Nature aging最新文献_第2页

Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging. 来自衰老肝细胞的细胞外囊泡驱动泛癌转移。

IF 19.4

Nature aging Pub Date : 2026-04-06 DOI: 10.1038/s43587-026-01102-5

Huilong Li, Ruzhou Zhao, Luming Wan, Yang Yuan, Enhao Ma, Yingang Li, Zhuangzhuang Chen, Binbin Liu, Yurong Song, Ziwei Cao, Xinxin Jiao, Yue Wang, Peng Wu, Hao Jin, Jiatong Li, Xiaopan Yang, Linfei Huang, Yanhong Zhang, Ke Yang, Jiang Huo, Haoran Jin, Hui Zhong, Min Min, Shaohua Zhang, Yuan Cao, Wenlong Li, Rui Zhang, Congwen Wei

{"title":"Extracellular vesicles derived from senescent hepatocytes drive pan-cancer metastasis in aging.","authors":"Huilong Li, Ruzhou Zhao, Luming Wan, Yang Yuan, Enhao Ma, Yingang Li, Zhuangzhuang Chen, Binbin Liu, Yurong Song, Ziwei Cao, Xinxin Jiao, Yue Wang, Peng Wu, Hao Jin, Jiatong Li, Xiaopan Yang, Linfei Huang, Yanhong Zhang, Ke Yang, Jiang Huo, Haoran Jin, Hui Zhong, Min Min, Shaohua Zhang, Yuan Cao, Wenlong Li, Rui Zhang, Congwen Wei","doi":"10.1038/s43587-026-01102-5","DOIUrl":"https://doi.org/10.1038/s43587-026-01102-5","url":null,"abstract":"<p><p>Malignant tumors are the leading cause of death in individuals over 65 years old, with metastasis as the primary driver. Emerging evidence suggests that age-related metabolic changes and secreted factors increase the risk of metastasis, but the underlying mechanisms remain unclear. Here we demonstrate in mice that extracellular vesicles (EVs) from senescent hepatocytes promote metastasis across tumor types. We show that aged liver tissue exhibits elevated expression of P2X purinoceptor 7 (P2RX7), which is associated with increased EV biogenesis. We identify EV-encapsulated miRNAs (miR-25, miR-92a, miR-30c and miR-30d) that reach primary tumors through the circulation and enhance tumor invasiveness and metastatic potential. Similarly, clinical samples from older patients show reduced expression of the miRNA target genes PTEN and LATS2, as well as enhanced epithelial-mesenchymal transition in metastatic tumors. Therapeutically, targeting senescence with dasatinib and quercetin (D + Q), inhibiting P2RX7, or silencing EV-associated miRNAs considerably reduces metastasis in aged mice. Together, our study uncovers a mechanism by which senescent hepatocyte-derived EVs drive tumor metastasis during aging and highlights potential strategies to mitigate this process.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":19.4,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629632","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}

引用次数: 0

Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer’s disease pathogenesis 神经元apoe4诱导的早期海马网络高兴奋性在阿尔茨海默病发病机制中的作用。

IF 19.4

Nature aging Pub Date : 2026-04-03 DOI: 10.1038/s43587-026-01096-0

Dennis R. Tabuena, Sung-Soo Jang, Brian Grone, Oscar Yip, Emily A. Aery Jones, Jessica Blumenfeld, Zherui Liang, Rajkamalpreet S. Mann, Yaqiao Li, Deanna Necula, Nicole Koutsodendris, Antara Rao, Leonardo Ding, Alex R. Zhang, Yanxia Hao, Qin Xu, Seo Yeon Yoon, Samuel De Leon, Yadong Huang, Misha Zilberter

{"title":"Neuronal APOE4-induced early hippocampal network hyperexcitability in Alzheimer’s disease pathogenesis","authors":"Dennis R. Tabuena, Sung-Soo Jang, Brian Grone, Oscar Yip, Emily A. Aery Jones, Jessica Blumenfeld, Zherui Liang, Rajkamalpreet S. Mann, Yaqiao Li, Deanna Necula, Nicole Koutsodendris, Antara Rao, Leonardo Ding, Alex R. Zhang, Yanxia Hao, Qin Xu, Seo Yeon Yoon, Samuel De Leon, Yadong Huang, Misha Zilberter","doi":"10.1038/s43587-026-01096-0","DOIUrl":"10.1038/s43587-026-01096-0","url":null,"abstract":"The full impact of APOE4 (apolipoprotein E4), the strongest genetic risk factor for Alzheimer’s disease (AD), on neuronal and network function remains unclear, particularly during early preclinical stages of disease. Here we show that young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that predicts later cognitive deficits. This early phenotype arises from cell-type-specific subpopulations of smaller, hyperexcitable neurons and is eliminated by selective removal of neuronal APOE4. With aging, E4-KI mice develop granule cell hyperexcitability, progressive inhibitory dysfunction and excitation–inhibition imbalance in the dentate gyrus. Single-nucleus RNA sequencing with multilevel gene filtering reveals age-dependent and cell-type-specific transcriptional changes and identifies candidate mediators of early neuronal hyperexcitability, including Nell2. Targeted CRISPR interference knockdown of Nell2 rescues abnormal excitability, implicating Nell2 as a contributor to APOE4-driven dysfunction. Together, these findings define molecular and circuit mechanisms linking neuronal APOE4-induced early network impairment to AD pathogenesis with aging. Young, cognitively normal APOE4 mice display hippocampal network hyperactivity that predicts later memory decline. This phenotype is driven by neuronal APOE4 expression, which causes hyperexcitability of hippocampal neurons and can be reversed by targeting Nell2.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 4","pages":"886-904"},"PeriodicalIF":19.4,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-026-01096-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147617077","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}

引用次数: 0

The case for space as a model of accelerated aging 太空是加速老化的典范。

IF 19.4

Nature aging Pub Date : 2026-04-03 DOI: 10.1038/s43587-026-01105-2

Max Manwaring-Mueller, Huixun Du, Taylor R. Valentino, Matias Fuentealba, Alexander Chebykin, Fei Wu, David Furman, Daniel A. Winer

{"title":"The case for space as a model of accelerated aging","authors":"Max Manwaring-Mueller, Huixun Du, Taylor R. Valentino, Matias Fuentealba, Alexander Chebykin, Fei Wu, David Furman, Daniel A. Winer","doi":"10.1038/s43587-026-01105-2","DOIUrl":"10.1038/s43587-026-01105-2","url":null,"abstract":"Aging is a complex biological and societal challenge, where modest advances can yield substantial clinical and economic benefits. While model organisms have uncovered key mechanisms of aging, their physiological relevance to humans remains limited. Astronauts offer a uniquely informative human model: despite being healthy and highly selected, they exhibit many hallmarks of aging and experience comparable declines in cardiovascular, musculoskeletal, cognitive and immune function—often on accelerated timelines. These changes are largely driven by four core exposures of the space environment: microgravity, circadian disruption, ionizing radiation and social isolation. Here, by tracing how environmental factors affect biological processes such as mitochondrial dysfunction, altered cytoskeletal dynamics, chronic inflammation and other canonical hallmarks of aging, we position spaceflight as a powerful model for human aging—one that unites environmental stress biology, multi-omic systems approaches and clinical research to advance both astronaut health and the healthspan of aging populations on Earth. Could astronauts serve as a unique model for human aging research? Manwaring-Mueller et al. review how spaceflight stressors, such as microgravity and radiation, accelerate biological aging pathways and could inform treatments for age-related diseases on Earth.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 4","pages":"752-769"},"PeriodicalIF":19.4,"publicationDate":"2026-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147617086","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}

引用次数: 0

Stem cell therapy might improve aging frailty 干细胞疗法可能改善衰老虚弱。

IF 19.4

Nature aging Pub Date : 2026-04-01 DOI: 10.1038/s43587-026-01114-1

Isobel Leake

引用次数: 0

Subcellular orchestration of microglial aging 小胶质细胞衰老的亚细胞编排。

IF 19.4

Nature aging Pub Date : 2026-03-31 DOI: 10.1038/s43587-026-01109-y

Philipp Schaible, Daniel Erny

引用次数: 0

Cellular and spatial remodeling of aging breast tissue revealed 揭示了衰老乳腺组织的细胞和空间重塑。

IF 19.4

Nature aging Pub Date : 2026-03-31 DOI: 10.1038/s43587-026-01111-4

引用次数: 0

Multiomic single-cell perturbation screens reveal critical lncRNA regulators of senescence 多组单细胞摄动筛选揭示了衰老的关键lncRNA调节因子。

IF 19.4

Nature aging Pub Date : 2026-03-31 DOI: 10.1038/s43587-026-01100-7

Shouxuan Zhu, Sunyang Ying, Donghong Cai, Ya Ren, Luoxi Wang, Zhi Qi, Vera Gorbunova, Jing-Dong J. Han

{"title":"Multiomic single-cell perturbation screens reveal critical lncRNA regulators of senescence","authors":"Shouxuan Zhu, Sunyang Ying, Donghong Cai, Ya Ren, Luoxi Wang, Zhi Qi, Vera Gorbunova, Jing-Dong J. Han","doi":"10.1038/s43587-026-01100-7","DOIUrl":"10.1038/s43587-026-01100-7","url":null,"abstract":"Long noncoding RNAs (lncRNAs) regulate transcriptional and epigenetic programs during aging and senescence. However, no comprehensive studies have systematically integrated multilayered analyses to reveal their diverse regulatory roles. Moreover, lncRNAs with therapeutic potential in age-related diseases remain unexplored. Here we systematically perturbed 32 high-abundance aging- and senescence-associated lncRNAs (PtbAlncs) using a Perturb-seq-based CRISPR–dCas9–KRAB knockdown system coupled with single-nucleus multiomics profiling, enabling simultaneous transcriptomic and chromatin accessibility analysis. This analysis uncovered essential roles for previously uncharacterized lncRNAs in senescence regulation, validated computationally and experimentally. These lncRNAs modulate distinct single-cell RNA-sequencing modules through diverse yet overlapping epigenetic motifs in single-cell ATAC-sequencing modules. Among them, HOTAIRM1, a DNA repair-associated PtbAlnc, stabilizes DNA repair by cooperating with BANF1 and p53 at double-strand break loci within condensates. Its deficiency impairs DNA repair and triggers p53-mediated senescence. In aged mouse lungs, adeno-associated virus-mediated HOTAIRM1 overexpression reduced fibrosis, alleviated tissue damage, and promoted cellular proliferation, underscoring its therapeutic potential. To dissect lncRNA functions in aging, here the authors perform a CRISPRi-based single-nucleus multiomics screen systematically perturbing 32 aging- and senescence-associated lncRNAs and measuring matched changes in gene expression and chromatin accessibility. They pinpoint a role for HOTAIRM1 linked to DNA repair-related gene control and show that replenishing HOTAIRM1 in mouse lungs reduces fibrosis.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 4","pages":"770-791"},"PeriodicalIF":19.4,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597161","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}

引用次数: 0

Single-cell spatial atlas of the aging human breast 衰老人类乳房的单细胞空间图谱。

IF 19.4

Nature aging Pub Date : 2026-03-31 DOI: 10.1038/s43587-026-01104-3

Pulkit Gupta, Eric Lee, Neus Masqué Soler, Ellen Schrader, Xiao Qian Wang, Shimrit Mayer, Cristina Flores, Sean Beatty, Andrew Roth, Samuel Aparicio, H. Raza Ali

{"title":"Single-cell spatial atlas of the aging human breast","authors":"Pulkit Gupta, Eric Lee, Neus Masqué Soler, Ellen Schrader, Xiao Qian Wang, Shimrit Mayer, Cristina Flores, Sean Beatty, Andrew Roth, Samuel Aparicio, H. Raza Ali","doi":"10.1038/s43587-026-01104-3","DOIUrl":"10.1038/s43587-026-01104-3","url":null,"abstract":"Breast cancer can develop over a wide age range and tumors in younger women differ from those in older women. Aging alters the spatial context of early tumors and may explain these differences, but breast tissue aging remains poorly characterized. Here, using imaging mass cytometry to profile the spatial expression of 40 proteins, we explore age-related remodeling of normal breast tissues in over 3 million cells from 527 reduction mammoplasties. Aged breast tissue was less cellular and less proliferative for all cell types (epithelial, stromal and immune). Tissue architecture was restructured with fewer heterotypic epithelial cell–cell interactions, far fewer lobules and increased fat. Older tissues had a more inflammatory microenvironment with increased M2 macrophages and granzyme B+ T cells, contrasted by younger tissues in which B cells were most enriched. Our multiscale atlas extensively details an unexpected general decline of breast tissue with age and reveals its changing spatial context. The dynamics of breast tissue aging are characterized by imaging mass cytometry of over 500 reduction mammoplasties, revealing nonlinear loss of cellularity and a compositional shift favoring inflammation.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 4","pages":"916-931"},"PeriodicalIF":19.4,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-026-01104-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147597182","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}

引用次数: 0

Spontaneous aging-associated inflammation and genome instability in the immune system of turquoise killifish 绿松石鳉免疫系统中自发衰老相关炎症和基因组不稳定。

IF 19.4

Nature aging Pub Date : 2026-03-20 DOI: 10.1038/s43587-026-01086-2

Gabriele Morabito, Handan Melike Dönertas, Luca Sperti, Jens Seidel, Aysan Poursadegh Zonouzi, Michael Poeschla, Dario Riccardo Valenzano

{"title":"Spontaneous aging-associated inflammation and genome instability in the immune system of turquoise killifish","authors":"Gabriele Morabito, Handan Melike Dönertas, Luca Sperti, Jens Seidel, Aysan Poursadegh Zonouzi, Michael Poeschla, Dario Riccardo Valenzano","doi":"10.1038/s43587-026-01086-2","DOIUrl":"10.1038/s43587-026-01086-2","url":null,"abstract":"Turquoise killifish (Nothobranchius furzeri) are naturally short-lived vertebrates that recapitulate key aspects of human aging. However, the molecular and cellular causes of systemic aging in killifish are poorly understood. Here we ask whether killifish undergo age-dependent changes in the main hematopoietic organ (kidney marrow), which may contribute to systemic aging. To characterize immune aging in killifish, we used single-cell RNA sequencing, cytometry and functional in vitro assays on kidney marrow cells from young-adult and old killifish, together with proteomic profiling of both kidney marrow-derived cells and plasma. We show that old killifish display increased markers of inflammation; while immune progenitor-like cell clusters from adult killifish display markers of active proliferation and replication-independent DNA repair, immune cell progenitors from old killifish display increased markers of DNA damage. Within less than 10 weeks, killifish exhibit age-related transformations within the immune system, underscoring the value of killifish for developing immune-system-targeted antiaging interventions. Turquoise killifish are naturally short-lived vertebrates that serve as a model system for aging. The authors show that killifish exhibit age-related transformation in the immune system, which rapidly develops inflammation, genome instability and functional decline.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 3","pages":"665-681"},"PeriodicalIF":19.4,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13004682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492403","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}

引用次数: 0

Longitudinal changes in epigenetic clocks predict long-term mortality 表观遗传时钟的纵向变化可以预测长期死亡率。

IF 19.4

Nature aging Pub Date : 2026-03-17 DOI: 10.1038/s43587-026-01095-1

引用次数: 0