Ageing Research Reviews最新文献

{"title":"Munc 18–1 is a multifaceted therapeutic target for dementia","authors":"Khuraijam Surjalal Singh,&nbsp;Prachi Rani,&nbsp;Anuja Arora,&nbsp;Rahul Verma,&nbsp;Akshita Gupta,&nbsp;Laishram Rajendrakumar Singh","doi":"10.1016/j.arr.2025.102899","DOIUrl":"10.1016/j.arr.2025.102899","url":null,"abstract":"<div><div>Dementia is a complex and multifactorial neurodegenerative condition, characterized by overlapping and interlinked pathophysiological implications including amyloid-β (Aβ) accumulation, Synaptic dysfunction, Lewy body formation, Tauopathy, neuroinflammation and oxidative stress. This complexity is one of the main reasons why single-target therapeutic strategies have largely failed to provide curative outcomes. As a result, there is a growing emphasis on identifying convergent molecular hubs that integrate multiple pathological pathways. In this context, Munc18–1 (STXBP1), a key regulator of synaptic vesicle exocytosis via SNARE complex assembly, has emerged as a central node connecting multiple facets of dementia pathology. Beyond its canonical role in neurotransmitter release, Munc18–1 influences amyloid precursor protein (APP) processing, modulates Tau phosphorylation through CDK5, and acts as a molecular chaperone for α-synuclein, thereby impacting amyloidogenic, Tauopathic, and Synucleinopathic pathways. Its dysfunction impairs synaptic integrity, disrupts BDNF signalling, and promotes neuroinflammatory responses through excitotoxicity and vesicle-mediated immune signalling. Notably, reductions or mutations in Munc18–1 have been consistently associated with cognitive decline in various dementia models. In the present article, we attempted to address that Munc18–1 could be a master regulator of multiple pathophysiologies associated with dementia and emerging therapeutic approaches that stabilize Munc18–1 and restore its multifaceted functions can be a novel strategy for the treatment of dementia.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102899"},"PeriodicalIF":12.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenium and brain aging: A comprehensive review with a focus on hippocampal neurogenesis","authors":"Arian Daneshpour ,&nbsp;Maria Eduarda Nastarino Leite ,&nbsp;Karl-Heinz Wagner ,&nbsp;Shaun Sabico ,&nbsp;Nasser M. Al-Daghri ,&nbsp;Dara Aldisi ,&nbsp;Daniel König ,&nbsp;José Francisco López Gil ,&nbsp;Brendon Stubbs","doi":"10.1016/j.arr.2025.102898","DOIUrl":"10.1016/j.arr.2025.102898","url":null,"abstract":"<div><div>Brain aging is accompanied by progressive cognitive decline and increased risk of neurodegenerative diseases, with adult hippocampal neurogenesis (AHN) playing a pivotal role in maintaining cognitive resilience. Selenium, an essential trace element, exerts significant neuroprotective and neurogenic effects predominantly through its incorporation into selenoproteins, which regulate oxidative stress, neuroinflammation, and synaptic plasticity. This review synthesizes recent advances delineating selenium’s metabolism, bioavailability, and its multifaceted roles in brain development, function, and aging, emphasizing mechanisms underpinning hippocampal neurogenesis. Key molecular pathways influenced by selenium include phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Wingless/Integrated (Wnt) and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathways that promote neural progenitor cell proliferation and differentiation. Selenium transport via selenoprotein P and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) is critical for adequate selenium delivery to the hippocampus to support neurogenesis, with exercise demonstrated to potentiate this axis. Selenium also mitigates ferroptosis, preserves mitochondrial integrity, and modulates neuroimmune interactions by attenuating microglial activation and inflammasome signaling, fostering a neurogenic environment. Emerging evidence highlights selenium’s regulatory effects on RNA expression, including microRNAs modifications, further influencing neuronal health. Despite promising preclinical and observational data, clinical translation remains limited by heterogeneous and short-term studies. Future research priorities include multi-omics investigations, longitudinal cohorts, and addressing global selenium intake disparities through policy initiatives and precision nutrition. By consolidating mechanistic insights with clinical perspectives, this review underscores selenium’s potential as a modifiable factor to enhance AHN and cognitive health, advocating for integrated translational strategies to combat brain aging and neurodegeneration.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102898"},"PeriodicalIF":12.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential connections between senescence and chemobrain: An early overview of literature","authors":"Nebras Melhem ,&nbsp;Shahd Qutifan ,&nbsp;Mohammad Alsalem ,&nbsp;Tareq Saleh","doi":"10.1016/j.arr.2025.102896","DOIUrl":"10.1016/j.arr.2025.102896","url":null,"abstract":"<div><div>Chemotherapy-induced cognitive impairment (CICI), commonly referred to as chemobrain, is a pervasive adverse effect of cancer treatment, characterized by deficits in memory, concentration, and executive function. Several observations have suggested a potential for senescence in mediating CICI. First, chemotherapeutic agents that are implicated in CICI can also trigger senescence in neurons and glial cells, accompanied by the senescence-associated secretory phenotype (SASP), that could propagate neuroinflammation, oxidative stress, and synaptic dysfunction. Second, the hippocampus, central to memory and learning, is particularly vulnerable to chemotherapy-induced dendritic spine loss, reduced neurogenesis, and mitochondrial damage and is also a site for senescent cell accumulation. Third, the role of senescence in CICI is further supported by recent studies showing that the selective elimination of senescent cells can mitigate features of CICI. In this work, we attempt to highlight the intricate interplay between the established mechanisms of CICI (oxidative stress, inflammation, DNA damage, and mitochondrial dysfunction) and explore their potential connection to senescence as a central mechanism contributing to CICI. If senescence is then proven to be an established mechanism of CICI, then the use of senolytics or senomorphics could represent novel pharmacological interventions for the treatment of chemobrain.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102896"},"PeriodicalIF":12.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic effects of multimorbidity clusters on health outcomes in adults: A systematic review and meta-analysis","authors":"Jing Xi ,&nbsp;Miao Miao ,&nbsp;Polly W.C. Li ,&nbsp;Doris S.F. Yu","doi":"10.1016/j.arr.2025.102897","DOIUrl":"10.1016/j.arr.2025.102897","url":null,"abstract":"<div><h3>Background</h3><div>Multimorbidity is an important global health concern. We evaluated the prognostic impacts of multimorbidity clusters on health outcomes in adults.</div></div><div><h3>Methods</h3><div>This study was registered in PROSPERO (CRD42024528148), and no funding was received. Eight databases (PubMed, EMBASE, Cochrane Library, Web of Science, PsycINFO, CINAHL, Wan Fang, and CNKI) were searched for longitudinal studies reporting the prognostic impacts of multimorbidity clusters. Methodological quality was assessed using Newcastle–Ottawa Scale. Data analysis incorporated narrative synthesis, random-effects meta-analysis, subgroup analysis, meta-regression, sensitivity analysis, and Egger’s test.</div></div><div><h3>Results</h3><div>Forty articles identifying 12 multimorbidity clusters were included. Cardiometabolic multimorbidity (adjusted hazard ratio [HR]: 1.97, 95 % confidence interval [CI]: 1.76–2.21; adjusted odds ratio [OR]: 1.44, 95 % CI: 1.16–1.80) had strong prognostic impact on all-cause mortality, followed by cardiopulmonary (adjusted HR: 1.70, 95 % CI: 1.38–2.09), and digestive multimorbidity (adjusted HR: 1.46, 95 % CI: 1.11–1.93). It also predicted circulatory (adjusted HR: 3.41, 95 % CI: 2.27–5.12) and cancer mortality (adjusted HR: 1.32, 95 % CI: 1.04–1.67), activities of daily living disability (adjusted OR: 1.76, 95 % CI: 1.57–1.99), and depression (adjusted OR: 1.53, 95 % CI: 1.27–1.85). Multi-system multimorbidity predicted all-cause mortality (adjusted OR: 1.41, 95 % CI: 1.12–1.77) and activities of daily living disability (adjusted OR: 2.04, 95 % CI: 1.36–3.05). Cardiometabolic multimorbidity predicted a higher risk of all-cause mortality when identified using a pre-determined method.</div></div><div><h3>Conclusion</h3><div>Multimorbidity clusters strongly impact activities of daily living, depression, and mortality, with cardiometabolic multimorbidity warranting particular attention. However, due to methodological limitations, heterogeneity, Asian-dominant samples, and language bias, these results should be interpreted with caution.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102897"},"PeriodicalIF":12.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of factor XI/XIa inhibitors in patients with atrial fibrillation: Current progress and future prospects","authors":"Yue Fan ,&nbsp;Xi Chen ,&nbsp;Yueyun Jiang ,&nbsp;Yugang Dong ,&nbsp;Chen Liu ,&nbsp;Yili Chen ,&nbsp;Gregory Y.H. Lip ,&nbsp;Wengen Zhu","doi":"10.1016/j.arr.2025.102895","DOIUrl":"10.1016/j.arr.2025.102895","url":null,"abstract":"<div><div>Stroke prevention is one of the pillars of management in elderly patients with atrial fibrillation (AF), hence effective and safe anticoagulation strategies are needed. While available anticoagulants target coagulation factors involved in thrombus formation, their bleeding complications and limitations in aging populations underscore the necessity for novel agents. Factor XI/XIa (FXI/XIa), which selectively targets the intrinsic coagulation pathway, offers a promising approach by attenuating thrombin generation without impairing hemostasis. Various novel inhibitors, including antisense oligonucleotides, monoclonal antibodies and small molecules, have been developed. Clinical trials have shown favorable safety profiles with reduced bleeding risks compared to traditional anticoagulants. Some efficacy in preventing thromboembolic events has also been demonstrated, with ongoing trials further evaluating long-term safety and efficacy. This narrative review explores the potential of FXI/XIa inhibitors as a novel anticoagulant approach for AF. We discuss the rationale, pharmacology, evidence and future directions to assess the application prospects of FXI/XIa inhibitors in elderly AF patients, highlighting their potential to improve anticoagulation therapy by decoupling thrombosis prevention from bleeding complications.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102895"},"PeriodicalIF":12.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145042423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the gut microbiota in neuropsychiatric disorders and therapy","authors":"Fan Zhang ,&nbsp;Kang Ding ,&nbsp;Lin-Mei Zhang ,&nbsp;Dong-Yao Liu ,&nbsp;Xin Dong ,&nbsp;Man-Ni Wang ,&nbsp;Fu-Lin Zhou ,&nbsp;Yi-Wei Sun ,&nbsp;Wei-Ku Zhang ,&nbsp;Yu Yan ,&nbsp;Jun He ,&nbsp;Jie-Kun Xu","doi":"10.1016/j.arr.2025.102894","DOIUrl":"10.1016/j.arr.2025.102894","url":null,"abstract":"<div><div>The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD), collectively affect over one billion individuals globally. Emerging scientific evidence has consistently demonstrated the presence of GM dysbiosis in various neuropsychiatric disorders, suggesting a potential etiological role of GM in these conditions through MGBA-mediated mechanisms. In this comprehensive review, we systematically discussed the GM and MGBA, and presented evidence from both animal and human studies that highlighted the significance of GM in the occurrence and development of neuropsychiatric disorders. Subsequently, we emphasized the potential impact of GM and its metabolites on neuropsychiatric disorders. Next, we summarized the drugs used to treat diseases by regulating the GM. Finally, we proposed strategies to ameliorate the malignant progression of neuropsychiatric disorders by manipulating the composition of the GM. These strategies encompass the application of probiotics, prebiotics and synbiotics, postbiotics, fecal microbiota transplantation (FMT), and dietary interventions. Collectively, targeted GM therapy has the potential to be an effective treatment for neuropsychiatric disorders.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102894"},"PeriodicalIF":12.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unravelling the miscellaneous effects of exercise interventions on activities of daily living in frail older adults: A systematic review and meta-analysis","authors":"Emma De Keyser ,&nbsp;Jade Tambeur ,&nbsp;Elke De Smedt ,&nbsp;Lisa Schwab ,&nbsp;Dimitri Vrancken ,&nbsp;Wim Peersman ,&nbsp;Lieven Annemans ,&nbsp;Siddhartha Lieten ,&nbsp;Dominique Van de Velde ,&nbsp;Patricia De Vriendt ,&nbsp;David Beckwée","doi":"10.1016/j.arr.2025.102893","DOIUrl":"10.1016/j.arr.2025.102893","url":null,"abstract":"<div><h3>Introduction</h3><div>Frailty in older adults impairs Activities of Daily Living (ADL). While exercise interventions improve factors like muscle strength and physical function, their direct impact on ADL ability is inconsistent. This review aims to assess the effectiveness of exercise on ADL ability, identify the most beneficial interventions, and explore mediators.</div></div><div><h3>Method</h3><div>A systematic search in five databases included randomized controlled trials (RCTs) on frail adults (60 +) comparing exercise interventions to usual care, with ADL ability as an outcome. Methodological quality was assessed using the Cochrane risk of bias (ROB) tool. Meta-analyses were performed using random effects models, with heterogeneity assessed by the I² index. Subgroup analyses were conducted based on therapeutic validity (intervention according to exercise recommendations), adherence, cumulative therapeutic validity and adherence, ADL-measurement tool and ROB. Mediators were categorized based on study findings.</div></div><div><h3>Results</h3><div>Of 5975 records, 24 papers (20 RCTs) met criteria. Two had high ROB. Exercise improved ADL ability (Standardised mean difference = 0.59) but heterogeneity was high (I² = 83 %), partly explained by measurement tool and ROB. High therapeutic validity was associated with lower adherence rates, but interventions showing high therapeutic validity and/or adherence did not show larger ADL performance improvements. Potential mediators include physical function, cognition, balance confidence, quality of life, psychosocial factors, strength and self-perceived health/pain.</div></div><div><h3>Conclusion</h3><div>Exercise improves ADL performance, but high heterogeneity in results limits generalizability. Effective interventions should integrate physical, cognitive, and psychosocial components while ensuring gradual progression to balance therapeutic validity with adherence. Future research should use mediation analyses to clarify underlying mechanisms.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102893"},"PeriodicalIF":12.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perioperative neurocognitive disorders: Advances in molecular mechanisms and bioactive molecules","authors":"Liwei Mao ,&nbsp;Lian Wang ,&nbsp;Zhihai Huang ,&nbsp;Jeffrey A. Switzer ,&nbsp;David C. Hess ,&nbsp;Quanguang Zhang","doi":"10.1016/j.arr.2025.102885","DOIUrl":"10.1016/j.arr.2025.102885","url":null,"abstract":"<div><div>Perioperative neurocognitive disorders (PNDs) are common complications following surgery, especially in elderly patients, and are characterized by memory loss, attention deficits, and impaired executive function. The pathogenesis of PNDs involves a complex interplay of neuroinflammation, neurotransmitter imbalance, epigenetic modifications, and gut–brain axis disruption. This review summarizes the latest findings on the mechanisms underlying PNDs, with a focus on microglial activation, interleukin imbalance, and NLRP3 inflammasome-mediated pyroptosis. We further discuss how anesthesia and surgery impair synaptic plasticity by disrupting neurotransmitter systems, particularly GABA_A and NMDA receptors. Additionally, we highlight the roles of epigenetic regulation and gut microbiota dysbiosis in sustaining neuroinflammation and cognitive deficits. Finally, we explore potential therapeutic strategies, including bioactive compounds and neuroprotective agents, offering new directions for the prevention and treatment of PNDs.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102885"},"PeriodicalIF":12.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging","authors":"Emanuele Marzetti ,&nbsp;Rosa Di Lorenzo ,&nbsp;Riccardo Calvani ,&nbsp;Helio José Coelho-Junior ,&nbsp;Vito Pesce ,&nbsp;Francesco Landi ,&nbsp;Christiaan Leeuwenburgh ,&nbsp;Anna Picca","doi":"10.1016/j.arr.2025.102892","DOIUrl":"10.1016/j.arr.2025.102892","url":null,"abstract":"<div><div>Nuclear insertions of mitochondrial DNA (mtDNA) segments (NUMTs) represent an evolutionarily conserved phenomenon originating from the ancient endosymbiotic relationship between mitochondria and host cells. These insertions predominantly localize near intergenic or regulatory regions and are often enriched in tissues with high metabolic activity. Once regarded as inert pseudogenes or genomic artifacts, NUMTs are now recognized as dynamic elements capable of modulating nuclear architecture and cellular function. Advances in whole-genome sequencing have revealed a remarkable diversity of NUMTs across species, including polymorphic variants in humans that suggest ongoing NUMTogenesis. Stress-induced mitochondrial damage promotes mtDNA release and subsequent nuclear integration via non-homologous end joining, a mechanism that may be exacerbated in aging tissues. Studies suggest that NUMTs may intersect with some biological hallmarks of aging. Recently, NUMT accumulation in the brain was shown to correlate with cognitive decline and reduced lifespan, implicating NUMTs in biological aging and associated conditions. Additionally, NUMTs have been observed in oncogenic loci, suggesting potential roles in carcinogenesis. This review synthesizes current evidence on the molecular mechanisms underpinning NUMT generation and explores their intersection with aging biology. We examine how NUMTs may influence mitochondrial−nuclear communication, promote inflammation, and affect telomere dynamics and cellular senescence. We also highlight the relevance of understanding the biological impact of NUMTs across life stages and disease states to inform novel biomarkers and therapeutic strategies.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102892"},"PeriodicalIF":12.4,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TNF as a mediator of metabolic inflammation and body-brain interaction in obesity-driven neuroinflammation and neurodegeneration","authors":"Chih Hung Lo ,&nbsp;Jialiu Zeng","doi":"10.1016/j.arr.2025.102891","DOIUrl":"10.1016/j.arr.2025.102891","url":null,"abstract":"<div><div>Body–brain interaction (BBI) plays a critical role in coordinating the communication between peripheral organs and the brain, contributing to the comorbidity of metabolic disorders and neurological disorders. In the context of obesity, one of the key mediators driving systemic and neuroinflammatory responses is the soluble form of tumor necrosis factor (TNF), which primarily signals through TNF receptor 1 (TNFR1) to regulate inflammation and cell death. In this review, we examine how TNF/TNFR1-mediated metabolic inflammation in obesity disrupts cellular homeostasis across multiple organ systems, including the brain. In peripheral tissues, TNF is overproduced and secreted by activated macrophages, leading to lipid dysmetabolism, insulin resistance, and metabolic dysfunction in key cell types such as adipocytes and hepatocytes. Elevated circulating TNF also increases the permeability of the blood–brain barrier, enabling peripheral inflammatory mediators to infiltrate the brain and activate glial cells, thereby amplifying neuroinflammation. Within the brain, TNF induces metabolic and autolysosomal dysfunction in neurons, resulting in elevated reactive oxygen species, accumulation of toxic protein aggregates, and impaired insulin signaling, contributing collectively to neuronal death and the progression of neurodegeneration. We further highlight the metabolic-inflammatory crosstalk within the BBI as a potential therapeutic target, focusing on anti-inflammatory strategies that modulate TNF/TNFR1 signaling. Lastly, we provide future perspectives on the implications of body–brain axes, cell type–specific mechanisms, and disease comorbidities in the context of obesity.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"112 ","pages":"Article 102891"},"PeriodicalIF":12.4,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}