CCL8⁺ macrophages at a senescence-associated terminal differentiation state. Mechanistically, CCL8⁺ macrophages engage in pro-inflammatory crosstalk with neutrophils via the CCL8-CCR1 axis, promoting aberrant neutrophil recruitment and excessive neutrophil extracellular traps (NETs) formation within meningeal lymphatic niches. These NETs structurally and functionally impair meningeal lymphatic drainage. Importantly, pharmacological inhibition of CCR1 with BX471 or enzymatic degradation of NETs with DNase I restores meningeal lymphatic function and ameliorates spatial learning and memory deficits in aged mice. Notably, CCR1 antagonist BX471 has previously been evaluated in early human clinical trials and shown favorable tolerability, supporting the translational feasibility of targeting this pathway. In addition, machine learning approaches identify a robust predictive gene signature associated with this senescent macrophage phenotype. Collectively, our findings reveal a previously unrecognized macrophage-neutrophil-NETs axis that links meningeal immunosenescence to meningeal lymphatic dysfunction and cognitive decline and may represent a promising therapeutic target for aging-related neurodegenerative disorders.

Targeting Meningeal Lymphatic Vessels to Advance Stroke Therapy.

Yang Liu, Xiansheng Liu, Shihao Lin +7 more

Meningeal lymphatic vessels (mLVs) have recently emerged as pivotal regulators of central nervous system homeostasis, orchestrating cerebrospinal fluid (CSF) drainage, metabolic waste clearance, and neuroimmune surveillance at the brain and meningeal interface. Stroke, ischemic or hemorrhagic, exerts profound functional insults on mLVs, disrupting clearance pathways. These disturbances not only exacerbate acute edema and neuroinflammation but also dictate long-term outcomes, including post-stroke cognitive decline. In this review, we synthesize current understanding of mLVs anatomy and physiology, emphasizing their dynamic remodeling after stroke. We further examine the context-dependent immune functions of mLVs, and their role in shaping post-stroke brain injury and repair. In addition, we discuss emerging therapeutic strategies targeting the glymphatic-lymphatic axis and outline key translational challenges. Although these findings support a framework in which impaired fluid clearance contributes to stroke pathophysiology, most mechanistic insights derive from preclinical models, and direct evidence in human stroke remains limited. Accordingly, therapeutic implications should be interpreted with caution and require rigorous clinical validation.

Nanotherapeutic Strategies for Osteoarthritis: Targeting Aging, Metabolism and Inflammation.

Zhenglin He, Yimeng Chen, Kai Zhao +6 more

Osteoarthritis (OA) is no longer viewed as a mere "wear-and-tear" disease, but rather as a multifactorial joint failure syndrome driven by cellular senescence, metabolic dysregulation, and low-grade chronic inflammation. These pathological pillars synergistically disrupt cartilage homeostasis, subchondral bone remodeling, and synovial inflammation, collectively fueling disease progression. While conventional therapies offer only symptomatic relief, they fail to reverse or reprogram the underlying pathological microenvironment. Consequently, there is an urgent need to develop disease-modifying interventions that can simultaneously target these pathological pillars. Here, we critically examine how nanomaterial-based platforms-leveraging tailorable surface chemistry, cartilage-penetrating dimensions, and stimuli-responsive cargo release-enable precision targeting of these interconnected mechanisms. We highlight advances in senolytic delivery for senescent cell clearance, redox-modulating nanozymes for metabolic reprogramming, and immunoregulatory strategies for macrophage repolarization, emphasizing designs that transcend passive drug delivery to actively remodel the joint microenvironment. By integrating mechanistic insights with engineering innovation, this review outlines a roadmap for next-generation disease-modifying nanomedicines that promise not merely to slow OA progression, but to restore the biological clock of the joint. We also discuss current translational barriers and propose future directions for personalized OA therapy.

Noninvasive Estimation of Left Ventricular End-Diastolic Pressure Through a Mechanical Seal for a Rotary Blood Pump.

Daisuke Ogawa, Tadashi Motomura, Yasuyuki Shiraishi +5 more

Left ventricular end-diastolic pressure (LVEDP) is an important index of cardiac preload and heart failure (HF) severity. However, direct measurement of LVEDP requires invasive procedures, including local anesthesia and catheter insertion. To address these limitations, we developed a novel LVEDP estimation method based on the relationship between left ventricular pressure and the behavior of the mechanical seal (MS). In this study, we demonstrate that LVEDP can be estimated by measuring pressure inside the MS.

Retinal Pigment Epithelium Ageing: Cellular and Molecular Mechanisms of Long-Term Homeostasis and Age-Related Dysfunction.

Yijing Yang, Pei Liu, Jiangwei Li +4 more

The retinal pigment epithelium (RPE) is a long-lived, highly polarised epithelial monolayer that performs essential functions in retinal homeostasis, including outer blood-retina barrier maintenance, visual cycle activity, metabolic exchange, phagocytic clearance of photoreceptor outer segments, and regulation of oxidative and immune balance. Because RPE cells persist for decades under conditions of sustained oxidative, metabolic, and phagocytic stress, this tissue provides a valuable model for examining how long-lived post-mitotic cells preserve function over time and how age-related dysfunction emerges when that balance weakens. Although much of the current literature on RPE ageing has been shaped by age-related macular degeneration (AMD), age-dependent change in the RPE should not be understood solely as a preclinical stage of disease. Rather, the ageing RPE offers a broader framework for studying cellular maintenance under chronic physiological load. In this review, we synthesise current evidence on RPE ageing across four interrelated domains: structural remodelling, mitochondrial and metabolic imbalance, proteostatic and lysosomal burden, and chronic inflammatory dysregulation. Across these processes, ageing in the RPE is expressed less as widespread cell loss than as progressive decline in cellular organisation, buffering capacity, and functional precision. Structural irregularity, altered mitochondrial regulation, incomplete degradative clearance, and persistent low-grade inflammatory signalling together reduce the ability of the RPE to maintain long-term homeostasis and increase vulnerability to age-related retinal dysfunction. We further argue that ageing in the RPE is best understood not as abrupt failure of isolated pathways, but as gradual loss of system coherence among interacting homeostatic systems that remain active while operating under increasing constraint. This view helps integrate diverse cellular and molecular findings and highlights the RPE as an informative model for understanding ageing in long-lived post-mitotic tissues.

Immunosenescence and Inflammaging as Drivers of Neurodegeneration: Cellular Mechanisms, Neuroimmune Crosstalk, and Therapeutic Implications.

Gianmarco Bertoni, Sara Ristori, Daniela Monti

Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood-brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases.

The senescent niche hypothesis: microglial dysfunction and replacement strategies in drug-resistant epilepsy.

Jingheng Wu, Miaomiao Li, Yetong Shi +1 more

Epilepsy is one of the most prevalent neurological disorders, affecting over 70 million individuals worldwide. However, despite the introduction of more than 30 anti-seizure medications over three decades, approximately 30% of patients continue to suffer from drug-resistant epilepsy (DRE). Here, we advance the "Senescent Niche Hypothesis," proposing that the epileptogenic focus in DRE harbors a pathological accumulation of senescent microglia that have lost homeostatic surveillance capacity and acquired a toxic secretory phenotype. We present the "Iron-Senescence Axis" as the mechanistic driver: recurrent seizure-induced blood-brain barrier disruption leads to chronic parenchymal iron deposition; microglia accumulate iron through erythrophagocytosis and sustain sub-lethal ferroptotic stress-characterized by lipid peroxidation, mitochondrial dysfunction, and DNA damage-that drives their irreversible transition to a senescent state rather than acute cell death. Once senescent, these microglia paradoxically acquire resistance to ferroptosis through lysosomal iron sequestration, occupy the niche indefinitely, and perpetuate epileptogenesis via the senescence-associated secretory phenotype (SASP), establishing a positive feedback loop. Converging transcriptomic and experimental evidence from both human surgical specimens and rodent models substantiates this framework, demonstrating that senolytic clearance of senescent cells significantly reduces seizure burden and can prevent epilepsy development. Building on these findings, we evaluate two complementary therapeutic strategies: senolytic therapy using dasatinib plus quercetin (D+Q) for selective elimination of senescent cells, and the Microglial Intervention Strategy for Therapy and Enhancement by Replacement (MISTER) for comprehensive niche reconstitution through CSF1R inhibitor-mediated microglial depletion followed by donor cell engraftment. We critically assess donor cell sources, advances in non-genotoxic conditioning, and CSF1R-inhibitor resistant donor cells that may enable clinical translation. This synthesis argues that targeting the senescent microglial niche may represent a disease-modifying approach that shifts the therapeutic focus from seizure suppression to neuroimmune niche restoration.

Pink1 at the crossroads of aging, exercise, and diet in Parkinson's disease: a mechanistic review.

Ying Lin, Deng-Tai Wen

Pink1 (PTEN-induced kinase 1) is a key guardian of mitochondrial quality via mitophagy; its mutations are tightly linked to early-onset PD. This review synthesizes how aging, exercise, and high-fat diet (HFD) modulate Pink1 activity and thereby PD risk. Aging down-regulates Pink1, impairing clearance of damaged mitochondria and promoting α-synuclein aggregation. Exercise up-regulates Pink1-Parkin signaling, enhances PGC-1α and brain-derived neurotrophic factor (BDNF), and protects dopaminergic neurons in humans and rodents. Conversely, chronic HFD suppresses Pink1, exacerbates oxidative stress, microglial activation and insulin resistance, accelerating Parkinson's disease pathology. Cross-species cautions (mouse vs. primate) are highlighted. Targeting Pink1-mediated mitophagy through lifestyle interventions offers a non-pharmacological strategy to delay PD onset and progression in aging populations.

The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease.

Victoria Pozzi-Ruiz, Aida Giner de Gracia, Liliane Glauser +10 more

There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD. OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.

CD47 inhibiting antibody alleviates brain injury after intraventricular hemorrhage in aged rats.

Fenghui Ye, Jianru Li, Yingfeng Wan +4 more

Intraventricular hemorrhage (IVH) is a major contributor to acute brain injury and post-hemorrhagic hydrocephalus, especially in older adults. CD47 on erythrocytes delivers a "don't-eat-me" signal that inhibits macrophage/microglia (M/MΦ) mediated phagocytosis, slowing hematoma resolution. While CD47 blockade enhances hematoma clearance after IVH in young animals and in intracerebral hemorrhage models, its therapeutic potential in aged IVH has not been examined.

The joint association of intrinsic capacity and physical activity with cardiovascular risk in older adults: evidence from four longitudinal cohorts.

Zhengqiu Zhang, Ziyin Liu, Feng Ye +8 more

Immunosenescence and Inflammaging: From Pathological Hallmarks to Rejuvenation Strategies.

Yaoli Hou, Zhiying Zeng, Sheng He +8 more

Immunosenescence-the age-related decline of immune function-drives a state of chronic, sterile inflammation termed inflammaging. Far from passive deterioration, this process is actively orchestrated by distinct but interconnected hallmarks: erosion of lymphoid organs, myeloid-biased hematopoiesis, accumulation of immune-evasive senescent cells, and metabolic-epigenetic reprogramming that locks cells into dysfunctional states. These core nodes form a self-perpetuating cycle that propagates pathology across multiple organ systems, fueling neurodegeneration, cancer, musculoskeletal decline, and gut dysbiosis. Critically, the field has transitioned from descriptive phenomenology to mechanism-based intervention. This review synthesizes emerging therapeutic strategies targeting specific nodes of the immunosenescence network. We examine senotherapeutics that sensitize senescent cells for immune clearance, HSC and thymic rejuvenation to restore lymphocyte production, and metabolic-epigenetic interventions to correct intracellular deficits. By integrating these insights, we propose a precision medicine framework that moves beyond broad immunosuppression toward rational combinatorial regimens. This roadmap aims to decouple protective immunity from pathological drivers, extending healthspan and redefining the paradigm of geriatric care.

Mechanistic Insights Into OSM and IL-31 in Primary Localized Cutaneous Amyloidosis: A Narrative Review.

Yi Teng, Xingli Zhou, Yue Xiao +3 more

Primary localized cutaneous amyloidosis (PLCA) is a chronic pruritic dermatological disorder characterized by amyloid deposits in the papillary dermis, significantly impairing patients' quality of life. Although the pathogenesis of PLCA is multifaceted, emerging evidence highlights the pivotal role of dysregulated cytokines, particularly the members of interleukin-6 (IL-6) cytokines family in PLCA. Oncostatin M (OSM) mediates keratinocyte proliferation through the STAT5-KLF7 axis upon OSMRβ engagement. Pathogenic variants in OSMR disrupt receptor dimerization, thereby suppressing signal transduction. These alterations together with cytokine dysregulation concomitantly elevate the expression of AHNAK and suppress that of Bcl-xL, which accelerate keratinocyte differentiation and apoptosis respectively, leading to the thickening of the stratum corneum and amyloid fibril deposition. Furthermore, dysregulated expression of chemokine monocyte chemoattractant protein-1 (MCP-1) by pathogenic variant in IL-31RA reduces monocyte-mediated clearance of amyloid fibrils, thereby promoting their pathological retention. The mechanisms of IL-31-mediated pruritus remain to be elucidated, given the conflicting observations that while some studies report wider cutaneous innervation in FPLCA patients, others demonstrate opposing results in general lichen amyloidosis patients. This review aims to synthesize recent advances in understanding PLCA pathogenesis with a focus on IL-31 and OSM cytokines network dysregulation especially driven by pathogenic variants, and provide critical insights for identifying therapeutic targets and put forward challenges in the future.

The sleeping threat: targeting cancer dormancy to transform metastasis therapy.

Julio A Aguirre-Ghiso, Jose Javier Bravo-Cordero, Wenjun Guo +2 more

Metastatic cancer cell dormancy, wherein disseminated cancer cells (DCCs) persist in a quiescent state before reactivating to fuel metastasis, has emerged as a critical determinant of cancer relapse. In this Review, we synthesize recent advances in understanding the microenvironmental drivers of dormancy, including the role of niche-derived signals and extracellular matrix composition in maintaining DCC quiescence, as well as the epigenetic and transcriptional programmes, and chromatin remodelling that enforce and sustain dormancy. We also cover the mechanisms by which dormant DCCs evade immune surveillance, highlighting both innate and adaptive immune interactions, and the strategies tumours use to escape immune-mediated clearance. Although most data come from solid cancers, we also examine the biology of residual cells in haematologic malignancies that share key dormancy and relapse mechanisms with solid tumours. We also discuss how, despite these mechanistic insights, clinical translation remains limited, as available biomarkers or therapies targeting dormancy have yet to be effectively implemented. We conclude that by outlining the challenges and opportunities for leveraging dormancy biology, we may be able to prevent metastatic recurrence and improve patient outcomes.

Targeting the FOXO4-p53 axis by retro-inverso peptide senolytic agents: a pharmacological strategy to mitigate brain aging and cognitive decline.

Ayman Ali Mohammed Alameen, Hayder M Al-Kuraishy, Mohamed N Fawzy +1 more

Cellular senescence, driven by the interaction between FOXO4 and p53, is increasingly recognized as a crucial mechanism in brain aging and the development of neurodegenerative disorders. The senolytic peptide FOXO4-DRI, which has been thoughtfully designed, selectively disrupts the FOXO4-p53 complex, inducing apoptosis in senescent cells while preserving healthy tissue. In aged mammalian models, administering FOXO4-DRI decreases the accumulation of senescent cells, restores cerebral blood flow and the integrity of the blood-brain barrier (BBB), reverses hippocampal atrophy, and enhances cognitive function. Furthermore, in models of Alzheimer's disease (AD) and tauopathy, this intervention eliminates amyloid-β and pathological tau, leading to improved memory performance. Preliminary human studies involving FOXO4-axis modulators, such as high-dose fisetin, show a reduction in the senescence-associated secretory phenotype (SASP) and enhancements in cognitive and physical measures among older adults. These findings collectively identify the FOXO4-p53 axis as a potential pharmacological target in brain aging and highlight senolytic therapy as a promising strategy for altering diseases to postpone or reverse age-related cognitive decline. This review consolidates recent findings indicating that FOXO4-dependent senescence significantly contributes to neuroinflammation, synaptic dysfunction, and impaired neurogenesis in the aging brain.

Glymphatic System Dysfunction in Epilepsy: Clinical and Translational Perspectives.

Dong Ah Lee, Ho-Joon Lee, Kang Min Park

Epilepsy has traditionally been viewed as a disorder involving neuronal hyperexcitability and brain network dysfunction. However, growing evidence indicates that recurrent seizures are associated with widespread disturbances in brain homeostasis, including metabolic stress, neuroinflammation, vascular dysregulation, and sleep disruption. These processes extend beyond neurons and involve brain-wide clearance mechanisms that have received limited attention in epilepsy research. The glymphatic system is a specialized pathway that facilitates cerebrospinal fluid-interstitial fluid exchange and promotes the clearance of metabolic waste and neurotoxic solutes from the brain. Glymphatic transport depends on astrocytic aquaporin-4 channels and is strongly modulated by sleep-wake state, which is highly relevant to epilepsy given the close bidirectional relationship between seizures and sleep disturbances. Impaired glymphatic clearance has been linked to protein accumulation, neuroinflammation, and cognitive decline during aging and in neurodegenerative diseases, suggesting that similar mechanisms may contribute to epilepsy-related disease progression. In this review, we summarize current knowledge of glymphatic anatomy and physiology, focusing on advances in neuroimaging. We then synthesize emerging evidence demonstrating glymphatic dysfunction across multiple epilepsy syndromes. We discuss the clinical implications of impaired cerebral waste clearance for disease burden, treatment outcomes, and cognitive dysfunction and highlight potential therapeutic strategies aimed at modulating glymphatic function. Finally, we address the ongoing debates regarding glymphatic mechanisms, imaging biomarkers, and causal relationships in epilepsy. Collectively, the available data suggest that glymphatic system dysfunction represents a system-level abnormality in epilepsy, offering a complementary framework that integrates the metabolic, vascular, and sleep-related aspects of epileptic brain dysfunction.

Non-invasive MRI of choroid plexus vascular function.

Peiying Liu, Lori Donaldson, Beini Hu +2 more

Choroid plexus (ChP) is a highly vascularized tissue in the ventricles of the brain, and it plays an important role in the production of cerebrospinal fluid (CSF) and formation of the blood-CSF barrier. The function of ChP vessels has been implicated in waste clearance efficiency during aging and neurodegenerative diseases. At present, postmortem studies are the main method to assess choroid plexus vascular integrity, with a few tools to measure ChP function in living humans. Here, we proposed a non-invasive MRI approach to assess ChP vascular elasticity based on the detection of MRI signal changes in response to vasoactive challenges. The mechanism of the signal is hypothesized to be due to reciprocal blood and stroma volume alterations during vessel expansion. We demonstrated that ChP vascular elasticity can be evaluated with BOLD MRI using a hypercapnia challenge of CO2 inhalation. This effect is specifically located in the brain ventricles where ChP is abundant. We revealed the ability of the technique in detecting age-related reduction in ChP vascular elasticity. We further showed that this effect can be assessed with gas-free methods, including intermittent breath modulation and resting-state BOLD fMRI. We characterized the image contrast requirement under which this effect can be detected. This technique may provide a clinically feasible tool for assessing ChP vascular function in health and disease.

Spermidine alleviates sepsis-induced cardiomyopathy by improving mitochondrial quality and quantity via a Metallothionein 1-dependent antioxidant pathway.

Shiyun Long, Jiaxin Sun, Yaguang Wu +7 more

Sepsis-induced cardiomyopathy (SICM) is characterized by mitochondrial dysfunction, impaired mitophagic flux, and overwhelming oxidative stress. Spermidine (SPD), a natural polyamine known to enhance autophagy and preserve cardiac function in aging and metabolic disorders, has not been systematically evaluated in the context of septic cardiomyopathy.

Aging disrupts the temporal organization of slow oscillations beyond density reduction.

Lucila Capurro, Michael Radloff, María C González +4 more

Macroscopic and rhythmic brain oscillations have recently been shown to play a crucial role in glymphatic function by promoting cerebrospinal fluid flow and facilitating the clearance of metabolic waste. While age-related reductions in the number and amplitude of slow oscillations (SOs; 0.5-1 Hz) are well documented and associated with impaired clearance, little is known about how aging affects the temporal structure of these oscillations. Here, we propose that the rhythmic dynamics with which SOs occur represent a critical, yet overlooked, feature supporting glymphatic function. We introduce a novel classification of SOs based on their temporal organization, distinguishing isolated SOs from trains of consecutive oscillations according to inter-SO intervals. Using overnight electroencephalographic recordings from 57 young and 51 elderly adults across three independent datasets, we compared the proportions of isolated and consecutive SOs as well as the distribution of train lengths. Elderly adults displayed a significantly higher proportion of isolated SOs and shorter oscillatory trains than young adults, even after controlling for SO density and stage composition. Temporal shuffling procedures and analyses of density-matched epochs further supported that these differences cannot be attributed solely to density but instead reflect a genuine age-related loss of rhythmicity. These findings reveal that natural aging not only reduces the amount and amplitude of SOs but also disrupts their temporal regularity. This alteration may weaken the sustained ionic currents that drive cerebrospinal fluid flow, compromise the efficiency of metabolic clearance during sleep, and thereby contribute to increased vulnerability to age-related neurodegenerative processes.

Spatial coupling of enlarged perivascular spaces and white matter lesions across the Alzheimer's disease continuum.

Serena Tang, Pamela Thropp, Isabella Hausle +2 more

Emerging evidence suggests that impaired waste-clearance systems contribute to Alzheimer's disease pathogenesis, yet the etiology of clearance dysfunction markers, such as enlarged perivascular spaces, remains unclear. Because enlarged perivascular spaces and white matter lesions are both consequences of microvascular injury involving neuroinflammation and impaired cerebrovascular function, we hypothesize that these markers may be spatially coupled through local interstitial fluid stagnation, where impaired perivascular clearance associates with white matter injury.

Intraventricular hemorrhage, suspected EBV reactivation, and TBA-positive epilepsy after deep cervical lymphovenous anastomosis in Alzheimer's disease: a case report.

Tiantian Jiang, Fang Yan, Bin Liu +6 more

Lymphovenous anastomosis (LVA) is emerging as a potential surgical intervention to ameliorate cervical lymphatic outflow and enhance glymphatic clearance in Alzheimer's disease (AD). However, the spectrum of neurological sequelae associated with this procedure remains poorly characterized. We report the case of a 67-years-old male with amyloid PET-confirmed AD who underwent bilateral deep cervical LVA. Twenty-three days postoperatively, he presented with high-grade fever and altered consciousness. Head CT revealed acute hemorrhage in the posterior horn of the left lateral ventricle (∼2 mL). Cerebrospinal fluid (CSF) analysis demonstrated lymphocytic pleocytosis and significantly elevated protein levels; the fluid was uniformly bloody, confirming intraventricular hemorrhage. Plasma metagenomic next-generation sequencing (mNGS) identified Epstein-Barr virus (EBV), with serology supporting reactivation. Following antiviral and empirical antibiotic therapy, the patient's condition stabilized, and the hemorrhage resolved. Four months postoperatively, he developed new-onset generalized seizures. Despite negative results from a conventional autoimmune encephalitis antibody panel in both serum and CSF, a tissue-based assay (TBA) proved positive in both samples. Seizures were successfully controlled with levetiracetam. This case suggests a potential association between invasive lymphatic procedures and a hemorrhage-infection-immune cascade in highly vulnerable AD patients with preexisting metabolic and neurodegenerative risk factors.

Spleen-Targeting Delivery of the Liposomal Antigen via an RBC-Based Platform for Cancer Immunotherapy.

Shengmin Yang, Yanning Bao, Nana Meng +12 more

Efficient delivery of tumor antigens to the spleen remains a challenge for systemic cancer vaccination. Although nanoparticles provide versatile platforms for antigen delivery, intravenous administration often results in preferential sequestration by the reticuloendothelial system, leading to dominant hepatic accumulation and limited spleen-targeting. Here, leveraging the intrinsic splenic clearance property of senescent red blood cells (RBCs), we developed an RBC-based liposomal antigen delivery system by covalently conjugating antigen- and adjuvant-coloaded liposomes onto the RBC surface, thereby inducing senescence-like changes in the carrier RBCs and endowing the modified RBCs with enhanced splenic sequestration. Following intravenous administration, the RBC-liposome vaccine delivery system achieved highly efficient accumulation in the spleen, where the antigen was effectively internalized by splenic immune cells, leading to T cell activation and induction of robust immune responses. This delivery system demonstrated significant therapeutic efficacy in a melanoma-bearing mouse model with a remarkable tumor inhibition rate of 96.5%. Our study might offer a promising strategy for antigen spleen-targeting delivery in cancer immunotherapy.

From collapse to comeback: Luteolin rejuvenates nucleus pulposus progenitor cells via SIRT1/ATF5-UPRmt to reverse intervertebral disc degeneration cascade.

Huofeng Wu, Shuangjia Zai, Xuan You +8 more

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP) and one of the foremost causes of disability worldwide. Oxidative stress-induced senescence of nucleus pulposus progenitor cells (NPPC) and mitochondrial dysfunction are key drivers of IVDD. The mitochondrial unfolded protein response (UPRmt), orchestrated by the Silent Information Regulator 1 (SIRT1)-Activating Transcription Factor 5 (ATF5) axis, plays a pivotal role in maintaining mitochondrial proteostasis. However, its involvement in IVDD remains insufficiently characterized. Luteolin (Lut), a naturally occurring flavonoid with well-documented antioxidant and anti-senescence properties, has emerged as a promising disease-modifying candidate.

Simulated aquatic aging exacerbates pulmonary toxicity of graphite nanoplatelets by mechanically and chemically induced surface oxidation, enhancing oxidative potential.

Karthika Viswanathan, Youn-Joo Jung, Maruthupandy Muthuchamy +3 more

Graphite nanoplatelets (GNPs) are increasingly used in advanced materials, yet their environmental transformation and resulting health impacts remain poorly understood. This study investigated how long-term aquatic aging alters the physicochemical properties and pulmonary toxicity of GNPs.

From mechanisms to therapeutics: The expanding role of cell-based strategies in Alzheimer's disease.

Xuan Sun, Wenwen Deng, Jiangnan Yu +1 more

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. Its core pathologies include the deposition of amyloid-β plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, chronic neuroinflammation, and neuronal loss. With the rapidly aging global population, the prevalence of AD continues to rise. Current pharmacological treatments offer only limited symptomatic relief and cannot modify the underlying disease trajectory, leaving a significant unmet clinical need. In this context, cell-based therapy has emerged as a promising therapeutic strategy, leveraging its unique multi-targeted and regenerative capacities. This review systematically examines the therapeutic potential of various cell types, including mesenchymal stem cells, neural stem cells, immune cells, and engineered cells. We elaborate on their mechanisms of action, which encompass neurotrophic support, immunomodulation, and clearance of pathological proteins. These concerted actions contribute to remodeling the hostile brain microenvironment and promoting neuroregeneration in AD. Although preclinical evidence is robust, the clinical translation of cellular therapies faces considerable challenges. These hurdles include selecting the optimal cell source, developing efficient delivery strategies, determining the ideal intervention timing, and establishing standardized manufacturing protocols. Looking forward, we discuss how the development of precise disease models, the integration of gene editing and engineering strategies, advances in combination therapies, and the establishment of personalized treatment regimens are poised to position cell therapy at the forefront of comprehensive AD management. These innovations hold new promise for achieving true disease modification.

Clinical Decision-Making in Laparoscopic Common Bile Duct Exploration: Choosing Between Primary Closure and T-Tube Drainage.

Kun Liu, Zhang Liu, Jie Gao +2 more

Choledocholithiasis, or common bile duct (CBD) stones, is increasingly prevalent in aging populations worldwide. Laparoscopic common bile duct exploration (LCBDE) is a well-established minimally invasive procedure; however, the optimal method for choledochotomy closure-primary closure (PC) versus T-tube drainage (TTD)-remains controversial.

Overcoming Challenges in Wound Infection: Biofilm and Antimicrobial Resistance.

Markus Rothmaier, Matthew J Hardman, Bithi Chatterjee +3 more

Chronic wounds represent a growing clinical and economic burden, affecting 1-2% of the global population, with prevalence expected to rise due to aging and increasing rates of diabetes, obesity, and vascular diseases. Wound persistence is often driven by infection and compounded by antimicrobial resistance (AMR), resulting in poor patient outcomes. High prevalence of microbial biofilms, which shield pathogens from immune clearance and promote AMR, further promotes the chronicity of infected wounds.

Immune signaling and function in neurodegeneration.

Yvonne L Latour, Dorian B McGavern

Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.

B cell-driven refractory hemocytopenia in immune checkpoint inhibitor therapy: a report of two cases.

Feng Li, Chunyan Wang, Guohua Yao +4 more

The integration of immune checkpoint inhibitors (ICIs) with chemotherapy has revolutionized lung cancer treatment, yet it amplifies the risk of severe hematologic toxicities.

Sleep-Dependent Clearance of Brain Metabolites via the Glymphatic System: Implications for Alzheimer's Pathophysiology.

Farshad Zare, Gulnora Shakhmurova, Jasur Rizaev +4 more

This review aims to examine how sleep-dependent glymphatic function contributes to the clearance of brain metabolites involved in Alzheimer's disease (AD), with particular emphasis on amyloid-beta (Aβ), tau, astrocytic aquaporin-4 (AQP4), and emerging biomarkers of clearance-related dysfunction.

The Role of the Glymphatic System in Alzheimer's Disease: Mechanisms, Evidence, and Therapeutic Implications.

Yaran Li, Juan Li, Xinhong Liu +4 more

Alzheimer's disease (AD) is an aging-associated neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation and progressive cognitive decline. Increasing evidence implicates the glymphatic system, a brain-wide perivascular pathway involved in cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, in the removal of Aβ, tau, and other solutes relevant to AD pathogenesis. Aging-related alterations in aquaporin-4 polarization, arterial pulsatility, sleep architecture, and cerebrovascular integrity may impair glymphatic transport and thereby promote protein retention and neurodegeneration. In this review, we summarize current knowledge of glymphatic anatomy and function and discuss its implications for AD, with particular emphasis on modifiable factors such as sleep, exercise, vascular health, and aging-associated decline. We further highlight emerging therapeutic and potential intervention strategies aimed at restoring glymphatic function, and critically evaluate current methods for assessing this system in humans together with the evidence obtained to date. Although human studies increasingly support the relevance of perivascular fluid transport to AD-related pathology and cognitive outcomes, mechanistic insights remain largely derived from animal models, and human assessment is still constrained by methodological and imaging limitations. Overall, the glymphatic system provides a useful framework for linking brain aging to impaired clearance in AD. Further refinement of human biomarkers and longitudinal translational studies will be essential for clarifying their clinical relevance and therapeutic potential.

Clearance of Senescent Cells by BCLXL-PROTAC: A Novel Approach to Treat COPD?

Justine V Devulder, Peter S Fenwick, Ewa Kolosionek +9 more

Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD. Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a and senescence-associated β-galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment. These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.

Cellular Microenvironment Triggered Ferroptosis and Photodynamic Therapy for Selective Senescent Cell Clearance.

Hang Wang, Yuli Kang, Qiqiang Zhang +7 more

Biomedical strategies based on the cellular microenvironment often lead to significant improvements in diagnosis and therapy. In this study, based on the elevated reactive oxygen species (ROS) microenvironment of senescent cells, we designed Fe3+ coordinated nitrogen doped graphene quantum dots (Fe@N-GQDs) with both photodynamic and ferroptotic activity. The results demonstrated that Fe3+ modulated the electronic structure of nitrogen doped graphene quantum dots (N-GQDs) and enhanced their photodynamic activity. Meanwhile, the high ROS levels in endoplasmic reticulum and mitochondria enabled accumulated Fe@N-GQDs to synergistically amplify oxidative stress through the Fe3+/Fe2+ redox cycle and activate the ferroptosis related process. Under the synergistic photodynamic and ferroptosis effects, the clearance efficiency of senescent cells reached 98%. More importantly, leveraging the senescent cell microenvironment, Fe@N-GQDs showed minimal impact on healthy cells without targeting modifications, significantly improving therapeutic safety.

GV1001 Reprograms CD47 Immune Checkpoint to Restore Macrophage Antitumor Activity in Oral Squamous Cell Carcinoma.

Wei Chen, Seojin Kim, Cheyenne Beheshtian +3 more

Cluster of Differentiation 47 (CD47) functions as a key "don't-eat-me" signal that enables cancer cells to evade macrophage-mediated immune clearance. GV1001, a 16-amino-acid peptide derived from human telomerase reverse transcriptase (hTERT), has been reported to exhibit antitumor and anti-inflammatory properties and to downregulate CD47 expression in human cells. In this study, we investigated whether GV1001 modulated CD47 expression and enhanced antitumor immunity in oral squamous cell carcinoma (OSCC). In vitro, GV1001 significantly reduced CD47 expression in both murine and human OSCC cells in dose- and time-dependent manners, resulting in a marked increase in macrophage-mediated phagocytosis. Mechanistically, GV1001 suppressed CD47 promoter activity and inhibited multiple upstream regulator expression in murine and human OSCC cell lines, while exerting minimal effects on normal human keratinocytes and fibroblasts. In vivo, GV1001 significantly inhibited tumor growth, suppressed CD47 expression, increased macrophage infiltration, and induced tumor cell necrosis and apoptosis in both murine OSCC syngeneic graft model and human OSCC xenograft model. GV1001 administered alone or in combination with cisplatin produced antitumor effects. Collectively, these findings demonstrate that GV1001 functions as a potent immunomodulatory anticancer peptide that downregulates CD47 expression and restores macrophage-mediated tumor clearance, highlighting its potential as a therapeutic strategy for OSCC.

[Protective effect and mechanism of TSPAN9-mediated mitocytosis in interleukin-1β-induced rat chondrocyte senescence].

Quan Chen, Wacili Da, Naijia Luo +1 more

To investigate the regulatory role and molecular mechanisms of TSPAN9-mediated mitocytosis in an interleukin-1β (IL-1β)-induced rat chondrocyte senescence model, and to identify novel therapeutic targets for osteoarthritis (OA).

Oxidative Stress as a Mechanistic Link Between Severe Respiratory Viral Infection and Pulmonary Fibrosis.

Shynggys Sergazy, Alexander Gulyaev, Zarina Shulgau

Post-viral pulmonary fibrosis represents a clinically significant and mechanistically complex consequence of severe respiratory infection. The COVID-19 pandemic has highlighted that a subset of survivors, particularly those with severe pneumonia or acute respiratory distress syndrome, develop persistent fibrosis-like lung abnormalities, including reticulation and traction bronchiectasis, often accompanied by impaired gas transfer. Although the clinical course is heterogeneous and many lesions regress over time, longitudinal studies indicate that structural and functional impairment may persist for years in susceptible individuals. Oxidative stress has emerged as a plausible convergent mechanism linking acute epithelial injury, dysregulated inflammatory resolution, and chronic fibrotic remodeling. Reactive oxygen and nitrogen species amplify inflammatory signaling, promote epithelial cell death and senescence, influence macrophage polarization, and activate canonical profibrotic pathways, notably the TGF-β axis. Redox imbalance is embedded within reinforcing circuits involving NOX4-dependent ROS amplification, mitochondrial dysfunction, endoplasmic reticulum stress, inflammasome activation, and senescence-associated secretory programs. Persistent immune activation and organelle stress may sustain redox dysregulation beyond viral clearance, thereby bridging acute lung injury to maladaptive remodeling. This review integrates epidemiological, clinical, and mechanistic evidence to position oxidative stress as a central mediator of post-viral lung fibrosis and discusses therapeutic and translational implications.

A potential multimodal biomarker - cognitive signature associated with the conversion from subjective cognitive decline to mild cognitive impairment.

Mohamed Haddad, Mohamed Raâfet Ben Khedher, Chadi Ouechtati +2 more

The disruption of key mechanisms involved in amyloid beta (Aβ) clearance during the early stages of dementia may contribute to the progression of cognitive decline toward irreversible brain damage. In this study, we investigated multiple immune-related pathways implicated in the management and clearance of Aβ within circulating extracellular vesicles (cEVs) and serum from individuals with subjective cognitive decline (SCD) who later progressed to mild cognitive impairment (MCI).

The Roles of Macrophage Lineage Cells (MLCs) in Brain Aging.

Qin Qin, Liubin Zhang, Manning Guo +10 more

Brain aging poses a major public health challenge and is the primary risk factor for neurodegenerative diseases. Macrophage lineage cells (MLCs) have emerged as pivotal mediators of brain aging. While fundamental to central nervous system (CNS) homeostasis through their scavenging, detoxification, and neurotrophic functions, their transition to a senescent state is a primary driver of pathology. This shift is marked by a loss of clearance capacity and the adoption of a pro-inflammatory senescence-associated secretory phenotype (SASP).

Ceftazidime-avibactam-based regimens for the treatment of central nervous system infections caused by carbapenem-resistant Klebsiella pneumoniae in a pediatric patient.

Liming He, Wanzhen Li, Weiming Chen +8 more

Carbapenem-resistant Klebsiella pneumoniae (CRKP) central nervous system (CNS) infections are difficult to treat in children because effective and safe therapeutic options are limited. We report a pediatric case of CRKP meningitis successfully treated with ceftazidime-avibactam (CZA) combination with intraventricular polymyxin B (PMB).

Late-onset dyskeratosis congenita due to a TERC (n.269G > C) variant-first reported case from Indonesia: a case report.

Benedreky Leo, Intan Hartandy, Susanna Hilda Hutajulu +4 more

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by defective telomere maintenance. It often presents with mucocutaneous features, cytopenias, and progressive organ involvement, but remains underrecognized in resource-limited settings.

Antagonistic Pleiotropy Governing Reproductive Aging: Evolutionary Regulation of Endometrial Receptivity.

Hiroshi Kobayashi, Miki Nishio, Mai Umetani +3 more

This review aims to integrate current knowledge on how mTORC1-centered metabolic and stress-response pathways regulate endometrial decidualization, cellular senescence, and receptivity, with particular emphasis on their impact on implantation in advanced maternal age and metabolic disorders. A literature search was conducted using PubMed and Google Scholar without temporal restrictions, and studies were selected according to predefined inclusion and exclusion criteria focusing on metabolic signaling and reproductive function. Physiological mTORC1 activation during the proliferative phase supports stromal cell proliferation, protein synthesis, and initiation of decidualization, while facilitating formation and clearance of physiological senescent cells. Conversely, sustained mTORC1 activation associated with aging or metabolic dysfunction enhances cellular senescence and the senescence-associated secretory phenotype (SASP) through autophagy suppression, increased oxidative stress, and DNA damage, leading to impaired decidualization and reduced endometrial receptivity. This pattern aligns with the principle of antagonistic pleiotropy, whereby traits advantageous for reproduction in youth become detrimental to tissue function later. Dysregulation of mTORC1 and its related pathways-including AMPK, Tuberous Sclerosis Complex 2 (TSC2), and the p53 axis-is linked to implantation failure, particularly in advanced maternal age, obesity, and insulin resistance. In conclusion, mTORC1-centered metabolic and stress-response networks are fundamental regulators of endometrial maturation and senescence. Incorporating the assessment of mTORC1 activity and aging-associated markers may improve endometrial evaluation and reproductive outcomes, particularly in women of advanced reproductive age. Furthermore, such approaches may also enhance diagnostic precision and potentially increase success rates in assisted reproductive technologies (ART).

Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice.

Masahiro Fukui, Takashi Kaise, Taimu Masaki +2 more

Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously showed that inducing Plagl2 and antagonizing Dyrk1a (iPaD) rejuvenates aged neural stem cells (NSCs), enhancing neurogenesis and cognition in aged mice. Here, we found that NSC-specific iPaD treatment activates neurogenesis, reduces amyloid-β deposition, and improves cognition in Alzheimer's disease model mice. Transcriptomic analysis revealed widespread changes in gene expression in the hippocampus after iPaD treatment. The upregulated genes include those associated with astrocyte and microglial activation involved in amyloid-β clearance, while several genes upregulated in Alzheimer's disease are downregulated. Among the latter genes, knockdown of Prkag2 in the hippocampus most effectively enhances neurogenesis and reduces amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activate AMP-activated protein kinase signaling, upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.

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.