Aging Cell最新文献

{"title":"MTR4: A Conserved Youth Factor for Vascular Endothelium.","authors":"Zhenyuan Guo, Zhiqiang Chen, Jiaqi Sun, Xiaojun Zhou, Chengzhi Ni, Yuxiang Zhang, Pengfei Qiang, Lu Zhang","doi":"10.1111/acel.70774","DOIUrl":"10.1111/acel.70774","url":null,"abstract":"<p><p>Vascular endothelial cell (VEC) senescence drives organismal aging and age-related pathologies, yet the intrinsic factors preserving endothelial youthfulness remain poorly defined. Here, we identify MTR4, an evolutionarily conserved RNA helicase and nuclear RNA exosome cofactor, as a novel regulator of VEC senescence. MTR4 protein declines markedly in senescent HUVECs and aged mouse aortas, independent of general cell cycle exit. Mechanistically, senescence-induced upregulation of the E3 ubiquitin ligase synoviolin 1 (SYVN1) promotes K638-linked ubiquitination and proteasomal degradation of MTR4. MTR4 depletion drives proliferating HUVECs into premature senescence, whereas its overexpression restores a youthful phenotype in senescent cells by binding BUB3 to stabilize BUB3 and sustain BUBR1 expression. In mice, endothelial Mtr4 knockdown promotes vascular dysfunction and multi-organ aging, while endothelium-specific Mtr4 overexpression alleviates these phenotypes. In C. elegans, mtr-4 overexpression dramatically extends lifespan, comparable to classic longevity models and surpassing most single-gene interventions, while its knockdown accelerates aging. Our findings establish MTR4 as a critical guardian of endothelial homeostasis and organismal aging, with strong translational potential for mitigating age-related vascular dysfunction.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70774"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190122","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":"Young Mice Exhibit Increased Relative Ventricular Remodeling After AMI-A Longitudinal CMR Study.","authors":"Heiko Lemcke, Paul Wörner, Antonia Dalmer, Ralf Gäbel, Praveen Vasudevan, Matti Raitza, Moritz Schweins, Tobias Lindner, Hüseyin Ince, Bernd Joachim Krause, Brigitte Vollmar, Robert David, Felix G Meinel, Cajetan Immanuel Lang","doi":"10.1111/acel.70748","DOIUrl":"https://doi.org/10.1111/acel.70748","url":null,"abstract":"<p><p>Cardiovascular diseases are the leading cause of mortality worldwide, with myocardial infarction (MI) contributing significantly to this burden. While age-related differences in cardiac remodeling and healing post MI are well-documented clinically, appropriate pre-clinical studies are needed to evaluate the underlying pathological mechanisms and to further improve therapeutic interventions. Here, we compared LV remodeling between young and aged C57BL/6 mice, following permanent LAD ligation, using CMR imaging after 2, 7, and 28 days of MI induction. At baseline conditions, aged mice exhibited higher end-diastolic and end-systolic volumes and tended to have a reduced deformation capacity. Post-MI, both groups showed significant LV dilation, loss of contractility, and impaired ejection fraction. Interestingly, young mice undergo larger proportional geometric changes relative to their pre-infarction state. At the same time, histological data of labeled heart sections pointed to a more rapid healing process in young animals. These findings highlight the critical role of age in modulating cardiac remodeling and, thus, challenge the commonly held hypothesis of an age-dependent increase of LV remodeling.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70748"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13627973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101634","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":"Novel Flavonoid Senotherapeutics Identified by Phenotypic Drug Discovery Reduce Senescence and Improve Multiple Markers of Healthspan.","authors":"Lei Justan Zhang, Rahagir Salekeen, Carolina Soto-Palma, Qiuming Wu, Yuanjun He, Osama Elsallabi, Bilel Bdiri, Brian Hughes, Allancer Nunes, Wandi Xu, Borui Zhang, Abdalla Mohamed, Sara J McGowan, Luise Angelini, Ryan O'Kelly, Theodore M Kamenecka, Laura J Niedernhofer, Paul D Robbins","doi":"10.1111/acel.70736","DOIUrl":"10.1111/acel.70736","url":null,"abstract":"<p><p>Senescent cells are a key driver of aging and contribute to many age-related diseases. Senolytics, agents that selectively eliminate senescent cells, offer a promising therapeutic strategy to treat age-related diseases but face significant barriers to clinical translation. Fisetin, a natural flavonoid senolytic, has progressed to clinical trials but is limited by suboptimal efficacy and poor bioavailability. To address these challenges, we developed two novel fisetin-derived flavonoid senolytics, SR29384 and SR31133, using an integrative phenotypic drug discovery approach. These compounds exhibit enhanced senolytic activity, targeting a broad range of senescent cell types, reducing tissue senescence, and improving healthspan-associated parameters in mouse models of aging. Mechanistic investigations combining transcriptomics, machine learning, network pharmacology, and molecular docking revealed that these novel senolytics may target key molecular pathways, including PARP1, CDK2, and possibly BCL-xL to selectively induce apoptosis in senescent cells. These findings provide novel senolytics with high translational potential for clinical applications in promoting healthy aging and treating age-related diseases.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70736"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13640056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101686","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":"ZNF865 (BLST) a Novel Regulator of DNA Damage and Cell Senescence in Back Pain.","authors":"Christian Lewis, Hunter Levis, Jonah Holbrook, Jacob T Polaski, Timothy D Jacobsen, Josh Mizels, Molly Czachor, Sarah E Gullbrand, Brian Diekman, James C Iatridis, Jason Gertz, Brandon Lawrence, Robby D Bowles","doi":"10.1111/acel.70754","DOIUrl":"10.1111/acel.70754","url":null,"abstract":"<p><p>Senescence has been shown to contribute to the progression of aging-related diseases including degenerative disc disease (DDD). However, the mechanisms regulating senescence in the intervertebral disc (IVD) and other tissues/diseases remain poorly understood. Recently, ZNF865 (BLST) was identified as a previously uncharacterized zinc finger protein that regulates a wide array of genes related to protein processing, cell senescence, and DNA damage repair. Here, we show that ZNF865 expression decreases with age and pathology in human and mouse IVD samples. Utilizing CRISPR-guided gene modulation, we show that ZNF865 is necessary for healthy cell function and is a critical protein in regulating senescence and DNA damage in IVD cells, with implications for a wide range of tissues and organs. We also demonstrate that downregulation of ZNF865 induces senescence in asymptomatic human nucleus pulposus (NP) cells. Conversely, restoration in degenerative NP cells mitigates senescence, SASP expression, and DNA damage, enhances ECM anabolism, and restores chromatin accessibility and gene expression to a healthy state. In vivo, CRISPRi of ZNF865 induces disc degeneration and painful behaviors. Collectively, our findings establish ZNF865 as a novel regulator of genome stability and a potential therapeutic target for mediating senescence/DNA damage in aging related diseases.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70754"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653039/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149147113","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":"Ginsenoside Rg3 Promotes Healthy Aging Through Phosphoinositide-Associated Lysosomal Regulation in Caenorhabditis elegans.","authors":"Haiyang Yu, Shiming Li, Yongsheng Chen, Yaoyong Zeng, Junbu Li, Yuxin Guo, Wanxiang Zhang, Lizhu Zhang, Longnong You, Kuncan Chen, Jinhong Wu, Dan Gan, Jiane-Kang Liu, Lingjun Zheng","doi":"10.1111/acel.70755","DOIUrl":"https://doi.org/10.1111/acel.70755","url":null,"abstract":"<p><p>Lysosomal decline and proteostasis collapse are defining features of aging and major contributors to neurodegenerative vulnerability, yet interventions that preserve neuronal lysosomal function across aging remain poorly defined. Here, we identify 20(S)-ginsenoside Rg3, a ginseng-derived natural product, as a geroprotective small molecule in Caenorhabditis elegans. Rg3 extended lifespan and preserved key physiological outputs, including locomotion and pharyngeal pumping, indicating that Rg3 delays functional aging. Rg3 also maintained mechanosensory neuron integrity and touch sensitivity, suppressed neuronal polyglutamine aggregation, and protected dopaminergic neurons against α-synuclein-induced degeneration. At the cellular level, Rg3 restored age-impaired lysosomal function and autophagic flux in neurons. Mechanistically, Rg3 shifted neuronal phosphoinositide reporter signatures toward a PI(4)P-enriched and PI(3)P-reduced state, consistent with signaling lipid remodeling at lysosomal membranes. This phosphoinositide shift coincided with reduced RSKS-1/S6K phosphorylation, indicating suppression of TOR complex 1 (TORC1), and promoted nuclear localization of HLH-30, the C. elegans ortholog of transcription factor EB (TFEB), thereby engaging a conserved lysosomal program. Collectively, these results define Rg3 as a natural-product geroprotector that couples lysosomal lipid remodeling to TORC1-HLH-30 signaling to preserve lysosomal competence, neuronal proteostasis, and organismal fitness during aging. Our study nominates phosphoinositide control of lysosomal identity as a therapeutic entry point for healthy aging and neuroprotection.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70755"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13653540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163762","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":"Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age-Related Bioenergetic Remodeling, and Microglial STING Phenotypes.","authors":"McKenna M Somerville, Sydney S Lin, Scott W Ballinger, Alecia K Gross","doi":"10.1111/acel.70771","DOIUrl":"10.1111/acel.70771","url":null,"abstract":"<p><p>Mitochondria are central regulators of retinal bioenergetics and innate immune signaling, yet how mitochondrial genetic background and aging jointly influence immunometabolic responses in the retina remains poorly defined. Here, we investigated the effects of mitochondrial DNA (mtDNA) variation on retinal function and the combined effects of mtDNA variation and age on bioenergetic composition, mtDNA damage, and the microglial expression and intracellular localization of stimulator of interferon genes (STING) protein. Using mitochondrial-nuclear eXchange (MNX) mice harboring identical C57BL/6J nuclear genomes but distinct C57 or C3H mtDNA haplotypes, we assessed oxidative phosphorylation complex composition, electrophysiological function, mtDNA damage, and microglial STING dynamics across the lifespan and following acute intraocular pressure (IOP) elevation. Aging was associated with increased mtDNA damage and remodeling of oxidative phosphorylation complex composition, characterized by reduced Complex III and V abundance and increased Complex IV. Despite these age-associated changes, photoreceptor- and retinal ganglion cell-associated retinal responses were preserved at early ages, whereas bipolar cell-associated responses differed by mtDNA background. Microglial STING expression increased with age. Acute IOP elevation was associated with differential microglial STING dynamics and STING association with lysosomal compartments decreased with age. Together, these findings demonstrate that mitochondrial genetic background and aging influence retinal bioenergetics and neuroimmune protein expression and identify mtDNA variation as a modifier of age-associated microglial STING expression in the retina.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70771"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190089","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":"Single-Cell Mapping Identifies Aging-Associated Neutrophil Remodeling Across Multiple Organs.","authors":"Yuman Wang, Teding Chang, Yangguang Fu, Guangyu Liang, Huicheng Liu, Le Zhang, Jinhua Yan, Man Liu, Anding Liu, Cuntai Zhang","doi":"10.1111/acel.70735","DOIUrl":"10.1111/acel.70735","url":null,"abstract":"<p><p>Aging is accompanied by progressive immune remodeling and functional decline across multiple organs. However, the role of neutrophils and their heterogeneous states in these processes remains incompletely understood. Here we integrated single-cell RNA sequencing datasets from multiple organs of young and aged mice to characterize aging-associated neutrophil remodeling. We identified organ-dependent changes in neutrophil abundance and state composition, together with neutrophil subsets enriched for inflammatory, oxidative stress, complement, and IL-6-related transcriptional programs. In vitro, exposure to conditioned media from neutrophils isolated from aged mice or IL-6-stimulated neutrophil-like cells increased inflammatory and senescence-associated responses in vascular smooth muscle and hepatocyte-derived cells. Bone marrow single-cell analysis further revealed aging-associated shifts in progenitor composition and transcriptional states, including an old-enriched HPC11 population characterized by enhanced myeloid priming. Silico perturbation analysis nominated FGF didate regulators of HPC subtype-specific transcriptional programs. Together, our study provides a multi-organ single-cell resource for defining neutrophil remodeling during aging and highlights candidate neutrophil states and potential signaling axes associated with age-related inflammatory tissue environments.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70735"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13624379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079306","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":"Multimodal Ageing Biomarkers and Plasma Proteomic Signatures Associated With All-Cause Mortality.","authors":"Maira Pyrgioti, Ines Mesa Eguiagaray, Paul Redmond, Janie Corley, Mark E Bastin, Maria Valdés Hernández, Tom C Russ, Joanna M Wardlaw, Eilis Hannon, Ian J Deary, Keenan A Walker, Elliot M Tucker-Drob, Simon R Cox, Riccardo E Marioni, Sarah E Harris","doi":"10.1111/acel.70747","DOIUrl":"https://doi.org/10.1111/acel.70747","url":null,"abstract":"<p><p>Ageing biomarkers quantify molecular, physiological or functional features that vary between individuals as they age and may improve prediction of health outcomes beyond chronological age. Recently, plasma proteomics have been used to estimate the biological ages of 11 human organs. Although accelerated organ ageing is associated with higher mortality risk, systematic benchmarking against established ageing biomarkers is lacking. Here, we pursued two complementary aims. First, we benchmarked proteomic organ clocks against multimodal ageing biomarkers for associations with 16-year all-cause mortality in the Lothian Birth Cohort 1936 (LBC1936) using Cox regression (861 participants; 444 deaths). Biomarkers included the epigenetic clock GrimAge2, telomere length, physical function (grip strength, walk time and respiratory function), neuroimaging and cognitive measures. Among proteomic clocks, accelerated liver (HR_perSD [95% CI] = 1.43 [1.30-1.58]), immune (1.42 [1.29-1.57]) and heart (1.38 [1.25-1.53]) ageing were most strongly associated with increased mortality risk. However, older epigenetic age, smaller total brain and grey matter volumes, reduced respiratory function and poorer cognition showed stronger associations with mortality (HR_perSD = 1.44-1.62). Second, survival analyses of 9703 plasma protein targets identified 368 candidates associated with mortality, with high-risk proteins enriched for immune functions, and low-risk proteins involved in genomic stability and cellular maintenance. GDF15 (HR_perSD [95% CI] = 1.56 [1.42-1.72]), WFDC2 (1.47 [1.33-1.62]) and TIMP1 (1.45 [1.29-1.62]) were the leading proteomic candidates associated with mortality. This study provides a systematic, cross-modal benchmarking of proteomic organ clocks against established ageing biomarkers and identifies proteins and biological functions associated with mortality risk.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70747"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101673","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":"High-Fat Diet-Induced Metabolic Stress Durably Reprograms the Liver Regenerative Compartment Toward a Senescence-Like State.","authors":"Mirai Yamazaki, Hiroya Yamada, Eiji Munetsuna, Yoshitaka Ando, Genki Mizuno, Takuya Wakasugi, Tomohide Sakakibara, Kumpei Hada, Hayato Ichikawa, Ryoga Senga, Moeno Asai, Hiroaki Ishikawa, Koji Suzuki, Koji Ohashi, Nobutaka Ohgami","doi":"10.1111/acel.70769","DOIUrl":"10.1111/acel.70769","url":null,"abstract":"<p><p>Chronic metabolic stress is increasingly recognized as a driver of aging-like tissue dysfunction, but whether it durably reprograms liver regenerative cells, potentially compromising tissue maintenance and repair, remains unknown. Here, we show that high-fat diet (HFD)-induced metabolic stress promotes a persistent senescence-like state in the liver regenerative compartment. In male rats, chronic HFD feeding induced hepatic steatosis together with oxidative stress, inflammatory responses, and senescence-associated changes. Following carbon tetrachloride-induced liver injury, HFD-fed animals exhibited reduced proliferative responses. To determine whether these abnormalities were durably retained within regenerative cell populations, we established liver organoids from control and HFD-fed rats. HF-derived organoids showed reduced formation efficiency and impaired serial propagation capacity outside the original metabolic environment. Senescence-associated abnormalities, including increased senescence-associated β-galactosidase staining, reduced Lamin B1 staining, and decreased Ki67 positivity, remained detectable through Passage 3. Transcriptomic and functional analyses revealed mitochondrial dysfunction and enhanced oxidative and inflammatory responses. These organoids also exhibited enhanced lipid accumulation and inflammatory secretion following fatty acid challenge. Treatment with the mitochondria-targeted antioxidant MitoQ reduced oxidative stress and inflammatory secretion, improved oxygen consumption, and partially restored organoid formation efficiency, supporting a functional contribution of mitochondrial dysfunction to regenerative impairment. Together, these findings support a model in which chronic metabolic stress leaves persistent senescence-like dysfunction within the liver regenerative compartment, extending its consequences beyond abnormalities in mature liver tissue.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 10","pages":"e70769"},"PeriodicalIF":7.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13673232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149190450","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":"3D Culture Reverses Limbal Niche Cell Replicative Aging via FOSL1 Upregulation.","authors":"Xuying Wang, Shen Li, Zibin Liu, Xinghan Guo, Jiachao Shen, Tianyu Zhou, Shuying Liao, Xiaoyu Huang, Wei Wang, Lingjuan Xu, Xinjie Zang, Guigang Li","doi":"10.1111/acel.70705","DOIUrl":"10.1111/acel.70705","url":null,"abstract":"<p><p>Limbal niche cells (LNCs) serve as essential regulators of limbal microenvironmental homeostasis and corneal epithelial wound repair, representing a promising therapeutic resource for limbal stem cell deficiency (LSCD). However, their clinical application is constrained by replicative aging during in vitro expansion. In this study, we investigated whether a three-dimensional (3D) Matrigel-based culture system could modulate replicative aging in LNCs. Compared with conventional two-dimensional (2D) culture, 3D-cultured LNCs restored stemness marker expression and enhanced proliferative capacity. Concurrently, these cells displayed reduced senescence-associated β-galactosidase (SA-β-gal) activity and decreased expression of senescence-associated proteins, including p16, p21, p53, and γ-H2AX. Single-cell RNA sequencing (scRNA-seq) analysis revealed prominent upregulation of FOS-like antigen 1 (FOSL1). FOSL1 is a component of the AP-1 transcription factor family and participates in cell proliferation and stress adaptation. Functional assays using an in vitro replicative aging model showed that FOSL1 knockdown in early-passage (P4) LNCs accelerated senescence, whereas FOSL1 overexpression in late-passage (P11) LNCs attenuated senescence. Mechanistically, FOSL1 knockdown induced mitochondrial dysfunction characterized by elevated levels of mitochondrial superoxide and cellular reactive oxygen species (ROS), as well as a decrease in mitochondrial membrane potential, while FOSL1 overexpression preserved mitochondrial integrity and function. Collectively, our findings demonstrate that 3D culture reverses LNC replicative aging through FOSL1-mediated enhancement of mitochondrial function, providing a microenvironment-based strategy to counteract replicative aging in adult stem cells for corneal regenerative therapy.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 9","pages":"e70705"},"PeriodicalIF":7.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910212","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}