Nature agingPub Date : 2025-06-30DOI: 10.1038/s43587-025-00902-5
Roméo S Blanc, Nidhi Shah, Sarah Hachmer, Noah A S Salama, Fanju W Meng, Alireza Mousaei, Gayatri Puri, Jeonghye Hannah Hwang, Elizabeth E Wacker, Benjamin A Yang, Carlos A Aguilar, Joe V Chakkalakal, John O Onukwufor, Patrick J Murphy, Laura M Calvi, F Jeffrey Dilworth, Robert T Dirksen
{"title":"Epigenetic erosion of H4K20me1 induced by inflammation drives aged stem cell ferroptosis.","authors":"Roméo S Blanc, Nidhi Shah, Sarah Hachmer, Noah A S Salama, Fanju W Meng, Alireza Mousaei, Gayatri Puri, Jeonghye Hannah Hwang, Elizabeth E Wacker, Benjamin A Yang, Carlos A Aguilar, Joe V Chakkalakal, John O Onukwufor, Patrick J Murphy, Laura M Calvi, F Jeffrey Dilworth, Robert T Dirksen","doi":"10.1038/s43587-025-00902-5","DOIUrl":"10.1038/s43587-025-00902-5","url":null,"abstract":"<p><p>Aging is characterized by a decline in the functionality and number of stem cells across the organism. In this study, we uncovered a mechanism by which systemic inflammation drives muscle stem cell (MuSC) aging through epigenetic erosion. We demonstrate that age-related inflammation decreases monomethylation of H4K20 in MuSCs, disrupting their quiescence and inducing ferroptosis, a form of iron-dependent cell death. Our findings show that inflammatory signals downregulate Kmt5a, the enzyme responsible for depositing H4K20me1, leading to the epigenetic silencing of anti-ferroptosis genes. This results in aberrant iron metabolism, increased reactive oxygen species levels and lipid peroxidation in aged MuSCs. Notably, long-term inhibition of systemic inflammation that is initiated at 12 months of age effectively prevents ferroptosis, preserves MuSC numbers and enhances muscle regeneration and functional recovery. These findings reveal an epigenetic switch that links chronic inflammation to MuSC aging and ferroptosis, offering potential therapeutic strategies for combating age-related muscle degeneration.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532092","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}
Nature agingPub Date : 2025-06-30DOI: 10.1038/s43587-025-00888-0
Maximilien Franck, Kamaryn T Tanner, Robert L Tennyson, Camille Daunizeau, Luigi Ferrucci, Stefania Bandinelli, Benjamin C Trumble, Hillard S Kaplan, Jacob E Aronoff, Jonathan Stieglitz, Thomas S Kraft, Amanda J Lea, Vivek V Venkataraman, Ian J Wallace, Yvonne A L Lim, Kee Seong Ng, Joe Poh Sheng Yeong, Roger Ho, Xinru Lim, Ameneh Mehrjerd, Eleftheria G Charalambous, Allison E Aiello, Graham Pawelec, Claudio Franceschi, Johannes Hertel, Tamàs Fülöp, Maël Lemoine, Michael Gurven, Alan A Cohen
{"title":"Nonuniversality of inflammaging across human populations.","authors":"Maximilien Franck, Kamaryn T Tanner, Robert L Tennyson, Camille Daunizeau, Luigi Ferrucci, Stefania Bandinelli, Benjamin C Trumble, Hillard S Kaplan, Jacob E Aronoff, Jonathan Stieglitz, Thomas S Kraft, Amanda J Lea, Vivek V Venkataraman, Ian J Wallace, Yvonne A L Lim, Kee Seong Ng, Joe Poh Sheng Yeong, Roger Ho, Xinru Lim, Ameneh Mehrjerd, Eleftheria G Charalambous, Allison E Aiello, Graham Pawelec, Claudio Franceschi, Johannes Hertel, Tamàs Fülöp, Maël Lemoine, Michael Gurven, Alan A Cohen","doi":"10.1038/s43587-025-00888-0","DOIUrl":"10.1038/s43587-025-00888-0","url":null,"abstract":"<p><p>Inflammaging, an age-associated increase in chronic inflammation, is considered a hallmark of aging. However, there is no consensus approach to measuring inflammaging based on circulating cytokines. Here we assessed whether an inflammaging axis detected in the Italian InCHIANTI dataset comprising 19 cytokines could be generalized to a different industrialized population (Singapore Longitudinal Aging Study) or to two indigenous, nonindustrialized populations: the Tsimane from the Bolivian Amazon and the Orang Asli from Peninsular Malaysia. We assessed cytokine axis structure similarity and whether the inflammaging axis replicating the InCHIANTI result increased with age or was associated with health outcomes. The Singapore Longitudinal Aging Study was similar to InCHIANTI except for IL-6 and IL-1RA. The Tsimane and Orang Asli showed markedly different axis structures with little to no association with age and no association with age-related diseases. Inflammaging, as measured in this manner in these cohorts, thus appears to be largely a byproduct of industrialized lifestyles, with major variation across environments and populations.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532093","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}
Nature agingPub Date : 2025-06-30DOI: 10.1038/s43587-025-00908-z
Ninghe Sun, Chun-Hsin Lin, Michelle Y Li, Yuting Wang, Danyang Chen, Xiangle Ren, Feng Zhang, Yi Zhang
{"title":"Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function.","authors":"Ninghe Sun, Chun-Hsin Lin, Michelle Y Li, Yuting Wang, Danyang Chen, Xiangle Ren, Feng Zhang, Yi Zhang","doi":"10.1038/s43587-025-00908-z","DOIUrl":"10.1038/s43587-025-00908-z","url":null,"abstract":"<p><p>Aged hematopoietic stem cells (HSCs) exhibit diminished self-renewal and myeloid-biased differentiation with a decline in hematopoiesis and adaptive immune function. However, the molecular regulation of this impaired function remains largely unknown. Here, through an in vivo CRISPR-Cas9-based screen, we uncovered clusterin (Clu) as a driver of biased differentiation. Clu is upregulated in aged HSCs, and its knockout diminishes biased differentiation. Clu promotes mitochondrial hyperfusion by interacting with Mfn2 in aged HSCs, and its ablation attenuates oxidative phosphorylation, improves mitophagy, and reverses myeloid-biased differentiation via the OXPHOS-p38-Cebpb axis. Transplantation of Clu-depleted aged HSCs into middle-aged mice results in balanced hematopoiesis and improved physical functions. Together, our data identify Clu as a critical regulator of aging-associated myeloid bias and reveal an Mfn2-OXPHOS-p38-Cebpb axis as the mechanism underlying how Clu upregulation in aged HSCs leads to myeloid-biased differentiation, providing a target for rejuvenation of aged hematopoietic and immune systems.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532091","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}
Nature agingPub Date : 2025-06-23DOI: 10.1038/s43587-025-00900-7
Yu Liu, Meiling Ge, Xina Xiao, Ying Lu, Wanyu Zhao, Kun Zheng, Kexin Yu, Yanting He, Qian Zhong, Lixing Zhou, Shan Hai, Xiaohui Liu, Na Jiang, Dan Du, Yan Zhang, Guo Cheng, Zhenmei An, Yi Zhao, Heng Xu, Biao Dong, Shuangqing Li, Binwu Ying, Huiyuan Zhang, Jirong Yue, Birong Dong, Lunzhi Dai
{"title":"Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating anti-inflammatory macrophages.","authors":"Yu Liu, Meiling Ge, Xina Xiao, Ying Lu, Wanyu Zhao, Kun Zheng, Kexin Yu, Yanting He, Qian Zhong, Lixing Zhou, Shan Hai, Xiaohui Liu, Na Jiang, Dan Du, Yan Zhang, Guo Cheng, Zhenmei An, Yi Zhao, Heng Xu, Biao Dong, Shuangqing Li, Binwu Ying, Huiyuan Zhang, Jirong Yue, Birong Dong, Lunzhi Dai","doi":"10.1038/s43587-025-00900-7","DOIUrl":"https://doi.org/10.1038/s43587-025-00900-7","url":null,"abstract":"<p><p>Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals, uncovering the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging patients and those with sarcopenia. Functional studies in mice showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. We demonstrate here that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. This study underscores the potential of sarcosine supplementation as an adjunctive strategy via macrophage modulation for preventing sarcopenia in older adults.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478351","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}
Nature agingPub Date : 2025-06-23DOI: 10.1038/s43587-025-00904-3
Guoyu Lan, Mengjie Wang, Fernando Gonzalez-Ortiz, Laihong Zhang, Anqi Li, Binyin Li, Mingxing Jiang, Jie Yang, Xuhui Chen, Dai Shi, Xiang Fan, Yue Cai, Pan Sun, Lin Liu, Jieyin Li, Zhengbo He, Lili Fang, Xin Zhou, Linting Chen, Yiying Wang, Mingxu Li, Zhen Liu, Qingyong Wang, Linsen Xu, Liemin Zhou, Guanxun Cheng, Xinlu Wang, Pengcheng Ran, Lu Wang, Kun Sun, Ying Han, Yihui Guan, Kaj Blennow, Fang Xie, Tengfei Guo
{"title":"Comprehensive evaluation of plasma tau biomarkers for detecting and monitoring Alzheimer's disease in a multicenter and multiethnic aging population.","authors":"Guoyu Lan, Mengjie Wang, Fernando Gonzalez-Ortiz, Laihong Zhang, Anqi Li, Binyin Li, Mingxing Jiang, Jie Yang, Xuhui Chen, Dai Shi, Xiang Fan, Yue Cai, Pan Sun, Lin Liu, Jieyin Li, Zhengbo He, Lili Fang, Xin Zhou, Linting Chen, Yiying Wang, Mingxu Li, Zhen Liu, Qingyong Wang, Linsen Xu, Liemin Zhou, Guanxun Cheng, Xinlu Wang, Pengcheng Ran, Lu Wang, Kun Sun, Ying Han, Yihui Guan, Kaj Blennow, Fang Xie, Tengfei Guo","doi":"10.1038/s43587-025-00904-3","DOIUrl":"10.1038/s43587-025-00904-3","url":null,"abstract":"<p><p>Over 20% of patients with Alzheimer's disease (AD) worldwide are Chinese, although the efficacy of existing blood-based measures of AD biomarkers is largely unknown in Asian cohorts. Here we explored how plasma tau biomarkers correlated with cross-sectional and longitudinal AD-related outcomes and their diagnostic performance in 1,085 participants from three independent studies, including two Chinese cohorts, Greater-Bay-Area Healthy Aging Brain Study (n = 425) and Huashan (n = 297), and the North American Alzheimer's Disease Neuroimaging Initiative cohort (n = 363). Plasma p-tau217 performed best in classifying Aβ-positron emission tomography (PET) and tau-PET positivity throughout the AD continuum and correlated with all AD-related outcomes. A two-cutoff approach suggested that participants with intermediate plasma p-tau217 levels experienced rapid accumulation of Aβ-PET and entorhinal tau-PET, as well as accelerated hypometabolism and cognitive decline. Increased plasma p-tau217 was also associated with rapid longitudinal changes in Aβ-PET, tau-PET and neurodegeneration. These results suggest that plasma p-tau217 is superior in detecting multiple aspects of AD-related pathological changes and tracking disease progression.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478350","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}
Nature agingPub Date : 2025-06-20DOI: 10.1038/s43587-025-00896-0
Guoqiang Sun, Xiaolong Fu, Yandong Zheng, Guodong Hong, Ziyi Liu, Bilan Luo, Jinghui Lei, Dongliang Lv, Miao Chang, Yu Xiao, Siwei Guo, Shuai Ma, Ling Lu, Weiqi Zhang, Juan Carlos Izpisua Belmonte, Jing Qu, Si Wang, Renjie Chai, Guang-Hui Liu
{"title":"Single-cell profiling identifies hair cell SLC35F1 deficiency as a signature of primate cochlear aging.","authors":"Guoqiang Sun, Xiaolong Fu, Yandong Zheng, Guodong Hong, Ziyi Liu, Bilan Luo, Jinghui Lei, Dongliang Lv, Miao Chang, Yu Xiao, Siwei Guo, Shuai Ma, Ling Lu, Weiqi Zhang, Juan Carlos Izpisua Belmonte, Jing Qu, Si Wang, Renjie Chai, Guang-Hui Liu","doi":"10.1038/s43587-025-00896-0","DOIUrl":"10.1038/s43587-025-00896-0","url":null,"abstract":"<p><p>Cochlear aging causes substantial hearing impairment in older adults, yet primate-specific mechanisms remain poorly characterized. Our comprehensive analysis combining single-cell and histopathological profiling in aging Macaca fascicularis demonstrates progressive cochlear degeneration featuring accelerated sensory hair cell loss, senescent spiral ganglion neurons with elevated neuroinflammation, and marked stria vascularis atrophy. We discovered that downregulation of transmembrane transport proteins, particularly SLC35F1, serves as a critical biomarker of hair cell aging. Functional validation through Slc35f1 knockdown in adult mice successfully recapitulated key aspects of age-related hearing loss, including hair cell degeneration and auditory function decline. Notably, we showed that long-term metformin administration at clinically relevant doses effectively delays cochlear aging in primates. These findings provide fundamental insights into the cellular and molecular basis of primate cochlear aging while establishing a foundation for developing targeted interventions against age-related hearing loss.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144337388","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}
Nature agingPub Date : 2025-06-01Epub Date: 2025-05-12DOI: 10.1038/s43587-025-00864-8
Seyed Soheil Saeedi Saravi, Benoit Pugin, Florentin Constancias, Khatereh Shabanian, Marianne Spalinger, Aurélien Thomas, Sylvain Le Gludic, Taraneh Shabanian, Gergely Karsai, Manuel Colucci, Cristina Menni, Ilias Attaye, Xinyuan Zhang, Meret Sarah Allemann, Pratintip Lee, Alessia Visconti, Mario Falchi, Andrea Alimonti, Frank Ruschitzka, Francesco Paneni, Jürg H Beer
{"title":"Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.","authors":"Seyed Soheil Saeedi Saravi, Benoit Pugin, Florentin Constancias, Khatereh Shabanian, Marianne Spalinger, Aurélien Thomas, Sylvain Le Gludic, Taraneh Shabanian, Gergely Karsai, Manuel Colucci, Cristina Menni, Ilias Attaye, Xinyuan Zhang, Meret Sarah Allemann, Pratintip Lee, Alessia Visconti, Mario Falchi, Andrea Alimonti, Frank Ruschitzka, Francesco Paneni, Jürg H Beer","doi":"10.1038/s43587-025-00864-8","DOIUrl":"10.1038/s43587-025-00864-8","url":null,"abstract":"<p><p>Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 (Clos). We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H<sub>2</sub>O<sub>2</sub> production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut-vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"1025-1045"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039440","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}
Nature agingPub Date : 2025-06-01DOI: 10.1038/s43587-025-00905-2
George Andrew S Inglis
{"title":"Mid-life adipogenesis.","authors":"George Andrew S Inglis","doi":"10.1038/s43587-025-00905-2","DOIUrl":"10.1038/s43587-025-00905-2","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"956"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183115","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}
Nature agingPub Date : 2025-06-01DOI: 10.1038/s43587-025-00903-4
{"title":"Pace of aging matters for healthspan and lifespan in older adults.","authors":"","doi":"10.1038/s43587-025-00903-4","DOIUrl":"10.1038/s43587-025-00903-4","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"964-965"},"PeriodicalIF":17.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188741","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}
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