{"title":"Mechanistic Role of Astrocytic Rac1 Protein in Alzheimer's Disease.","authors":"Fengwen Jiang, Niya Wang, Qiang Meng","doi":"10.14336/AD.2025.0502","DOIUrl":"https://doi.org/10.14336/AD.2025.0502","url":null,"abstract":"<p><p>The prevalence of Alzheimer's disease (AD) has been increasing worldwide due to the aging population, placing a substantial burden on both society and families. To date, the underlying pathogenesis of AD has not been comprehensively elucidated, and advancements in drug development for this disease have been relatively slow. Astrocytes are crucial for maintaining the homeostasis of the brain microenvironment. Astrocyte dysfunction has been closely linked to AD onset and progression. The Rac1 protein, which belongs to the Rho GTPase family, exhibits hyperactivation in the astrocytes of AD model mice. Nevertheless, the exact role of Rac1 in the pathogenesis of AD remains ambiguous. The TLR4/Rac1/NLRP3 signaling pathway is involved in diverse cellular activities and inflammatory responses and plays a significant role in the AD neuroinflammatory process. This review explores the mechanism of action of Rac1 in astrocytes in the context of AD and how the TLR4/Rac1/NLRP3 pathway influences the pathological process, offering novel theoretical foundations and potential therapeutic targets for preventing and treating this disease.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ka Li, Safia Arbab, Qiujing Du, Jiao Zhou, Yuwen Chen, Yali Tian, Li Qijie, Hanif Ullah, Ben Zhang
{"title":"Regulatory and Influencing Factors of Digestive Function in Elderly People: Roles of the Gut Microbiota and Nutritional Interventions.","authors":"Ka Li, Safia Arbab, Qiujing Du, Jiao Zhou, Yuwen Chen, Yali Tian, Li Qijie, Hanif Ullah, Ben Zhang","doi":"10.14336/AD.2025.0565","DOIUrl":"https://doi.org/10.14336/AD.2025.0565","url":null,"abstract":"<p><p>Aging is a natural and gradual biological process through which living organisms undergo physical, physiological, and sometimes psychological changes over time. Aging is commonly associated with a decline in gastrointestinal function, leading to various digestive disorders that impact the quality of life of older adults. The gut microbiota is a highly complex ecosystem that plays crucial roles in digestion, metabolic processes, immune functions, and overall health. However, emerging evidence indicates that many elderly individuals maintain relatively stable digestive health, suggesting the influence of modifiable regulatory factors. In this review, we describe the key physiological, microbial, and nutritional factors that regulate and influence digestive function in an aging population. Additionally, we explored the impact of age-associated alterations in the gut microbiota on digestive health challenges in older adults and emphasized the therapeutic potential of targeted nutritional intervention approaches, such as dietary modifications, prebiotics, probiotics, and symbiotic and fecal microbiota transplantation, which have shown promise in rebalancing the gut microbiome and reducing inflammation.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Unveiling the Relation between Cellular Ageing, Epigenetics and Cancer.","authors":"Pawel Kordowitzki, Arkadiusz Grzeczka","doi":"10.14336/AD.2025.0677","DOIUrl":"https://doi.org/10.14336/AD.2025.0677","url":null,"abstract":"<p><p>This Editorial article intends to unravel the relationships among cellular ageing, epigenetic changes, and tumorigenesis, thereby offering perspectives that could improve therapeutic approaches in cancer management and promote future research on these topics. Furthermore, selected fundamental principles concerning cellular ageing will be presented to elucidate how this process contributes to the comprehension of tumorigenesis. As humans age, there is a progressive decline in physiological functions, which significantly increases the risk of cancer. Epigenetic alterations-heritable yet reversible modifications of the genome without changes in DNA sequence-play a pivotal role in both ageing and tumorigenesis. Age-associated epigenetic drift, involving widespread DNA methylation changes, histone modification shifts, and chromatin remodelling, disrupts normal gene regulatory networks, leading to genomic instability and impaired cellular homeostasis. Additionally, the accumulation of senescent cells, driven by epigenetic dysregulation, fosters a pro-inflammatory environment that can promote tumorigenesis. Moreover, the epigenetic landscape of aged tissues resembles that of cancerous tissues, suggesting that ageing establishes a permissive environment for malignant transformation. Understanding the interplay between ageing, epigenetic regulation, and cancer is critical for the development of preventive strategies and novel therapeutics. Epigenetic reprogramming technologies, aiming to restore youthful epigenetic states, hold promise for delaying ageing and reducing cancer incidence. However, challenges remain in selectively targeting pathogenic epigenetic changes without disrupting essential cellular functions.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Botond Gaál, Roland Takács, Csaba Matta, Krisztián Juhász, Béla Fülesdi, Zoltán Szekanecz, Szilvia Benkő, László Ducza
{"title":"The Inflammasome-miR Axis in Alzheimer's Disease and Chronic Pain: Molecular Mechanisms and Therapeutic Opportunities.","authors":"Botond Gaál, Roland Takács, Csaba Matta, Krisztián Juhász, Béla Fülesdi, Zoltán Szekanecz, Szilvia Benkő, László Ducza","doi":"10.14336/AD.2025.0353","DOIUrl":"https://doi.org/10.14336/AD.2025.0353","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and chronic neuroinflammation. Mounting evidence suggests that inflammasome activation plays a pivotal role in the onset and progression of AD by promoting neuronal damage, Tau pathology, and amyloid-β (Aβ) accumulation. Among the various inflammasome types expressed in the central nervous system (CNS), NLRP3 has received particular attention due to its strong association with both AD and pain-related neuroinflammation. Chronic pain, frequently observed in older adults and individuals with dementia, shares overlapping inflammatory mechanisms with AD, including glial activation and cytokine dysregulation. The inflammasome-microRNA (miR) axis has recently emerged as a key regulatory pathway modulating these neuroinflammatory responses. Specific inflammation-associated miRs, such as miR-22, miR-34a, miR-146a, miR-155, and miR-223, influence innate immune signaling and critically affect both neuronal homeostasis and pain sensitization. Emerging evidence also implicates dysfunction of the locus coeruleus-noradrenergic (LC-NE) system-an early target of AD pathology-in amplifying neuroinflammation and pain sensitivity, partly through interactions with dysregulated miRs. While previous studies have addressed the roles of inflamma-miRs in AD or chronic pain individually, this review uniquely examines their interconnected roles-highlighting how dysregulated miR expression and inflammasome activation may converge to drive persistent neuroinflammation across both conditions. By elucidating shared molecular pathways, we propose that targeting the inflammasome-miR axis may offer dual therapeutic potential: slowing AD progression while addressing pain-related neural dysfunction. As the prevalence of AD rises, such integrated insights are essential for the development of more precise, mechanism-based interventions.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Retinal Pigment Epithelium Phagocytosis and Retinal Degenerative Diseases.","authors":"Yuxiang Du, Yong Xia","doi":"10.14336/AD.2025.0542","DOIUrl":"https://doi.org/10.14336/AD.2025.0542","url":null,"abstract":"<p><p>In the mammalian retina, photoreceptors rely on the continuous renewal of their outer segments to preserve their function as light-sensing cells, thereby ensuring lifelong vision. This process entails the routine phagocytosis of shed photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE). Phagocytosis of POS by RPE is a highly circadian-regulated process that is dependent on intricate and tightly controlled cellular signaling pathways. This article provides a systematic review of the research on the regulation and functional implications of the RPE phagocytic signaling system. Therefore, a deeper understanding of the role of retinal pigment epithelial phagocytosis in the pathogenesis of retinal degeneration can inform the development of potential therapeutic targets to prevent the irreversible loss of retinal pigment epithelium and photoreceptor cells, thereby preventing retinal degenerative diseases. This article summarizes the soluble and membrane-bound molecules produced by the RPE that are associated with phagocytosis and discusses their specific roles in POS phagocytosis and retinal degenerative disorders, potentially aiding in the prevention or treatment of retinal degenerative diseases.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuangshuang Hai, Yadan Hou, Meiyan Zhang, Xiaoyan Gao, Tuo Yang, Xiuli Shang, Xiaohong Sun
{"title":"Glucose Metabolism, Lactate, Lactylation and Alzheimer's Disease.","authors":"Shuangshuang Hai, Yadan Hou, Meiyan Zhang, Xiaoyan Gao, Tuo Yang, Xiuli Shang, Xiaohong Sun","doi":"10.14336/AD.2025.0338","DOIUrl":"https://doi.org/10.14336/AD.2025.0338","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by cognitive decline; however, its pathogenesis remains incompletely understood. In recent years, the role of lactate metabolism and its derived lactylation modifications in AD has received increasing attention. As a product of glycolysis, lactate is not only a key molecule in energy metabolism but also regulates gene expression and protein function through lactylation modifications. Studies have shown that in the brains of AD patients, glucose metabolism is significantly reduced, while glycolysis is upregulated, and lactate levels are elevated. Nevertheless, the research regarding the relationship between lactylation and AD remains limited. Building on recent advances in understanding lactylation in neurodegenerative diseases and related conditions, we analyze and explore the potential relationships between lactylation and AD from the perspectives of β-amyloid (Aβ) deposition, tau protein pathology, and neuroinflammation. In summary, lactylation, as a novel post-translational modification holds significant promise in elucidating the pathological mechanisms and advancing the treatment of AD. A deeper investigation into its molecular mechanisms and regulatory networks may open new avenues for the diagnosis and treatment of AD.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hong Wu, Jia-Yi Wu, Shao-Jie Gao, Lin Liu, Xin-Yi Dai, Wen-Lu Song, Long-Qing Zhang, Dai-Qiang Liu, Ying-Xin Tang, Ya-Qun Zhou, Wei Mei
{"title":"Resveratrol: Harnessing Nature's Potential for Chronic Pain Relief.","authors":"Hong Wu, Jia-Yi Wu, Shao-Jie Gao, Lin Liu, Xin-Yi Dai, Wen-Lu Song, Long-Qing Zhang, Dai-Qiang Liu, Ying-Xin Tang, Ya-Qun Zhou, Wei Mei","doi":"10.14336/AD.2025.0530","DOIUrl":"https://doi.org/10.14336/AD.2025.0530","url":null,"abstract":"<p><p>Resveratrol, a natural polyphenol with anti-inflammatory, antioxidant, and neuroprotective properties, shows great potential in managing chronic pain. This review explores its analgesic mechanisms, including the inhibition of neuroinflammation, enhancement of antioxidant activity, induction of autophagy, reduction of endoplasmic reticulum stress, modulation of the serotonin system, restoration of gut microbiota homeostasis, regulation of the neuroendocrine system, and promotion of mitochondrial biogenesis. While its analgesic potential is considerable, future research should prioritize enhancing its bioavailability, investigating drug interactions, and confirming long-term safety to develop more effective therapies for chronic pain.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
YuXing Zhang, Ahmad El Hamamy, Zahid Iqbal, Arya Ranjan, Destiny Sumani, Hung Wen Lin, Louise D McCullough, Jun Li
{"title":"Stroke Exacerbates Respiratory Disorder and Cognition Impairment in Mice with Cerebral Amyloid Angiopathy.","authors":"YuXing Zhang, Ahmad El Hamamy, Zahid Iqbal, Arya Ranjan, Destiny Sumani, Hung Wen Lin, Louise D McCullough, Jun Li","doi":"10.14336/AD.2025.0474","DOIUrl":"https://doi.org/10.14336/AD.2025.0474","url":null,"abstract":"<p><p>Stroke is a known risk factor for dementia. Most Alzheimer's patients exhibit mixed neuropathology, with evidence of both ischemic damage and amyloid-beta (Aβ) plaque accumulation. Breathing disorders, such as apnea, are also associated with cognitive dysfunction and dementia progression. We hypothesized that stroke exacerbates respiratory dysfunction and cognitive impairment in Tg-SwDI mice, a model of cerebral amyloid angiopathy (CAA). Female CAA mice (11-13 months old) underwent permanent distal middle cerebral artery occlusion (pd-MCAO) surgery, with age- and sex-matched wild-type and sham-operated controls. Cognitive assessments included the Barnes maze, and novel object recognition test (NORT). Respiratory metrics were quantified using whole-body plethysmography, while immunohistochemistry measured Aβ deposition in the hippocampus and cortex, astrocytic markers (C3⁺GFAP⁺ for A1; S100A10⁺GFAP⁺ for A2) in the retrotrapezoid nucleus (RTN), and lymphatic vessel area (LYVE1) in deep cervical lymph nodes (dCLNs). Aβ in cerebrospinal fluid was also assessed. CAA mice without stroke exhibited higher apnea rates and impaired cognitive performance compared to wild-type controls. Stroke further increased apnea events and worsened Barnes maze escape latencies in CAA mice. Molecular analysis revealed an increase in GFAP as well as in A1 astrocytes and a reduction in A2 astrocytes in the RTN following stroke. Additionally, stroke accelerated Aβ deposition in the hippocampus and cortex while reducing Aβ clearance via cerebrospinal fluid and dCLNs. These findings suggest that stroke exacerbates respiratory dysfunction, impairs glymphatic-lymphatic clearance, and accelerates cognitive decline in CAA mice. Targeting post-stroke respiratory dysfunction may offer therapeutic potential for mitigating ischemic damage in dementia patients.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exercise-Induced Short-Chain Fatty Acids: A Novel Therapeutic Target in Type 2 Diabetes Mellitus with Sarcopenia.","authors":"Fan Shi, Jun Chen","doi":"10.14336/AD.2025.0670","DOIUrl":"https://doi.org/10.14336/AD.2025.0670","url":null,"abstract":"<p><p>Type 2 diabetes mellitus accompanied by sarcopenia is an emerging clinical challenge in aging populations, characterized by coexisting metabolic dysfunction and the progressive loss of skeletal muscle mass and function. This comorbidity substantially elevates the risk of frailty, functional impairment, and poor clinical outcomes, highlighting the urgent need for targeted therapeutic interventions. Growing evidence suggests that gut microbiota dysbiosis contributes to the pathogenesis of both Type 2 diabetes mellitus and sarcopenia through mechanisms such as chronic inflammation, insulin resistance, and mitochondrial and autophagic dysfunction. Among gut-derived metabolites, short-chain fatty acids exert anti-inflammatory and insulin-sensitizing effects and also promote muscle metabolism and mitochondrial function. Notably, exercise increases the abundance of short-chain fatty acid-producing bacteria, thereby elevating circulating short-chain fatty acid levels and contributing to improved glucose homeostasis and skeletal muscle function. This review summarizes the effects of various exercise modalities on short-chain fatty acid production and explores the mechanisms by which short-chain fatty acids mediate the benefits of exercise in Type 2 diabetes mellitus complicated by sarcopenia, emphasizing their potential as novel therapeutic targets for integrated disease management.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrés M Baraibar, Carlos G Ardanaz, Susana Mato, Paulo Kofuji, Alfonso Araque, Maite Solas
{"title":"Astrocytic Glucose Sensing Drives Synaptic Depression under Metabolic Stress.","authors":"Andrés M Baraibar, Carlos G Ardanaz, Susana Mato, Paulo Kofuji, Alfonso Araque, Maite Solas","doi":"10.14336/AD.2025.0507","DOIUrl":"https://doi.org/10.14336/AD.2025.0507","url":null,"abstract":"<p><p>Glucose is the primary energy source for the brain, and its continuous supply is essential for neuronal function. Astrocytes play a pivotal role in brain energy metabolism by mediating glucose uptake, sensing metabolic fluctuations, and modulating synaptic activity. However, astrocyte responses to transient glucose deprivation remain incompletely understood. Here, we demonstrate that astrocytic glucose uptake is crucial for network adaptation to metabolic stress. Using electrophysiology and calcium imaging approaches, we show that glucose deprivation depresses hippocampal synaptic transmission through an astrocyte-dependent mechanism that involves decreased glucose transporter 1 (GLUT1)-facilitated extracellular glucose uptake, intracellular calcium elevations, and ATP/adenosine-mediated signaling, which leads to excitatory neurotransmission depression via A1 receptors. Moreover, astrocyte-specific GLUT1 depletion prevents astrocytic responses to glucose deprivation and precludes the effects of glucose deprivation on synaptic transmission, thereby indicating that GLUT1-dependent glucose uptake is involved in astrocyte-mediated modulation of synaptic function. These findings extend the concept of astrocytic metabolic regulation beyond regions canonically classified as glucose-sensing and establish astrocytes as key integrators of energy availability and synaptic function. Our study provides new insights into the role of astrocytes in brain energy homeostasis and identifies potential therapeutic targets for metabolic disorders affecting the nervous system.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}