Ageing Research Reviews最新文献

{"title":"Transformative advances in modeling brain aging and longevity: Success, challenges and future directions","authors":"Varsha Pai ,&nbsp;Bhisham Narayan Singh ,&nbsp;Abhishek Kumar Singh","doi":"10.1016/j.arr.2025.102753","DOIUrl":"10.1016/j.arr.2025.102753","url":null,"abstract":"<div><div>Research on brain aging is crucial for understanding age-related neurodegenerative disorders and developing several therapeutic interventions. Numerous models ranging from two-dimensional (2D) cell-based, invertebrate, vertebrate, and sophisticated three-dimensional (3D) models have been used to understand the process of brain aging. Invertebrate models are ideal for researching conserved aging processes because of their simplicity, short lifespans, and genetic tractability. Moreover, vertebrate models, including zebrafish and rodents, exhibit more complex nervous systems and behaviors, enabling the exploration of age-related neurodegeneration and cognitive decline. 2D cell culture models derived from primary cells or immortalized cell lines are widely used for mechanistic studies at the cellular level but lack the physiological complexity of brain tissue. Recent advancements have shifted focus to 3D models, which better recapitulate the brain’s microenvironment. Organoids derived from induced pluripotent stem cells mimic human brain architecture and enable the study of cell-cell interactions and aging in a human-specific context. Brain-on-a-chip systems integrate microfluidics and 3D cultures to model blood-brain barrier dynamics and neuronal networks. Additionally, scaffold-based 3D cultures and spheroids provide intermediate complexity, allowing researchers to study extracellular matrix interactions and age-related changes in neuronal function. These 3D models bridge the gap between traditional 2D cultures and animal-based <em>in vivo</em> studies, offering unprecedented insights into brain aging mechanisms. By combining these diverse models, researchers can unravel the multifaceted processes of brain aging and accelerate the development of targeted therapies for age-related neurodegenerative disorders.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102753"},"PeriodicalIF":12.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143833247","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 three major intestinal barriers in ulcerative colitis in the elderly","authors":"Min Fu ,&nbsp;Qi-Wen Wang ,&nbsp;Ya-Ru Liu ,&nbsp;Shu-Jie Chen","doi":"10.1016/j.arr.2025.102752","DOIUrl":"10.1016/j.arr.2025.102752","url":null,"abstract":"<div><div>With the unprecedented pace of global population aging, there has been a parallel epidemiological shift marked by increasing incidence rates of ulcerative colitis (UC) in geriatric populations, imposing a substantial disease burden on healthcare systems globally. The etiopathogenesis of UC in the elderly remains poorly delineated, while current therapeutic strategies require further optimization to accommodate the unique pathophysiological characteristics of elderly patients. This review systematically elucidates the three barrier dysfunction - encompassing the gut microbiota ecosystem, mucosal epithelial integrity, and immunoregulatory network - that collectively drives UC pathogenesis during biological senescence. We emphasize the therapeutic potential of barrier-targeted interventions, particularly highlighting emerging modalities including fecal microbiota transplantation, intestinal organoid regeneration techniques, mesenchymal stem cell-mediated immunomodulation, and precision-engineered Chimeric Antigen Receptor T-cell therapies. Through this multidimensional analysis, we propose a paradigm-shifting approach to UC management in the elderly, advocating for the development of tailored and evidence-based therapeutic interventions that address the complex interplay between age-related biological changes and intestinal barrier homeostasis in elderly patients.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102752"},"PeriodicalIF":12.5,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143817733","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":"Reducing Alzheimer’s disease risk with SGLT2 inhibitors: From glycemic control to neuroprotection","authors":"Mehdi Alami ,&nbsp;Mojgan Morvaridzadeh ,&nbsp;Abdellatif El Khayari ,&nbsp;Kaoutar Boumezough ,&nbsp;Rachid El Fatimy ,&nbsp;Abdelouahed Khalil ,&nbsp;Tamas Fulop ,&nbsp;Hicham Berrougui","doi":"10.1016/j.arr.2025.102751","DOIUrl":"10.1016/j.arr.2025.102751","url":null,"abstract":"<div><div>Recent research has established a strong link between metabolic abnormalities and an increased risk of dementia. In parallel, there is growing epidemiological evidence supporting the neuroprotective effects of antidiabetic medications against cognitive impairments. Among these, sodium-glucose co-transporter (SGLT2) inhibitors have emerged as pharmacological candidates with promising potential in alleviating the burden of age-related diseases, particularly neurodegenerative diseases (NDD). SGLT2 inhibitor therapies are FDA-approved medications routinely prescribed to manage diabetes. This novel class was initially developed to address cardiovascular disorders and to reduce the risk of hypoglycemia associated with insulin-secretagogue agents. It subsequently attracted growing interest for its beneficial effects on central nervous system (CNS) disorders. However, the molecular mechanisms through which these glucose-lowering therapies mitigate cognitive decline and limit the progression of certain brain degenerative diseases remain largely unexplored. Consequently, the neuroscientific community needs further studies that gather, analyze, and critically discuss the available mechanistic evidence regarding the neuroprotective effects of SGLT2 inhibitors. This review aims to critically examine the most relevant published findings, both <em>in vitro</em> and <em>in vivo</em>, as well as human studies evaluating the impact of SGLT2 inhibitors exposure on Alzheimer’s disease (AD). It seeks to integrate the current understanding of their beneficial effects at the molecular level and their role in addressing the pathophysiology and neuropathology of AD. These insights will help extend our knowledge of how SGLT2 inhibitor therapies are associated with reduced risk of dementia and thus shed light on the link between diabetes and AD.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102751"},"PeriodicalIF":12.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808151","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":"Umbrella review of nonpharmacological interventions for intrinsic capacity in older adults","authors":"Yu-Tai Lo ,&nbsp;Hui-Chen Su ,&nbsp;Chanisara Chuenchomnoy ,&nbsp;Ting-Wei Liao ,&nbsp;Yi-Lin Wu ,&nbsp;Sin-Hang Tam ,&nbsp;Chieh-Hsiu Liu ,&nbsp;Chih-Wen Chou ,&nbsp;Yi-Ching Yang ,&nbsp;Yen-Hsu Chen ,&nbsp;Yen-Chin Chen","doi":"10.1016/j.arr.2025.102742","DOIUrl":"10.1016/j.arr.2025.102742","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aims to synthesize existing evidence on the effectiveness of nonpharmacological interventions designed to increase the intrinsic capacity (IC) of community-dwelling older adults.</div></div><div><h3>Methods</h3><div>An umbrella review of systematic reviews from 2015 to October 31, 2024, with no language restrictions, was conducted. The review included five databases, including Embase, Ovid MEDLINE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Joanna Briggs Institute (JBI) Library. Studies followed the preferred reporting items for overviews of reviews (PRIOR) statement. Eligible studies were systematic review and meta-analysis (SRMAs) that included any type of research aimed at enhancing IC in community-dwelling older adults (aged ≥60 years). The interventions covered seven domains: locomotion, vitality, cognitive function, psychological health, sensory function, sleep, and continence. Risk of bias and study quality were extracted via the AMSTAR tool, and GRADE approach was applied to assess the certainty of evidence.</div></div><div><h3>Findings</h3><div>Out of 6407 initially identified articles, 29 SRMAs comprising 400 studies with a total sample size of 43,849 participants were included. Mobility-focused interventions were the most studied among the seven domains of IC. Moderate to low-quality evidence supports the effectiveness of intrinsic foot muscle strengthening and gait/muscle training for improving locomotor functions in older adults with frailty or acute functional decline. Nonpharmacological interventions targeting cognitive and psychological functions ranked second in the volume of available evidence. No effective sensory or continence interventions were identified. Overall, interventions have demonstrated varying effectiveness, with impacts ranging from moderate to very low across the domains of IC.</div></div><div><h3>Interpretations</h3><div>This umbrella review provides a comprehensive assessment of nonpharmacological interventions for enhancing IC in older adults, highlighting the effectiveness of mobility/muscle strength training for improving locomotor function among frail older adult or those experiencing functional decline. However, the evidence for interventions targeting other IC domains remains limited, particularly for sensory function, and continence management. Future research should prioritize high-quality trials evaluating interventions in these areas to develop evidence-based guidelines for improving overall IC and promoting healthy aging in older adults.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102742"},"PeriodicalIF":12.5,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805049","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":"E2 conjugating enzymes: A silent but crucial player in ubiquitin biology","authors":"Somya Parashar ,&nbsp;Aastha Kaushik ,&nbsp;Rashmi K. Ambasta ,&nbsp;Pravir Kumar","doi":"10.1016/j.arr.2025.102740","DOIUrl":"10.1016/j.arr.2025.102740","url":null,"abstract":"<div><div>E2 conjugating enzymes serve as the linchpin of the Ubiquitin-Proteasome System (UPS), facilitating ubiquitin (Ub) transfer to substrate proteins and regulating diverse processes critical to cellular homeostasis. The interaction of E2s with E1 activating enzymes and E3 ligases singularly positions them as middlemen of the ubiquitin machinery that guides protein turnover. Structural determinants of E2 enzymes play a pivotal role in these interactions, enabling precise ubiquitin transfer and substrate specificity. Regulation of E2 enzymes is tightly controlled through mechanisms such as post-translational modifications (PTMs), allosteric control, and gene expression modulation. Specific residues that undergo PTMs highlight their impact on E2 function and their role in ubiquitin dynamics. E2 enzymes also cooperate with deubiquitinases (DUBs) to maintain proteostasis. Design of small molecule inhibitors to modulate E2 activity is emerging as promising avenue to restrict ubiquitination as a potential therapeutic intervention. Additionally, E2 enzymes have been implicated in the pathogenesis and progression of neurodegenerative disorders (NDDs), where their dysfunction contributes to disease mechanisms. In summary, examining E2 enzymes from structural and functional perspectives offers potential to advance our understanding of cellular processes and assist in discovery of new therapeutic targets.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102740"},"PeriodicalIF":12.5,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805107","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 artificial intelligence to support quality of life of people with dementia: A scoping review","authors":"Dirk Steijger ,&nbsp;Hannah Christie ,&nbsp;Sil Aarts ,&nbsp;Wijnand IJselsteijn ,&nbsp;Hilde Verbeek ,&nbsp;Marjolein de Vugt","doi":"10.1016/j.arr.2025.102741","DOIUrl":"10.1016/j.arr.2025.102741","url":null,"abstract":"<div><h3>Background</h3><div>Dementia has an impact on the quality of life (QoL) of people with dementia. Tailored services are crucial for improving their QoL. Advances in artificial intelligence (AI) offer opportunities for personalised care, potentially delaying institutionalisation and enhancing QoL. However, AI's specific role in approaches to support QoL for people with dementia remains unclear. This scoping review aims to synthesise the scientific evidence and grey literature on how AI can support the QoL of people with dementia.</div></div><div><h3>Method</h3><div>Following Joanna Briggs Institute guidelines, we searched PubMed, Scopus, ACM Digital Library, and Google Scholar in January 2024. Studies on AI, QoL (using Lawton’s four-domain QoL definition), and people with dementia across various care settings were included. Two reviewers conducted a two-stage screening, and a narrative synthesis identified common themes arising from the individual studies to address the research question.</div></div><div><h3>Results</h3><div>The search yielded 5.467 studies, after screening, thirty studies were included<strong>.</strong> Three AI categories were identified: monitoring systems, social robots, and AI approaches for performing activities of daily living. Most studies were feasibility studies, with little active involvement of people with dementia during the research process. Most AI-based approaches were monitoring systems targeting Lawton’s behavioural competence (capacity for independent functioning) domain.</div></div><div><h3>Conclusion</h3><div>This review highlights that AI applications for enhancing QoL in people with dementia are still in early development, with research largely limited to small-scale feasibility studies rather than demonstrating clinical effectiveness. While AI holds promise, further exploration and rigorous real-world validation are needed before AI can meaningfully impact the daily lives of people with dementia.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102741"},"PeriodicalIF":12.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interoception and aging","authors":"Erliang Li ,&nbsp;Wenjing Niu ,&nbsp;Chao Lu ,&nbsp;Min Wang ,&nbsp;Xin Xu ,&nbsp;Ke Xu ,&nbsp;Peng Xu","doi":"10.1016/j.arr.2025.102743","DOIUrl":"10.1016/j.arr.2025.102743","url":null,"abstract":"<div><div>Interoception refers to the body's perception and regulation of internal physiological states and involves complex neural mechanisms and sensory systems. The current definition of interoception falls short of capturing the breadth of related research; here, we propose an updated definition. Homeostasis, a foundational principle of integrated physiology, is the process by which organisms dynamically maintain optimal balance across all conditions through neural, endocrine, and behavioral functions. This review examines the role of interoception in body homeostasis. Aging is a complex process influenced by multiple factors and involving multiple levels, including physical, psychological, and cognitive. However, interoceptive and aging interoceptive interactions are lacking. A new perspective on interoception and aging holds significant implications for understanding how aging regulates interoception and how interoception affects the aging process. Finally, we summarize that arachidonic acid metabolites show promise as biomarkers of interoception-aging. The aim of this study is to comprehensively analyze interoceptive-aging interactions, understand the aging mechanism from a novel perspective, and provide a theoretical basis for exploring anti-aging strategies.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102743"},"PeriodicalIF":12.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143797082","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":"Mitophagy in Alzheimer's disease and other metabolic disorders: A focus on mitochondrial-targeted therapeutics","authors":"Shadt Skawratananond ,&nbsp;Daniel X. Xiong ,&nbsp;Charlie Zhang ,&nbsp;Sahil Tonk ,&nbsp;Aljon Pinili ,&nbsp;Brad Delacruz ,&nbsp;Patrick Pham ,&nbsp;Shane C. Smith ,&nbsp;Rahul Navab ,&nbsp;P. Hemachandra Reddy","doi":"10.1016/j.arr.2025.102732","DOIUrl":"10.1016/j.arr.2025.102732","url":null,"abstract":"<div><div>Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy—the selective removal of impaired mitochondria—is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer’s disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions—MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management—that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria’s central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102732"},"PeriodicalIF":12.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694743","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":"Advanced biomarkers: Beyond amyloid and tau: Emerging non-traditional biomarkers for alzheimer`s diagnosis and progression","authors":"Meher Rijwana Afrin ,&nbsp;Pankaj Ghritakousik Upadhyaya ,&nbsp;Abdul Hashim ,&nbsp;Kunal Bhattacharya ,&nbsp;Nongmaithem Randhoni Chanu ,&nbsp;Dibyajyoti Das ,&nbsp;Pukar Khanal ,&nbsp;Satyendra Deka","doi":"10.1016/j.arr.2025.102736","DOIUrl":"10.1016/j.arr.2025.102736","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the most common neurodegenerative disorder that leads to progressive cognitive decline and imposes a significant socio-economic burden. Traditional diagnostic methods, primarily based on amyloid-beta (Aβ) and tau biomarkers, often identify the disease at late stages, highlighting the need for more sensitive and accessible early detection tools. This review explores emerging non-traditional biomarkers, including salivary, lipid, urinary, synaptic, blood-based, microRNA (miRNA), cerebrospinal fluid (CSF), fecal, and inflammatory markers, which provide deeper insights into AD pathophysiology. These biomarkers reflect key pathological processes such as neuroinflammation, mitochondrial dysfunction, oxidative stress, synaptic damage, lipid dysregulation, and genetic factors. Non-invasive biomarkers, such as those found in saliva and urine, present promising avenues for large-scale screening, while advanced blood-based markers like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) offer precise monitoring of neurodegeneration and inflammation. Additionally, miRNAs and lipid biomarkers shed light on molecular alterations in neuronal health and signaling. Integrating these biomarkers with imaging techniques, proteomics, and genetic profiling enhances diagnostic accuracy and enables personalized treatment approaches. This shift toward multi-dimensional biomarker assessment not only improves early detection but also aids in tailoring therapeutic strategies to individual disease profiles. By reviewing recent advancements, this article highlights the transformative potential of emerging biomarkers in overcoming the limitations of conventional diagnostics. Standardization and validation across diverse populations will be crucial in expanding their clinical applicability, ultimately improving disease management, reducing societal burden, and enhancing the quality of life for individuals affected by AD.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102736"},"PeriodicalIF":12.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685789","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":"Microglial NOX2 as a therapeutic target in traumatic brain injury: Mechanisms, consequences, and potential for neuroprotection","authors":"Nargis Bano ,&nbsp;Sameera Khan ,&nbsp;Shakir Ahamad ,&nbsp;Nawab John Dar ,&nbsp;Hamad H. Alanazi ,&nbsp;Aamir Nazir ,&nbsp;Shahnawaz Ali Bhat","doi":"10.1016/j.arr.2025.102735","DOIUrl":"10.1016/j.arr.2025.102735","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a leading cause of long-term disability worldwide, with secondary injury mechanisms, including neuroinflammation and oxidative stress, driving much of its chronic pathology. While NADPH oxidase 2 (NOX2)-mediated reactive oxygen species (ROS) production is a recognized factor in TBI, the specific role of microglial NOX2 in perpetuating oxidative and inflammatory damage remains underexplored. Addressing this gap is critical, as current therapeutic approaches primarily target acute symptoms and fail to interrupt the persistent neuroinflammation that contributes to progressive neurodegeneration. Besides NOX, other ROS-generating enzymes, such as CYP1B1, COX2, and XO, also play crucial roles in triggering oxidative stress and neuroinflammatory conditions in TBI. However, this review highlights the pathophysiological role of microglial NOX2 in TBI, focusing on its activation following injury and its impact on ROS generation, neuroinflammatory signaling, and neuronal loss. These insights reveal NOX2 as a critical driver of secondary injury, linked to worsened outcomes, particularly in aged individuals where NOX2 activation is more pronounced. In addition, this review evaluates emerging therapeutic approaches targeting NOX2, such as GSK2795039 and other selective NOX2 inhibitors, which show potential in reducing ROS levels, limiting neuroinflammation, and preserving neurological functions. By highlighting the specific role of NOX2 in microglial ROS production and secondary neurodegeneration, this study advocates for NOX2 inhibition as a promising strategy to improve TBI outcomes by addressing the unmet need for therapies targeting long-term inflammation and neuroprotection. Our review highlights the potential of NOX2-targeted interventions to disrupt the cycle of oxidative stress and inflammation, ultimately offering a pathway to mitigate the chronic impact of TBI.</div></div>","PeriodicalId":55545,"journal":{"name":"Ageing Research Reviews","volume":"108 ","pages":"Article 102735"},"PeriodicalIF":12.5,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694741","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}