Nature aging最新文献

{"title":"Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis.","authors":"Chuantao Tu, Cheng Qian, Shuyu Li, De-Ying Lin, Zhi-Yang Liu, Wan-Gan Ouyang, Xin-Lei Kang, Fangyuan Chen, Shu Song, Shi-Qing Cai","doi":"10.1038/s43587-025-00862-w","DOIUrl":"10.1038/s43587-025-00862-w","url":null,"abstract":"<p><p>With increased age, the liver becomes more vulnerable to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Deciphering the complex interplay between aging, the emergence of senescent cells in the liver and MASH fibrosis is critical for developing treatments. Here we report an epigenetic mechanism that links liver aging to MASH fibrosis. We find that upregulation of the chromatin remodeler BAZ2B in a subpopulation of hepatocytes (HEPs) is linked to MASH pathology in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b in mice attenuates HEP senescence and MASH fibrosis by preserving peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aged and MASH mouse livers. Mechanistically, Baz2b downregulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Thus, our study unravels the BAZ2B-PPARα-lipid metabolism axis as a link from liver aging to MASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for HEP senescence and fibrosis.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"1063-1078"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant engagement of P-selectin drives hematopoietic stem cell aging in mice.","authors":"Daozheng Yang, Natalia Skinder, Yun-Ruei Kao, Jiahao Chen, Victor Thiruthuvanathan, Arthur Flohr Svendsen, Chi Zhang, Bertien Dethmers-Ausema, Ellen Weersing, Maria Maryanovich, Britta Will, Gerald de Haan","doi":"10.1038/s43587-025-00880-8","DOIUrl":"10.1038/s43587-025-00880-8","url":null,"abstract":"<p><p>During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driven by a proinflammatory milieu in mice. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with highly abundant P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation capacity upon regenerative stress. Ectopic expression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and impair erythropoiesis. Mechanistically, we uncovered that P-selectin receptor activation by its primary ligand, P-selectin glycoprotein ligand-1, suppressed aging-associated gene expression, and, reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"1010-1024"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increasing transparency and recognition in peer review.","authors":"","doi":"10.1038/s43587-025-00913-2","DOIUrl":"10.1038/s43587-025-00913-2","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"951"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.","authors":"Rowan Saloner, Adam M Staffaroni, Eric B Dammer, Erik C B Johnson, Emily W Paolillo, Amy Wise, Hilary W Heuer, Leah K Forsberg, Argentina Lario-Lago, Julia D Webb, Jacob W Vogel, Alexander F Santillo, Oskar Hansson, Joel H Kramer, Bruce L Miller, Jingyao Li, Joseph Loureiro, Rajeev Sivasankaran, Kathleen A Worringer, Nicholas T Seyfried, Jennifer S Yokoyama, Salvatore Spina, Lea T Grinberg, William W Seeley, Lawren VandeVrede, Peter A Ljubenkov, Ece Bayram, Andrea Bozoki, Danielle Brushaber, Ciaran M Considine, Gregory S Day, Bradford C Dickerson, Kimiko Domoto-Reilly, Kelley Faber, Douglas R Galasko, Tania Gendron, Daniel H Geschwind, Nupur Ghoshal, Neill Graff-Radford, Chadwick M Hales, Lawrence S Honig, Ging-Yuek R Hsiung, Edward D Huey, John Kornak, Walter Kremers, Maria I Lapid, Suzee E Lee, Irene Litvan, Corey T McMillan, Mario F Mendez, Toji Miyagawa, Alexander Pantelyat, Belen Pascual, Joseph Masdeu, Henry L Paulson, Leonard Petrucelli, Peter Pressman, Rosa Rademakers, Eliana Marisa Ramos, Katya Rascovsky, Erik D Roberson, Rodolfo Savica, Allison Snyder, Anna Campbell Sullivan, M Carmela Tartaglia, Marijne Vandebergh, Brad F Boeve, Howie J Rosen, Julio C Rojas, Adam L Boxer, Kaitlin B Casaletto","doi":"10.1038/s43587-025-00878-2","DOIUrl":"10.1038/s43587-025-00878-2","url":null,"abstract":"<p><p>The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here we leveraged aptamer-based proteomics (>4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of (1) sporadic progressive supranuclear palsy-Richardson syndrome and (2) frontotemporal dementia spectrum clinical syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"1143-1158"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12234358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144087141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using RNA therapeutics to promote healthy aging.","authors":"Shuying Chen, Qian Chen, Xinru You, Zhuoming Zhou, Na Kong, Fabrisia Ambrosio, Yihai Cao, Reza Abdi, Wei Tao","doi":"10.1038/s43587-025-00895-1","DOIUrl":"10.1038/s43587-025-00895-1","url":null,"abstract":"<p><p>Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and have several advantages over traditional drug therapies, including high specificity, low toxicity and the potential for rapid development and production. Here, we discuss the latest developments in RNA therapeutics designed to promote healthy aging, including RNA activation, messenger RNA therapy, RNA interference, antisense oligonucleotides, aptamers and CRISPR-Cas-mediated RNA editing. We also review the latest preclinical and clinical studies of RNA technology for treating age-related diseases, including neurodegenerative, cardiovascular and musculoskeletal diseases. Finally, we discuss the challenges of RNA technology aimed at supporting healthy aging. We anticipate that the fusion of RNA therapeutics and aging biology will have an important effect on the development of new medicines and maximization of their efficacy.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"968-983"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal hematopoiesis driven by microbial metabolite.","authors":"Yahyah Aman","doi":"10.1038/s43587-025-00912-3","DOIUrl":"10.1038/s43587-025-00912-3","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"957"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144287684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent somatic mutation and progerin expression in early vascular aging of chronic kidney disease.","authors":"Gwladys Revêchon, Anna Witasp, Nikenza Viceconte, Hafdis T Helgadottir, Piotr Machtel, Fabiana Stefani, Daniel Whisenant, Agustin Sola-Carvajal, Dagmara McGuinness, Nadia O Abutaleb, Gonzalo Artiach, Emelie Wallén Arzt, Inga Soveri, Anne Babler, Susanne Ziegler, Rafael Kramann, Magnus Bäck, Anders Thorell, George A Truskey, Lars Wennberg, Paul G Shiels, Annika Wernerson, Peter Stenvinkel, Maria Eriksson","doi":"10.1038/s43587-025-00882-6","DOIUrl":"10.1038/s43587-025-00882-6","url":null,"abstract":"<p><p>Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries. Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"1046-1062"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144268277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale plasma proteomic profiling unveils diagnostic biomarkers and pathways for Alzheimer's disease.","authors":"Gyujin Heo, Ying Xu, Erming Wang, Muhammad Ali, Hamilton Se-Hwee Oh, Patricia Moran-Losada, Federica Anastasi, Armand González Escalante, Raquel Puerta, Soomin Song, Jigyasha Timsina, Menghan Liu, Daniel Western, Katherine Gong, Yike Chen, Pat Kohlfeld, Allison Flynn, Alvin G Thomas, Joseph Lowery, John C Morris, David M Holtzman, Joel S Perlmutter, Suzanne E Schindler, Natalia Vilor-Tejedor, Marc Suárez-Calvet, Pablo García-González, Marta Marquié, Maria Victoria Fernández, Mercè Boada, Amanda Cano, Agustín Ruiz, Bin Zhang, David A Bennett, Tammie Benzinger, Tony Wyss-Coray, Laura Ibanez, Yun Ju Sung, Carlos Cruchaga","doi":"10.1038/s43587-025-00872-8","DOIUrl":"10.1038/s43587-025-00872-8","url":null,"abstract":"<p><p>Proteomic studies have been instrumental in identifying brain, cerebrospinal fluid and plasma proteins associated with Alzheimer's disease (AD). Here, we comprehensively examined 6,905 aptamers corresponding to 6,106 unique proteins in plasma in more than 3,300 well-characterized individuals to identify new proteins, pathways and predictive models for AD. We identified 416 proteins (294 new) associated with clinical AD status and validated the findings in two external datasets representing more than 7,000 samples. AD-related proteins reflected blood-brain barrier disruption and other processes implicated in AD, such as lipid dysregulation or immune responses. A machine learning model was used to identify a set of seven proteins that were highly predictive of both clinical AD (area under the curve (AUC) of >0.72) and biomarker-defined AD status (AUC of >0.88), which were replicated in multiple external cohorts and orthogonal platforms. These findings underscore the potential of using plasma proteins as biomarkers for the early detection and monitoring of AD and for guiding treatment decisions.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"1114-1131"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging.","authors":"Zhenguo Wang, Zhe Li, Hongyu Liu, Chenghua Yang, Xin Li","doi":"10.1038/s43587-025-00890-6","DOIUrl":"https://doi.org/10.1038/s43587-025-00890-6","url":null,"abstract":"<p><p>Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144163299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The advantages and challenges of disability-free survival as outcome measure in clinical studies.","authors":"Johannes T Neumann, John J McNeil","doi":"10.1038/s43587-025-00853-x","DOIUrl":"10.1038/s43587-025-00853-x","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"721-722"},"PeriodicalIF":17.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}