Aging Cell最新文献

{"title":"Skeletal Maturity and Age-Related Changes in Immune Cells and Circulatory Factors Impair Large-Scale Bone Regeneration.","authors":"Luciana Yamamoto de Almeida, Catharine Dietrich, Ashleigh S Hanner, Katelyn M McTighe, Daniel Martin, Todd Fairbanks, Thomas M Link, John M Le, Natasha Curry, Priyam Jani, Xin Gao, Wenli Yu, Francesca V Mariani, Olivier Duverger, Janice S Lee","doi":"10.1111/acel.70177","DOIUrl":"https://doi.org/10.1111/acel.70177","url":null,"abstract":"<p><p>Large-scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarkable ability to spontaneously regenerate large-scale bone defects. However, we show here that skeletal maturity and age are associated with a decrease in the regenerative potential of human ribs. To investigate skeletal maturity and age-related cellular and transcriptional changes during large-scale bone regeneration, we used a mouse model that mimics the regenerative clinical features of human ribs. Unlike immature mice, mature mice lose the ability to regenerate after rib resection, and instead of bone, the resected rib space is repaired with abundant fibronectin cells. In addition, bone repair in mature mice presents reduced immune cell infiltration, which coincides with decreased levels of circulatory pro-inflammatory factors. To address the role of cell-cell communication and test whether skeletal maturity and age-related changes in immune cells and circulatory factors influence bone regeneration, we used immunodeficient mouse strains and performed heterochronic parabiosis. In immature mice, defective immune cell function altered callus composition rather than inhibiting bone regeneration. Remarkably, under parabiosis, a systemic pro-regenerative response is triggered exclusively in resected immature mice and is capable of partially rescuing bone regeneration in mature mice otherwise unable to regenerate spontaneously. Collectively, these findings suggest that therapeutic strategies focused on identifying pro-regenerative immune factors are promising for supporting the regeneration of large bone defects.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70177"},"PeriodicalIF":8.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673412","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":"Smoking Promotes AT2 Cell Senescence and Exacerbates Pulmonary Fibrosis by Downregulating POT1 via Integratively Inducing CpG Methylation and MECP2-Mediated FOXP2 Transcriptional Binding Inhibition.","authors":"Mengkun Shi, Wei Wang, Posum Wan, Jialun Shi, Huixia Cui, Zhonghan Sun, Xiaofeng Chen, Jingyu Chen, Jiucun Wang, Xiangguang Shi","doi":"10.1111/acel.70174","DOIUrl":"https://doi.org/10.1111/acel.70174","url":null,"abstract":"<p><p>Smoking is one of the most recognized risk factors for pulmonary fibrosis (PF). However, the underlying mechanism is not well understood. This study reveals smoking increases the risk of developing idiopathic PF (IPF) and that smoked IPF patients exhibit higher levels of senescence markers than non-smoker IPF patients. Moreover, smoking enhances bleomycin (Bleo)-induced PF, along with obvious senescence of type II alveolar (AT2) cells. RNA-seq assay identifies cigarette downregulates protection of telomeres 1 (POT1), which is then validated to decrease in smoked PF patients and mice via upregulating the methyltransferase MECP2. Mechanistically, MECP2 binds to the DNA methyltransferases (DNMTs)-induced methylated CpG island in the POT1 promoter, and smoking inhibits the transcriptional activity of the CpG island. The transcription factor FOXP2 could bind to this CpG island to promote POT1 transcription. However, this process is inhibited by forming a MECP2-FOXP2 complex, which blunts the FOXP2-POT1 DNA binding. siRNA-mediated POT1 knockdown promoted AT2 cell senescence in a p-ATM and p-ATR-dependent manner and secreted inflammatory and profibrotic factors, further promoting fibrotic response in fibroblasts. In vivo, delivery of the adeno-associated virus 9-POT1 (AAV9-POT1) vector inhibits cigarette-induced cell senescence and effectively alleviates PF in mice. These findings demonstrate that POT1 is an essential protector in PF by protecting against AT2 cell senescence.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70174"},"PeriodicalIF":8.0,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144673413","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":"Beyond the Pseudogene: p17/PERMIT as a Mitochondrial Trafficking Protein Linking Aging and Neurodegeneration.","authors":"Onder Albayram, Natalia Oleinik, Besim Ogretmen","doi":"10.1111/acel.70175","DOIUrl":"https://doi.org/10.1111/acel.70175","url":null,"abstract":"<p><p>The misclassification of functional genomic loci as pseudogenes has long obscured critical regulators of cellular homeostasis, particularly in aging-related pathways. One such locus, originally annotated as RPL29P31, encodes a 17-kDa protein now redefined as PERMIT (Protein that Mediates ER-Mitochondria Trafficking). Through rigorous experimental validation-including antibody development, gene editing, lipidomics, and translational models-p17/PERMIT has emerged as a previously unrecognized mitochondrial trafficking chaperone. Under aging or injury-induced stress, p17 mediates the ER-to-mitochondria translocation of Ceramide Synthase 1 (CerS1), facilitating localized C18-ceramide synthesis and autophagosome recruitment to initiate mitophagy. Loss of p17 impairs mitochondrial quality control, accelerating neurodegeneration, and sensorimotor decline in both injury and aging models. This Perspective highlights p17 as a paradigm-shifting discovery at the intersection of lipid signaling, mitochondrial biology, and genome reannotation, and calls for a broader reassessment of the \"noncoding\" genome in aging research. We summarize a rigorous multi-platform validation pipeline-including gene editing, antibody generation, lipidomics, proteomics, and functional rescue assays-that reclassified p17 as a bona fide mitochondrial trafficking protein. Positioned at the intersection of lipid metabolism, organelle dynamics, and genome reannotation, p17 exemplifies a growing class of overlooked proteins emerging from loci historically labeled as pseudogenes, urging a systematic reevaluation of the \"noncoding\" genome in aging research.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70175"},"PeriodicalIF":8.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648067","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":"Age-Dependent Histone Deacetylase 3 Regulation by βA3/A1-Crystallin and Inositol Hexaphosphate in Retinal Pigmented Epithelial Cells Reveals a Novel Pathway in Age-Related Macular Degeneration.","authors":"Sujan Chatterjee, Sayan Ghosh, Zachary Sin, Vishnu Suresh Babu, Loretta Viera Preval, Emily Davis, Nguyen Tran, Sridhar Bammidi, Pooja Gautam, Stacey Hose, Yuri Sergeev, Miguel Flores-Bellver, Kevin Ritter, Henning J Jessen, Issam Al Diri, Debasish Sinha, Prasun Guha","doi":"10.1111/acel.70163","DOIUrl":"10.1111/acel.70163","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome-wide association studies (GWAS) risk variants. Our research on Cryba1, encoding βA3/A1-crystallin protein, reveals its crucial role in RPE cell function via a novel epigenetic mechanism, also evident in human atrophic AMD samples. Loss of Cryba1 in mouse RPE cells triggers epigenetic changes by reducing histone deacetylase 3 (HDAC3) activity through two mechanisms. First, Cryba1 depletion reduces inositol polyphosphate multikinase (IPMK) expression, which potentially reduces inositol hexakisphosphate (InsP6) generation since IPMK's kinase activity is essential for producing InsP4 and InsP5 as precursors to InsP6. Since InsP4, InsP5, or InsP6 is crucial for HDAC3's interaction with the corepressor's DAD domains, reduced IPMK expression in Cryba1-depleted cells likely diminishes the HDAC3-DAD interaction, leading to a reduction in HDAC3's activity. Second, reduced βA3/A1 protein in Cryba1-deficient cells impairs HDAC3's interaction with casein kinase 2 (CK2), resulting in decreased HDAC3 phosphorylation. Collectively, this increases H3K27 acetylation at the RET promoter region, likely enhancing the transcription of RET, a receptor tyrosine kinase critical for cell survival. Although RET is transcriptionally increased, Cryba1 loss disrupts its protein maturation, causing immature RET protein accumulation. This triggers age-dependent endoplasmic reticulum (ER) stress, potentially contributing to the pathogenesis of AMD. Interestingly, although Cryba1 is not identified as an AMD-linked variant in current GWAS, its loss may be linked to AMD mechanisms. These findings underscore the potential of gene-agnostic and epigenetic therapeutic strategies for treating AMD.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70163"},"PeriodicalIF":8.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635785","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 Association Between Accelerated Biological Aging and the Physical, Psychological, and Cognitive Multimorbidity and Life Expectancy: Cohort Study.","authors":"Zuliyaer Talifu, Ziyang Ren, Chen Chen, Shuai Guo, Yu Wu, Yuling Li, Binbin Su, Xiaoying Zheng","doi":"10.1111/acel.70142","DOIUrl":"https://doi.org/10.1111/acel.70142","url":null,"abstract":"<p><p>As the global population ages, multimorbidity has become a critical public health issue. We analyzed 332,012 adults from the UK Biobank (2006-2022) to investigate the association between biological age-measured by the Klemera-Doubal method (KDM-BA) and phenotypic age (PhenoAge)-and a new comorbidity model encompassing physical, psychological, and cognitive disorders, with overall mortality outcomes over a median follow-up of 13.6 years. Logistic regression models examined the association between baseline health status and accelerated aging, while Cox proportional hazards models assessed mortality risk and disorder development. Cross-sectional analysis showed that accelerated aging was linked to higher comorbidity prevalence. Longitudinal follow-up revealed that individuals in the highest quartile (Q4) of aging speed (residual difference between estimated biological age and chronological age) had a 16%-17% higher risk of developing a single disorder, a 41%-44% higher risk of multimorbidity, and a 54% higher overall mortality risk compared with the lowest quartile (Q1). Among those with baseline single disorder, dual comorbidity, and triple morbidity, Q4 mortality risk increased by 89%-116%, 118%-166%, and 119%-156%, respectively. Multistate Markov models confirmed that accelerated aging (residual > 0) increased the risk of transitioning to disorder, comorbidity, and death by 12%-37%. Individuals aged 45 with triple comorbidity lost an average of 5.3 years in life expectancy (LE), further reduced by 5.8 to 7.0 years due to accelerated aging. This study highlights that KDM-BA and PhenoAge robustly predict multimorbidity trajectories, mortality, and shortened LE, supporting their integration into risk stratification frameworks to optimize interventions for high-risk populations.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70142"},"PeriodicalIF":8.0,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615580","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":"Senescence Alters Antimicrobial Peptide Expression and Induces Amyloid-β Production in Retinal Pigment Epithelial Cells.","authors":"Jian Liu, Caijiao Yi, Jinyan Qi, Xuexue Cui, Xiangling Yuan, Wen Deng, Mei Chen, Heping Xu","doi":"10.1111/acel.70161","DOIUrl":"https://doi.org/10.1111/acel.70161","url":null,"abstract":"<p><p>Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70161"},"PeriodicalIF":8.0,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625090","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 Transcriptome Trajectory Reveals Sex- and Age-Dependent Changes in the Mouse Adrenal Gland.","authors":"Hui Wang, Ben Maggard, Huifei Sophia Zheng, Yuan Kang, Chen-Che Jeff Huang","doi":"10.1111/acel.70169","DOIUrl":"10.1111/acel.70169","url":null,"abstract":"<p><p>In both humans and mice, the adrenal gland is a sexually dimorphic organ, but the extent of this diversity throughout development remains unclear. Here, we analyzed the mouse adrenal gland transcriptome at postnatal days 0, 7, 15, 21, 28, 35, and 49 to uncover its transcriptomic trajectory. Sex-dependent differences, indicated by the number of differentially expressed genes, gradually increase over time. Two Y-linked genes are consistently expressed in male adrenal glands, suggesting that factors beyond sex hormones may contribute to adrenal sexual dimorphism. Genes involved in steroidogenesis, cholesterol synthesis, and catecholamine synthesis exhibit sex- and age-dependent differential expression. Weighted gene co-expression network analysis (WGCNA) identified many genes with known zone-specific adrenal expression, including Akr1c18, Pik3c2g, Cyp2f2, Dhcr24, Thrb, and Spp1, clustering within the same module. FRZB, a WNT inhibitor, was also part of this module, exhibiting sex- and age-dependent expression. Immunostaining confirmed that FRZB is specifically expressed in the inner cortex, aligning with other inner cortex markers. Additionally, heatmap analysis revealed that many WNT downstream genes show age-dependent increases in expression in males, corresponding to progressively lower Frzb levels, suggesting a regulatory role for Frzb in adrenal sexual dimorphism. Furthermore, collagen-related genes were highlighted in the clustered heatmap of all differentially expressed genes due to their gradual decrease in expression over time. These observations suggest that this comprehensive dataset not only enhances our understanding of adrenal development and sexual dimorphism, aids in identifying novel marker genes for specific adrenal cell types, but also holds potential for contributing to aging research.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70169"},"PeriodicalIF":8.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615581","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":"L-Tryptophan Produced by Bifidobacterium pseudocatenulatum NCU-08 Delays Aging in SAMP8 Mice by Activating the Sirt1/P53/P21/Rb Signaling Pathway.","authors":"Tangchang Xu, Xiaoyun Wu, Yifei Zhang, Yujie Cai, Xinfeng Zhang, Qingwei Zeng, Jie Luo, Jing Wei, Tingtao Chen","doi":"10.1111/acel.70166","DOIUrl":"https://doi.org/10.1111/acel.70166","url":null,"abstract":"<p><p>Gut microbiota delays aging by regulating the immune, metabolic, and neurological functions of the host. However, current research on novel probiotics with antiaging properties significantly lags, impacting their application in clinical treatments. In this study, metagenomics, culturomics, and probiotic property screening were used to identify Bifidobacterium pseudocatenulatum NCU-08 as a potential probiotic with anti-aging properties. In addition, B. pseudocatenulatum NCU-08 effectively improved the behavioral characteristics, significantly reduced the levels of the age-related protein β-galactosidase (β-gal) (BP: M = 0.81 vs. 1.13, p < 0.05), attenuated neuronal damage in the hippocampus, and improved the composition of the gut microbiota of senescence-accelerated mouse tendency-8 (SAMP8) mice. The targeted metabolomics suggested that L-tryptophan (L-Trp) may be a key substance for B. pseudocatenulatum NCU-08 to exert anti-aging effects (BP: M = 14878.6 ng/mL vs. 5464.99 ng/mL, p < 0.01). Mechanistically, using the aging model of SAMP8 mice and HT22 mouse hippocampal neuronal cells, it was found that B. pseudocatenulatum NCU-08 might enter the intestine to regulate L-Trp, and then transport it to the brain. In the brain, L-Trp was metabolized to NAD⁺, which activated the Sirt1/P53/P21/Rb signaling pathway, thereby exerting antiaging effects. Interestingly, this antiaging effect was inhibited after the intervention of the Sirt1 inhibitor EX-527. This study is the first to confirm the antiaging properties of NCU-08 isolated from the fecal samples of seven centenarians in Jiangxi Province, providing data support for the future development of probiotic preparations with antiaging effects.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70166"},"PeriodicalIF":8.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606929","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":"Transcriptional Diversity in Response to Aging Across Skeletal Muscles.","authors":"Can Liu, Dongbin Zheng, Rui Zhang, Hong Li, Xingyan Tong, Yujie Wu, Geng Zhang, Siyuan Wang, Hongyu Chen, Zhinong Ren, Ying Sun, Chengdong Wang, Desheng Li, Xuewei Li, Mingzhou Li, Long Jin","doi":"10.1111/acel.70164","DOIUrl":"https://doi.org/10.1111/acel.70164","url":null,"abstract":"<p><p>Aging leads to a gradual decline in muscle function, yet the mechanisms by which different skeletal muscles respond to aging remain unclear. Here, we constructed transcriptional maps of 11 skeletal muscles with extensive transcriptional diversity from young and old mice. Age-related changes in gene expression displayed distinct tissue-specific patterns, involving muscle diseases and metabolic processes. Notably, the mitochondrial-enriched soleus muscle exhibited superior resistance to aging compared to other skeletal muscles. Further, we generated a single-nuclei transcriptomic atlas on representative skeletal muscles, analyzing 73,170 nuclei. We found the age-related changes in the cellular composition of different skeletal muscles and the emergence of new cell states in aged mice. Among different types of myonuclei, type II myonuclei showed particular sensitivity to aging, with reduced metabolic activity of IIb myonuclei with age. We also found cell-specific changes occurring across nonmuscle nuclei populations, including adipocytes, fibro-adipogenic progenitors, and immune cells, accelerating muscle aging and associated pathologies. Intercellular communication analysis revealed more intensive intercellular interactions in aged skeletal muscles, particularly between myonuclei and other cell types. Specifically, we validated the regulatory role of the EGF/EGFR axis in age-related inflammatory processes. These findings provide insight into muscle biology and aging and highlight potential therapeutic targets for age-associated muscle disorders.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70164"},"PeriodicalIF":8.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590094","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":"Senescent Microglia Mediate Neuroinflammation-Induced Cognitive Dysfunction by Selective Elimination of Excitatory Synapses in the Hippocampal CA1.","authors":"Kai Liu, Di Fan, Hai-Peng Wu, Xiao-Yi Hu, Qiu-Li He, Xin-Miao Wu, Cui-Na Shi, Jian-Jun Yang, Mu-Huo Ji","doi":"10.1111/acel.70167","DOIUrl":"https://doi.org/10.1111/acel.70167","url":null,"abstract":"<p><p>Microglia-mediated neuroinflammation has been shown to exert an important effect on the progression of a growing number of neurodegenerative disorders. Prolonged exposure to detrimental stimuli leads to a state of progressive activation and aging-related features in microglia (also termed as senescent microglia). However, the mechanisms by which senescent microglia contribute to neuroinflammation-induced cognitive dysfunction remain to be elucidated. Here, we developed a mouse model of neuroinflammation induced by lipopolysaccharides at 0.5 mg/kg for 7 consecutive days. To evaluate cognitive function, C57BL/6J mice were employed and subjected to a series of behavioral assessments, including the open field, Y-maze, and novel object recognition tests. Employing single-cell RNA sequencing technology, we have delved into the differential expressions of RNA within microglia. Furthermore, to investigate anatomic and physiological alterations of pyramidal neurons, we utilized Golgi staining and whole-cell patch-clamp recordings, respectively. Validation of our results in protein expression was performed using western blotting and immunofluorescence. We specifically identified senescent microglia with a high expression of p16^INK4a and observed that microglia in the hippocampal CA1 region of the model exhibited signatures of elevated phagocytosis and senescence. A senolytic by ABT-737 treatment alleviated the production of senescence-associated secretory phenotypes, the accumulation of senescent microglia, and the microglial hyperphagocytosis of excitatory synapses following LPS exposures. This treatment also restored reduced excitatory synaptic transmission, impaired long-term potentiation, and cognitive function in the model. These results indicate that reducing senescent microglia may potentially serve as a therapeutic approach to prevent neuroinflammation-related cognitive dysfunction.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70167"},"PeriodicalIF":8.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582720","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}