Aging Cell最新文献

{"title":"A Prominent Pro-Inflammatory Phenotype Is Observed in Replication and Stress-Induced Senescent Mast Cells","authors":"A. Ibarra-Sánchez,&nbsp;I. Madera-Salcedo,&nbsp;D. Esparza-Reyes,&nbsp;P. Mendoza-Montiel,&nbsp;J. Padilla,&nbsp;C. González-Espinosa","doi":"10.1111/acel.70186","DOIUrl":"10.1111/acel.70186","url":null,"abstract":"<p>Mast cells (MC) are long-lived important immune effectors that control inflammation, allergies, and innate immunity reactions, but the expression of specific markers in replicative and stress-induced senescence in this cell type, together with its relevance in vivo, has not been described. Here, bone marrow-derived MCs (BMMC) were generated from young C57BL6/J mice and kept in culture for a long time or treated with the well-known stressor bacterial lipopolysaccharide (LPS) to promote replicative and stress-induced senescence, respectively. Changes in size, granularity, and expression of p16^INK4A and p21^CIP1/WAF1, together with cell cycle arrest and senescence-associated-β-Galactosidase (SA-β-Gal) activity, were observed after 12 weeks in culture, with minimal changes in cell viability but important modifications in cell metabolism. Senescence-associated secretory phenotype (SASP) included IL-23, IL-6, and VEGF, among other cytokines and chemokines. Maximal FcεRI and TLR4-dependent cell activation was diminished by replicative senescence in BMMC. Stress-induced senescence produced cell cycle arrest, increased β-Gal expression, and transient high cytokine expression. Utilizing aged MC-deficient (<i>c-Kit</i>^{<i>Wsh/Wsh</i>}) and <i>c-Kit</i>^{<i>Wsh/Wsh</i>} mice reconstituted with MC, the exacerbated cytokine production observed in senescent cells was confirmed in the rapid, canonical MC-dependent response to acute intraperitoneal LPS administration. Finally, high basal cytokine production was detected in MC purified from chronically LPS-treated animals. Our data show that (1) senescence markers appear in replication and stress-induced senescence of MCs; (2) basal and activated effector functions of MC are altered by senescence; and (3) aging is associated with increased MC-dependent inflammatory responses. Our results show that senescence importantly affects MC function, which could contribute to inflammaging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937029","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":"Late-Life Aerobic Exercise Attenuates DNA Damage and Telomere Dysfunction in Non-Atheroprone but Not in Atheroprone Aortic Regions","authors":"Jisok Lim,&nbsp;John Kim,&nbsp;Hossein Abdeahad,&nbsp;Shelby A. Hall,&nbsp;Lisa A. Lesniewski,&nbsp;Anthony J. Donato","doi":"10.1111/acel.70196","DOIUrl":"10.1111/acel.70196","url":null,"abstract":"<p>Cellular senescence is a state of persistent cell cycle arrest and is a critical contributor to arterial aging. The primary drivers of cellular senescence are the DNA damage response (DDR) and telomere dysfunction, which is induced by increasing exposure to DNA-damaging stimuli such as atheroprone shear stress. While late-life aerobic exercise is an effective intervention to mitigate arterial aging, its specific impact on the DDR and telomere dysfunction is unknown and may not show uniform benefits across aortic regions subjected to atheroprone and non-atheroprone shear stress. This study investigates the influence of late-life aerobic exercise on DDR and telomere dysfunction in endothelial cells (EC) and vascular smooth muscle cells (VSMC) within the aortic regions exposed to distinct shear stress patterns. Old male C57BL6 mice were randomly assigned to a negative control (NC) group and habitual voluntary wheel running (VWR) groups for 16 weeks. The habitual VWR groups were further categorized into low (LR), moderate (MR), and high running (HR) groups based on their daily running distance throughout the intervention. EC and VSMC DDR and telomere dysfunction in NC, LR, and MR groups were comparable across the aortic regions. Interestingly, EC DDR and telomere dysfunction were mitigated in the non-atheroprone aortic regions in HR, but not in VSMC. These improvements were independent of telomere length. Collectively, these data provide evidence that late-life aerobic exercise selectively mitigates DDR and telomere dysfunction in ECs within non-atheroprone aortic regions, rather than atheroprone aortic regions, in an exercise volume-dependent manner, independent of telomere length.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70196","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936875","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":"KDM4 Orchestrates Epigenomic Remodeling of Senescent Cells and Potentiates the Senescence-Associated Secretory Phenotype","authors":"Boyi Zhang,&nbsp;Qilai Long,&nbsp;Shanshan Wu,&nbsp;Qixia Xu,&nbsp;Shuling Song,&nbsp;Liu Han,&nbsp;Min Qian,&nbsp;Xiaohui Ren,&nbsp;Hanxin Liu,&nbsp;Jing Jiang,&nbsp;Jianming Guo,&nbsp;Xiaoling Zhang,&nbsp;Xing Chang,&nbsp;Qiang Fu,&nbsp;Eric W.-F. Lam,&nbsp;Judith Campisi,&nbsp;James L. Kirkland,&nbsp;Yu Sun","doi":"10.1111/acel.70194","DOIUrl":"10.1111/acel.70194","url":null,"abstract":"<p>Cellular senescence restrains the expansion of neoplastic cells through several layers of regulation. We report that the histone H3-specific demethylase KDM4 is expressed as human stromal cells undergo senescence. In clinical oncology, upregulated KDM4 and diminished H3K9/H3K36 methylation correlate with poorer survival of patients with prostate cancer after chemotherapy. Global chromatin accessibility mapping via assay for transposase-accessible chromatin with high-throughput sequencing, and expression profiling through RNA sequencing, reveals global changes of chromatin openness and spatiotemporal reprogramming of the transcriptomic landscape, which underlie the senescence-associated secretory phenotype (SASP). Selective targeting of KDM4 dampens the SASP of senescent stromal cells, promotes cancer cell apoptosis in the treatment-damaged tumor microenvironment, and prolongs survival of experimental animals. Our study supports dynamic changes of H3K9/H3K36 methylation during senescence, identifies an unusually permissive chromatin state, and unmasks KDM4 as a key SASP modulator. KDM4 targeting presents a new therapeutic avenue to manipulate cellular senescence and limit its contribution to age-related pathologies, including cancer.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144936822","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":"T-CLASS: An Online Tool for the Identification and Classification of Aging and Senescence Using Transcriptome Data","authors":"Seung-Chul J. Lee,&nbsp;Gee-Yoon Lee,&nbsp;Sieun S. Kim,&nbsp;Yunkyu Bae,&nbsp;Seokjin Ham,&nbsp;Jooyeon Sohn,&nbsp;Seong Kyu Han,&nbsp;Seung-Jae V. Lee","doi":"10.1111/acel.70193","DOIUrl":"10.1111/acel.70193","url":null,"abstract":"<p>Transcriptome analysis has become increasingly utilized in aging research. However, the identification of the key molecular changes underlying aging processes and longevity-promoting regimens from transcriptome data remains challenging. Here, we present Transcriptomic CLassification via Adaptive learning of Signature States (T-CLASS), an online tool that identifies, from transcriptome data, gene sets of several hundred genes that provide an optimal representation of longevity and aging paradigms. We systematically evaluated the effectiveness of T-CLASS with diverse datasets, including longevity-promoting regimens in <i>Caenorhabditis elegans</i>, cellular senescence by different means in both cultured mouse primary cells and cultured human cells, and human sarcopenia. We found that T-CLASS exhibited robust and high classification performance across datasets compared to preexisting machine/deep learning-based gene selection tools. By focusing our further analysis on longevity-promoting regimens in <i>C. elegans</i>, we showed that T-CLASS successfully classified transcriptomic changes caused by ten lifespan-extending small molecules, among which we experimentally validated the effect of rifampicin and atracurium as a proof of principle. Overall, T-CLASS is an effective and practical tool for uncovering and classifying physiological changes caused by genetic and pharmacological interventions that affect aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854098","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":"Differential Effects of Liver Regeneration on Aging-Related Changes in Gene Expression and Metabolic Function","authors":"Ryo Murayama,&nbsp;Kenichi Horisawa,&nbsp;Shizuka Miura,&nbsp;Sumiaki Taniguchi,&nbsp;Jinghao Shu,&nbsp;Masatomo Takahashi,&nbsp;Yoshihiro Izumi,&nbsp;Takeshi Bamba,&nbsp;Kousei Ishigami,&nbsp;Atsushi Suzuki","doi":"10.1111/acel.70197","DOIUrl":"10.1111/acel.70197","url":null,"abstract":"<p>Aging causes significant changes in gene expression and metabolic function of cells in various organs. Although it is known that liver regeneration is delayed by aging, the effects of aging on changes in gene expression and metabolic functions in liver regeneration need further investigation. In this study, we comprehensively analyzed changes in gene expression and metabolic function by liver regeneration in young and old mice to examine the effects of aging on these changes. During the process of liver regeneration, the gene expression profiles of hepatocytes from young and old mice changed significantly in a stepwise manner while each remained close together. After the completion of liver regeneration, the genes with aging-specific expression patterns in old mouse hepatocytes changed to expression levels close to those in young mouse hepatocytes. In contrast to the results of these transcriptome analyses, the aging-specific changes in metabolic state detected in old mouse livers were found to be largely maintained after the completion of liver regeneration. These results demonstrated that the gene expression state in the liver of old mice is flexibly altered by liver regeneration, whereas their metabolic state is robust. This finding helps to elucidate the relationship between aging and liver regeneration and to determine the basis of the increased incidence of liver disease with aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820229","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":"Anatomical Society Research Studentships 2025/26","authors":"","doi":"10.1111/acel.70202","DOIUrl":"https://doi.org/10.1111/acel.70202","url":null,"abstract":"","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832818","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":"Featured Cover","authors":"Jonathan Plessis-Belair,&nbsp;Taylor Russo,&nbsp;Markus Riessland,&nbsp;Roger B. Sher","doi":"10.1111/acel.70200","DOIUrl":"https://doi.org/10.1111/acel.70200","url":null,"abstract":"<p>Cover legend: The cover image is based on the article <i>Nuclear Import Defects Drive Cell Cycle Dysregulation in Neurodegeneration</i> by Jonathan Plessis-Belair et al.,\u0000https://doi.org/10.1111/acel.70091.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832819","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":"Additional Cover","authors":"Matias Fuentealba,&nbsp;Dobri Kiprov,&nbsp;Kevin Schneider,&nbsp;Wei-Chieh Mu,&nbsp;Prasanna Ashok Kumaar,&nbsp;Herbert Kasler,&nbsp;Jordan B. Burton,&nbsp;Mark Watson,&nbsp;Heather Halaweh,&nbsp;Christina D. King,&nbsp;Zehra Stara Y端ksel,&nbsp;Chelo Roska-Pamaong,&nbsp;Birgit Schilling,&nbsp;Eric Verdin,&nbsp;David Furman","doi":"10.1111/acel.70201","DOIUrl":"https://doi.org/10.1111/acel.70201","url":null,"abstract":"<p>Cover legend: The cover image is based on the article <i>Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange</i> by Matias Fuentealba et al., https://doi.org/10.1111/acel.70103.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832553","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":"Additional Cover","authors":"Silas A. Buck,&nbsp;Samuel J. Mabry,&nbsp;Tenzin Kunkhyen,&nbsp;Zilu Yang,&nbsp;Sophie A. Rubin,&nbsp;Jinting Yang,&nbsp;Claire E. J. Cheetham,&nbsp;Zachary Freyberg","doi":"10.1111/acel.70199","DOIUrl":"https://doi.org/10.1111/acel.70199","url":null,"abstract":"<p>Cover legend: The cover image is based on the article <i>dVGLUT Is a Mediator of Sex Differences in Dopamine Neuron Mitochondrial Function Across Aging and in a Parkinson's Disease Model</i> by Silas A. Buck et al., https://doi.org/10.1111/acel.70096.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 8","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144832548","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":"Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease","authors":"Boyang Li,&nbsp;Shaowei Wang,&nbsp;Bilal Kerman,&nbsp;Cristelle Hugo,&nbsp;E. Keats Shwab,&nbsp;Chang Shu,&nbsp;Ornit Chiba-Falek,&nbsp;Zoe Arvanitakis,&nbsp;Hussein N. Yassine","doi":"10.1111/acel.70189","DOIUrl":"10.1111/acel.70189","url":null,"abstract":"<p>Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia（iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"24 10","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820230","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}