Pub Date : 2025-11-24DOI: 10.1038/s43587-025-01017-7
Cheng Lv, Haiyue Wang, Liang Yu, Pengyan Hu, Xiao Xiao, Ruofei Li, Xiayidan Alimu, Yushan Tang, Na Lu, Cunjin Wu, Jun Zheng, Yu Zhang, Rutai Hui, Yibo Wang
Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and has been linked to cardiovascular disease. Apparent treatment-resistant hypertension (aTRH) is a severe, age-associated form of hypertension with poor response to therapy. Here we show that CHIP is enriched in patients with aTRH and is independently associated with poorer treatment response and adverse cardiac remodeling. In a multicenter discovery cohort and two community-based validation cohorts, CHIP was detected in ~23% of patients with aTRH versus ~7% of matched controlled-hypertension controls. CHIP carriers exhibited larger left ventricular dimensions, lower ejection fraction, elevated proinflammatory cytokines, smaller reductions in systolic and diastolic blood pressure after medication intensification and a substantially lower likelihood of achieving clinically controlled aTRH. Higher variant allele fraction and loss-of-function variants were linked to worse outcomes. These results identify CHIP as a common, clinically relevant biomarker in aTRH and suggest that targeting CHIP-related inflammation could improve antihypertensive treatment efficacy and outcomes. Antihypertensive medication does not always achieve goals, especially in older adults. Lv, Wang et al. identify clonal hematopoiesis as a biomarker of resistant hypertension, highlighting it as a potential contributor and therapeutic target for poor blood pressure control.
{"title":"Clonal hematopoiesis in apparent treatment-resistant hypertension, insights from multiple medical centers and community-based cohorts","authors":"Cheng Lv, Haiyue Wang, Liang Yu, Pengyan Hu, Xiao Xiao, Ruofei Li, Xiayidan Alimu, Yushan Tang, Na Lu, Cunjin Wu, Jun Zheng, Yu Zhang, Rutai Hui, Yibo Wang","doi":"10.1038/s43587-025-01017-7","DOIUrl":"10.1038/s43587-025-01017-7","url":null,"abstract":"Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and has been linked to cardiovascular disease. Apparent treatment-resistant hypertension (aTRH) is a severe, age-associated form of hypertension with poor response to therapy. Here we show that CHIP is enriched in patients with aTRH and is independently associated with poorer treatment response and adverse cardiac remodeling. In a multicenter discovery cohort and two community-based validation cohorts, CHIP was detected in ~23% of patients with aTRH versus ~7% of matched controlled-hypertension controls. CHIP carriers exhibited larger left ventricular dimensions, lower ejection fraction, elevated proinflammatory cytokines, smaller reductions in systolic and diastolic blood pressure after medication intensification and a substantially lower likelihood of achieving clinically controlled aTRH. Higher variant allele fraction and loss-of-function variants were linked to worse outcomes. These results identify CHIP as a common, clinically relevant biomarker in aTRH and suggest that targeting CHIP-related inflammation could improve antihypertensive treatment efficacy and outcomes. Antihypertensive medication does not always achieve goals, especially in older adults. Lv, Wang et al. identify clonal hematopoiesis as a biomarker of resistant hypertension, highlighting it as a potential contributor and therapeutic target for poor blood pressure control.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2466-2481"},"PeriodicalIF":19.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598534","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}
Pub Date : 2025-11-24DOI: 10.1038/s43587-025-01018-6
Vasilis Raptis, Youngjune Bhak, Timothy I. Cannings, Alasdair M. J. MacLullich, Albert Tenesa
Delirium is an acute change in cognition, common in hospitalized older adults, and associated with high healthcare and human cost; however, delirium’s genetic and proteomic background remains poorly understood. Here we conducted a genetic meta-analysis on delirium using multi-ancestry data from the UK Biobank, FinnGen, All of Us Research Program and Michigan Genomics Initiative cohorts (n = 1,059,130; 11,931 cases), yielding the Apolipoprotein E (APOE) gene as a strong delirium risk factor independently of dementia. A multi-trait analysis of delirium with Alzheimer disease identified five delirium genetic risk loci. Plasma proteins associated with up to 16-year incident delirium in UK Biobank (n = 32,652; 541 cases) revealed protein biomarkers implicating brain vulnerability, inflammation and immune response processes. Incorporating proteomic and genetic evidence via Mendelian randomization, colocalization and druggability analyses, we indicate potentially useful drug target proteins for delirium. Combining proteins, APOE-ε4 status and demographics significantly improved incident delirium prediction compared to demographics alone. Our results provide insight into delirium’s etiology and may guide further research on clinically relevant biomarkers. Delirium is a sudden change in mental function that is common in hospitalized older adults. To better understand this serious condition, Raptis et al. analyze large-scale genetic and proteomic datasets. They provide evidence that APOE-ε4 increases the risk for delirium independently of dementia, and highlight potentially clinically relevant plasma proteins.
谵妄是一种急性认知改变，常见于住院老年人，与高医疗保健和人力成本相关；然而，谵妄的遗传和蛋白质组学背景仍然知之甚少。在这里，我们使用来自英国生物银行、FinnGen、All of Us Research Program和Michigan Genomics Initiative队列的多祖先数据进行了一项关于谵妄的遗传荟萃分析（n = 1,059,130; 11,931例），得出载脂蛋白E （APOE）基因是独立于痴呆的谵妄危险因素。一项对谵妄合并阿尔茨海默病的多性状分析确定了5个谵妄遗传风险位点。在UK Biobank （n = 32,652； 541例）中，血浆蛋白与长达16年的谵妄事件相关，揭示了涉及大脑易感性、炎症和免疫反应过程的蛋白质生物标志物。通过孟德尔随机化、共定位和药物分析，结合蛋白质组学和遗传学证据，我们指出了谵妄可能有用的药物靶蛋白。结合蛋白质、APOE-ε4状态和人口统计学，与单独的人口统计学相比，显著提高了谵妄事件的预测。我们的研究结果提供了对谵妄病因的深入了解，并可能指导临床相关生物标志物的进一步研究。
{"title":"Dissecting the genetic and proteomic risk factors for delirium","authors":"Vasilis Raptis, Youngjune Bhak, Timothy I. Cannings, Alasdair M. J. MacLullich, Albert Tenesa","doi":"10.1038/s43587-025-01018-6","DOIUrl":"10.1038/s43587-025-01018-6","url":null,"abstract":"Delirium is an acute change in cognition, common in hospitalized older adults, and associated with high healthcare and human cost; however, delirium’s genetic and proteomic background remains poorly understood. Here we conducted a genetic meta-analysis on delirium using multi-ancestry data from the UK Biobank, FinnGen, All of Us Research Program and Michigan Genomics Initiative cohorts (n = 1,059,130; 11,931 cases), yielding the Apolipoprotein E (APOE) gene as a strong delirium risk factor independently of dementia. A multi-trait analysis of delirium with Alzheimer disease identified five delirium genetic risk loci. Plasma proteins associated with up to 16-year incident delirium in UK Biobank (n = 32,652; 541 cases) revealed protein biomarkers implicating brain vulnerability, inflammation and immune response processes. Incorporating proteomic and genetic evidence via Mendelian randomization, colocalization and druggability analyses, we indicate potentially useful drug target proteins for delirium. Combining proteins, APOE-ε4 status and demographics significantly improved incident delirium prediction compared to demographics alone. Our results provide insight into delirium’s etiology and may guide further research on clinically relevant biomarkers. Delirium is a sudden change in mental function that is common in hospitalized older adults. To better understand this serious condition, Raptis et al. analyze large-scale genetic and proteomic datasets. They provide evidence that APOE-ε4 increases the risk for delirium independently of dementia, and highlight potentially clinically relevant plasma proteins.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"235-251"},"PeriodicalIF":19.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01018-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598509","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}
Pub Date : 2025-11-24DOI: 10.1038/s43587-025-01014-w
Eva Mejía-Ramírez, Pablo Iáñez Picazo, Barbara Walter, Sara Montserrat-Vazquez, Francesco Affuso, Stefan Wieser, Fabio Pezzano, Loïc Reymond, Jorge Castillo-Robles, Francesca Matteini, Loris Mularoni, Dídac Maciá, Ángel Raya, Verena Ruprecht, Yi Zheng, Paula Petrone, M. Carolina Florian
Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechanosignaling, but its role in mechanotransduction in stem cell aging remains unclear. Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lympho/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function. Mejía-Ramírez, Iáñez Picazo, Walter et al. explore how nuclear biomechanical changes limit the regenerative capacity of aged hematopoietic stem cells and show that targeting RhoA rejuvenates aged hematopoietic stem cells by reducing nuclear envelope tension and remodeling nuclear architecture.
{"title":"Targeting RhoA nuclear mechanoactivity rejuvenates aged hematopoietic stem cells","authors":"Eva Mejía-Ramírez, Pablo Iáñez Picazo, Barbara Walter, Sara Montserrat-Vazquez, Francesco Affuso, Stefan Wieser, Fabio Pezzano, Loïc Reymond, Jorge Castillo-Robles, Francesca Matteini, Loris Mularoni, Dídac Maciá, Ángel Raya, Verena Ruprecht, Yi Zheng, Paula Petrone, M. Carolina Florian","doi":"10.1038/s43587-025-01014-w","DOIUrl":"10.1038/s43587-025-01014-w","url":null,"abstract":"Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechanosignaling, but its role in mechanotransduction in stem cell aging remains unclear. Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lympho/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function. Mejía-Ramírez, Iáñez Picazo, Walter et al. explore how nuclear biomechanical changes limit the regenerative capacity of aged hematopoietic stem cells and show that targeting RhoA rejuvenates aged hematopoietic stem cells by reducing nuclear envelope tension and remodeling nuclear architecture.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"68-87"},"PeriodicalIF":19.4,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01014-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598526","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}
Pub Date : 2025-11-20DOI: 10.1038/s43587-025-01020-y
Guoqiang Sun, Zan He, Dongliang Lv, Qiaoran Wang, Gang Xu, Feifei Liu, Peiyu Wang, Bilan Luo, Yandong Zheng, Jinghao Hu, Shuhui Sun, Shuai Ma, Concepcion Rodriguez Esteban, Jiayin Yang, Xiaobing Fu, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu
The prostate is a multifunctional organ of the male reproductive system whose aging process impairs sexual and urinary function and fertility and increases disease susceptibility, thereby compromising quality of life. However, the mechanisms underlying human prostate aging remain poorly understood. Here we integrated single-nucleus transcriptomics and histological analyses to elucidate the aging mechanisms of the primate prostate. We identified epithelial cell senescence, chronic inflammation and fibrosis as key hallmarks of prostate aging. In young epithelial cells, GRHL2 promotes CDK19 transcription, which sequesters p53, leading to the suppression of p21Waf1/Cip1. Aging-related downregulation of GRHL2 releases p53 from the CDK19−p53 complex, activating p21Waf1/Cip1 transcription and inducing cell senescence. Accordingly, a single injection of a GRHL2-based gene therapy strategy delayed prostate aging and alleviated age-related urinary dysfunction in vivo. Our findings elucidate key mechanisms of primate prostate aging and provide a foundation for developing therapies targeting prostate aging and associated pathologies. The prostate is an important part of the male reproductive system whose aging process is incompletely understood. Sun et al. identify GRHL2 downregulation as a driver of prostate aging. They show that GRHL2 transactivates CDK19 to inhibit p53−p21 signaling and demonstrate that GRHL2 gene therapy alleviates age-related urinary dysfunction in mice.
{"title":"Reprogramming the GRHL2−CDK19 axis by gene therapy alleviates prostate aging","authors":"Guoqiang Sun, Zan He, Dongliang Lv, Qiaoran Wang, Gang Xu, Feifei Liu, Peiyu Wang, Bilan Luo, Yandong Zheng, Jinghao Hu, Shuhui Sun, Shuai Ma, Concepcion Rodriguez Esteban, Jiayin Yang, Xiaobing Fu, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Si Wang, Guang-Hui Liu","doi":"10.1038/s43587-025-01020-y","DOIUrl":"10.1038/s43587-025-01020-y","url":null,"abstract":"The prostate is a multifunctional organ of the male reproductive system whose aging process impairs sexual and urinary function and fertility and increases disease susceptibility, thereby compromising quality of life. However, the mechanisms underlying human prostate aging remain poorly understood. Here we integrated single-nucleus transcriptomics and histological analyses to elucidate the aging mechanisms of the primate prostate. We identified epithelial cell senescence, chronic inflammation and fibrosis as key hallmarks of prostate aging. In young epithelial cells, GRHL2 promotes CDK19 transcription, which sequesters p53, leading to the suppression of p21Waf1/Cip1. Aging-related downregulation of GRHL2 releases p53 from the CDK19−p53 complex, activating p21Waf1/Cip1 transcription and inducing cell senescence. Accordingly, a single injection of a GRHL2-based gene therapy strategy delayed prostate aging and alleviated age-related urinary dysfunction in vivo. Our findings elucidate key mechanisms of primate prostate aging and provide a foundation for developing therapies targeting prostate aging and associated pathologies. The prostate is an important part of the male reproductive system whose aging process is incompletely understood. Sun et al. identify GRHL2 downregulation as a driver of prostate aging. They show that GRHL2 transactivates CDK19 to inhibit p53−p21 signaling and demonstrate that GRHL2 gene therapy alleviates age-related urinary dysfunction in mice.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"252-269"},"PeriodicalIF":19.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566839","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}
Pub Date : 2025-11-20DOI: 10.1038/s43587-025-01006-w
Ilana Caro, Daniel Western, Shinichi Namba, Na Sun, Shuji Kawaguchi, Yunye He, Masashi Fujita, Gennady Roshchupkin, Tim D’Aoust, Marie-Gabrielle Duperron, Muralidharan Sargurupremraj, Ami Tsuchida, Masaru Koido, Marziehsadat Ahmadi, Chengran Yang, Jigyasha Timsina, Laura Ibanez, Koichi Matsuda, Yutaka Suzuki, Yoshiya Oda, Akinori Kanai, Pouria Jandaghi, Markus Munter, Daniel Auld, Iana Astafeva, Raquel Puerta, Jerome I. Rotter, Bruce M. Psaty, Joshua C. Bis, WT Longstreth Jr, Thierry Couffinhal, Pablo García-González, Vanesa Pytel, Marta Marquié, Amanda Cano, Mercè Boada, Marc Joliot, Mark Lathrop, Quentin Le Grand, Lenore J. Launer, Joanna M. Wardlaw, Myriam Heiman, Agustin Ruiz, Paul M. Matthews, Sudha Seshadri, Myriam Fornage, Hieab Adams, Aniket Mishra, David-Alexandre Trégouët, Yukinori Okada, Manolis Kellis, Philip L. De Jager, Christophe Tzourio, Yoichiro Kamatani, Fumihiko Matsuda, Carlos Cruchaga, Stéphanie Debette
Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. Here we show that 49 proteins are associated with MRI markers of cSVD, most prominently in cerebrospinal fluid. We highlight associations that are consistent across platforms and ancestries, and supported by complementary observational analyses, and we explore differences between fluids. The proteins are enriched in pathways related to the extracellular matrix, immune response and microglial activity. Many also associate with stroke and dementia, and several correspond to existing drug targets. Together, these findings reveal a robust biological fingerprint of cSVD and highlight opportunities for biomarker and drug discovery and repositioning. By integrating large-scale genomic and proteomic data in cerebrospinal fluid and plasma, the authors identify 49 proteins linked to MRI markers of cerebral small vessel disease, highlighting extracellular matrix and immune pathways, with biomarker and therapeutic potential.
{"title":"Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease","authors":"Ilana Caro, Daniel Western, Shinichi Namba, Na Sun, Shuji Kawaguchi, Yunye He, Masashi Fujita, Gennady Roshchupkin, Tim D’Aoust, Marie-Gabrielle Duperron, Muralidharan Sargurupremraj, Ami Tsuchida, Masaru Koido, Marziehsadat Ahmadi, Chengran Yang, Jigyasha Timsina, Laura Ibanez, Koichi Matsuda, Yutaka Suzuki, Yoshiya Oda, Akinori Kanai, Pouria Jandaghi, Markus Munter, Daniel Auld, Iana Astafeva, Raquel Puerta, Jerome I. Rotter, Bruce M. Psaty, Joshua C. Bis, WT Longstreth Jr, Thierry Couffinhal, Pablo García-González, Vanesa Pytel, Marta Marquié, Amanda Cano, Mercè Boada, Marc Joliot, Mark Lathrop, Quentin Le Grand, Lenore J. Launer, Joanna M. Wardlaw, Myriam Heiman, Agustin Ruiz, Paul M. Matthews, Sudha Seshadri, Myriam Fornage, Hieab Adams, Aniket Mishra, David-Alexandre Trégouët, Yukinori Okada, Manolis Kellis, Philip L. De Jager, Christophe Tzourio, Yoichiro Kamatani, Fumihiko Matsuda, Carlos Cruchaga, Stéphanie Debette","doi":"10.1038/s43587-025-01006-w","DOIUrl":"10.1038/s43587-025-01006-w","url":null,"abstract":"Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific treatment, of which molecular mechanisms remain poorly understood. To identify potential biomarkers and therapeutic targets, we applied Mendelian randomization to examine over 2,500 proteins measured in plasma and, uniquely, cerebrospinal fluid, in relation to magnetic resonance imaging (MRI) markers of cSVD in more than 40,000 individuals. Here we show that 49 proteins are associated with MRI markers of cSVD, most prominently in cerebrospinal fluid. We highlight associations that are consistent across platforms and ancestries, and supported by complementary observational analyses, and we explore differences between fluids. The proteins are enriched in pathways related to the extracellular matrix, immune response and microglial activity. Many also associate with stroke and dementia, and several correspond to existing drug targets. Together, these findings reveal a robust biological fingerprint of cSVD and highlight opportunities for biomarker and drug discovery and repositioning. By integrating large-scale genomic and proteomic data in cerebrospinal fluid and plasma, the authors identify 49 proteins linked to MRI markers of cerebral small vessel disease, highlighting extracellular matrix and immune pathways, with biomarker and therapeutic potential.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2514-2531"},"PeriodicalIF":19.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01006-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566830","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}
Pub Date : 2025-11-19DOI: 10.1038/s43587-025-01037-3
Daisy Sproviero, César Payán-Gómez, Chiara Milanese, Sander Barnhoorn, Shixiang Sun, Akos Gyenis, Domenico Delia, Tammaryn Lashley, Jan H. J. Hoeijmakers, Jan Vijg, Pier G. Mastroberardino
{"title":"Author Correction: A blood-based DNA damage signature in patients with Parkinson’s disease is associated with disease progression","authors":"Daisy Sproviero, César Payán-Gómez, Chiara Milanese, Sander Barnhoorn, Shixiang Sun, Akos Gyenis, Domenico Delia, Tammaryn Lashley, Jan H. J. Hoeijmakers, Jan Vijg, Pier G. Mastroberardino","doi":"10.1038/s43587-025-01037-3","DOIUrl":"10.1038/s43587-025-01037-3","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2564-2564"},"PeriodicalIF":19.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01037-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145552613","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}
Pub Date : 2025-11-19DOI: 10.1038/s43587-025-00998-9
Myechia Minter-Jordan, Vincenzo Paglia
On 9–10 May 2025, AARP, the Pontifical Academy for Life, the Età Grande Foundation, and the Franciscus Memorial co-organized a symposium in the Vatican on the global trend of population aging and the importance of ensuring the dignity, purpose, inclusion and well-being of older adults in the face of aging societies. A summary of this symposium is presented here alongside the declaration of pledges for global aging initiatives that was signed at the event.
2025年5月9日至10日，美国退休人员协会（AARP）、宗座生命学院（Pontifical Academy for Life）、et Grande基金会和方济各纪念馆在梵蒂冈共同举办了一场研讨会，讨论人口老龄化的全球趋势，以及在老龄化社会中确保老年人尊严、目标、包容和福祉的重要性。本次研讨会的摘要在此连同会议上签署的全球老龄化倡议认捐宣言一并提交。
{"title":"The Vatican City Declaration on Global Aging advocates advancing inclusive and productive futures for all","authors":"Myechia Minter-Jordan, Vincenzo Paglia","doi":"10.1038/s43587-025-00998-9","DOIUrl":"10.1038/s43587-025-00998-9","url":null,"abstract":"On 9–10 May 2025, AARP, the Pontifical Academy for Life, the Età Grande Foundation, and the Franciscus Memorial co-organized a symposium in the Vatican on the global trend of population aging and the importance of ensuring the dignity, purpose, inclusion and well-being of older adults in the face of aging societies. A summary of this symposium is presented here alongside the declaration of pledges for global aging initiatives that was signed at the event.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2369-2371"},"PeriodicalIF":19.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145552595","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}
Pub Date : 2025-11-17DOI: 10.1038/s43587-025-01011-z
Peijun Ren, Chen Zheng, Yidan Pang, Yu Qiang, Shixiang Sun, Qiyang Wang, Wanxing Xu, Moonsook Lee, Zhenzhen Lu, Min Zhou, Jian He, Ningning Liu, Alexander Y. Maslov, Xiao Dong, Changqing Zhang, Junjie Gao, Jan Vijg
Somatic mutation is now recognized as a cause of multiple human diseases other than cancer. Osteoarthritis (OA), a highly prevalent age-related disease, has been associated with increased chromosomal abnormalities in articular cartilage. Here we characterize the somatic mutational landscape of chondrocytes during normal aging and in affected cartilage of patients with OA. We used single-cell whole-genome sequencing to analyze single-nucleotide variants (SNVs) and small insertions and deletions (InDels) in 100 chondrocytes isolated from the cartilage of hip femoral heads of 17 research participants aged 26−90 years, including 9 patients with OA and 8 non-OA donors. Both SNVs and InDels accumulate with age in chondrocytes with a clock-like mutational signature. Surprisingly, the age-related accumulation rate in OA chondrocytes is lower than that in non-OA control chondrocytes. Differences in mutational signatures and Gene Ontology term enrichment were found between OA and non-OA control samples. In this study, to understand the role of somatic mutation in the pathogenesis of OA, we characterized somatic SNV and InDel mutations. With further progress in analytical approaches, structural variations in the chondrocyte genome are also expected to provide valuable information. Somatic mutations accumulate with age and have been linked to functional decline and disease. Single-cell analysis of human cartilage samples from donors with and without osteoarthritis shows that somatic mutations accumulate with age, but, in osteoarthritis, they show distinct mutational patterns and slower accumulation, possibly due to DNA-damage-induced chondrocyte death.
{"title":"Single-cell analysis of the somatic mutational landscape in human chondrocytes during aging and in osteoarthritis","authors":"Peijun Ren, Chen Zheng, Yidan Pang, Yu Qiang, Shixiang Sun, Qiyang Wang, Wanxing Xu, Moonsook Lee, Zhenzhen Lu, Min Zhou, Jian He, Ningning Liu, Alexander Y. Maslov, Xiao Dong, Changqing Zhang, Junjie Gao, Jan Vijg","doi":"10.1038/s43587-025-01011-z","DOIUrl":"10.1038/s43587-025-01011-z","url":null,"abstract":"Somatic mutation is now recognized as a cause of multiple human diseases other than cancer. Osteoarthritis (OA), a highly prevalent age-related disease, has been associated with increased chromosomal abnormalities in articular cartilage. Here we characterize the somatic mutational landscape of chondrocytes during normal aging and in affected cartilage of patients with OA. We used single-cell whole-genome sequencing to analyze single-nucleotide variants (SNVs) and small insertions and deletions (InDels) in 100 chondrocytes isolated from the cartilage of hip femoral heads of 17 research participants aged 26−90 years, including 9 patients with OA and 8 non-OA donors. Both SNVs and InDels accumulate with age in chondrocytes with a clock-like mutational signature. Surprisingly, the age-related accumulation rate in OA chondrocytes is lower than that in non-OA control chondrocytes. Differences in mutational signatures and Gene Ontology term enrichment were found between OA and non-OA control samples. In this study, to understand the role of somatic mutation in the pathogenesis of OA, we characterized somatic SNV and InDel mutations. With further progress in analytical approaches, structural variations in the chondrocyte genome are also expected to provide valuable information. Somatic mutations accumulate with age and have been linked to functional decline and disease. Single-cell analysis of human cartilage samples from donors with and without osteoarthritis shows that somatic mutations accumulate with age, but, in osteoarthritis, they show distinct mutational patterns and slower accumulation, possibly due to DNA-damage-induced chondrocyte death.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2417-2431"},"PeriodicalIF":19.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01011-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145544583","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}
Pub Date : 2025-11-17DOI: 10.1038/s43587-025-01036-4
Poor outcomes in both young and older patients with breast cancer have lacked a clear biological explanation. An analytic framework with experimental validation reveals age-associated molecular landscapes, which offers insight into age-dependent cancer biology and potential avenues for identifying therapeutic targets.
{"title":"Age distinguishes breast cancer cellular and molecular profiles","authors":"","doi":"10.1038/s43587-025-01036-4","DOIUrl":"10.1038/s43587-025-01036-4","url":null,"abstract":"Poor outcomes in both young and older patients with breast cancer have lacked a clear biological explanation. An analytic framework with experimental validation reveals age-associated molecular landscapes, which offers insight into age-dependent cancer biology and potential avenues for identifying therapeutic targets.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2378-2379"},"PeriodicalIF":19.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01036-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145544602","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}
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