Nature agingPub Date : 2026-08-26DOI: 10.1038/s43587-026-01217-9
{"title":"Loss of cGAS disrupts H3K9me3 organization and derepresses LINE1 to cause inflammaging.","authors":"","doi":"10.1038/s43587-026-01217-9","DOIUrl":"https://doi.org/10.1038/s43587-026-01217-9","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835697","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":"Contractile myografts confer systemic anti-aging benefits.","authors":"Xupeng Liu, Ziyue Yao, Liping Zhang, Peng Wang, Siyu Guo, Honglin Xiang, Pengbin Yin, Ng Shyh-Chang","doi":"10.1038/s43587-026-01190-3","DOIUrl":"https://doi.org/10.1038/s43587-026-01190-3","url":null,"abstract":"<p><p>Skeletal muscle is the main motor organ and plays a vital role in regulating systemic metabolism and aging. Exercise interventions can address many metabolic and degenerative diseases associated with aging, though alternative strategies may be needed when exercise is contraindicated, inaccessible or insufficient. Here we developed subcutaneous transplantation of differentiated autologous myocytes (myografts). Myografts exhibited mature, vascularized structures that self-contract continuously in mice. Myografts improve whole-body muscle mass and function, and metabolic and regenerative outcomes in aging and obese mouse models. In addition, myografts provide a stable source of virally transduced therapeutic proteins, such as parathyroid hormone and growth hormone, which may counteract bone or muscle loss without observed side effects. This approach opens a path for the application of cell and gene therapy in the treatment of diseases of aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148835656","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 : 2026-08-25DOI: 10.1038/s43587-026-01180-5
Jiaming Li, Dan-Dan Gao, Jing Li, Lei Cao, Yuanyuan Du, Muzhao Xiong, Xi Chu, Wan Lei, Wei-Dong Ye, Gang Xu, Lina Ma, Jiazhen Tang, Qing Fu, Zikai Zheng, Hongkai Zhao, Ming Yi, Chunyu Lan, Liu-Jun Xu, Yanling Fan, Guohua Zhu, Liwen Xiao, Quan Zheng, Sicong Si, Huabiao Cheng, Beier Jiang, Shuhui Sun, Wenjian Jiang, Shuai Ma, Hongjia Zhang, Si Wang, Yun-Gui Yang, Jiayin Yang, Jing Qu, Feng Zhang, Zhili Liu, Guoguang Zhao, Guang-Hui Liu, Weiqi Zhang
{"title":"Sex-specific aging clocks from a large-scale human phenome reveal distinct aging transitions and circulating signatures.","authors":"Jiaming Li, Dan-Dan Gao, Jing Li, Lei Cao, Yuanyuan Du, Muzhao Xiong, Xi Chu, Wan Lei, Wei-Dong Ye, Gang Xu, Lina Ma, Jiazhen Tang, Qing Fu, Zikai Zheng, Hongkai Zhao, Ming Yi, Chunyu Lan, Liu-Jun Xu, Yanling Fan, Guohua Zhu, Liwen Xiao, Quan Zheng, Sicong Si, Huabiao Cheng, Beier Jiang, Shuhui Sun, Wenjian Jiang, Shuai Ma, Hongjia Zhang, Si Wang, Yun-Gui Yang, Jiayin Yang, Jing Qu, Feng Zhang, Zhili Liu, Guoguang Zhao, Guang-Hui Liu, Weiqi Zhang","doi":"10.1038/s43587-026-01180-5","DOIUrl":"https://doi.org/10.1038/s43587-026-01180-5","url":null,"abstract":"<p><p>Aging is a primary risk factor for chronic diseases, yet its progression varies among individuals and between sexes. Here, under the X-Age Project, we profiled the clinical aging phenome of the Multicentric Chinese Aging Study (mCAS) through a cross-sectional analysis of 172 clinical measures from more than 100,000 participants aged 18-98 years across three centers. These profiles enabled sex-specific clinical aging clocks that revealed divergent aging trajectories between women and men during midlife that converged in later life. Phenome-wide analyses revealed age-related accumulation of metabolic factors, including low-density lipoprotein, triglycerides, glucose and uric acid, and tumor markers, such as carcinoembryonic antigen and human epithelial protein 4. These age-accumulating factors induced senescence-related phenotypes in human endothelial cells. Furthermore, a high-fat diet mouse model with dietary reversal supported the modifiability of metabolic burden-induced aging. Together, this work establishes metabolic and tumor marker accumulation as actionable drivers of human aging, paving the way for personalized, sex-stratified geroprotective interventions.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820879","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":"A geroprotective probiotic and its functional metabolite counteract inflammaging to extend healthspan.","authors":"Xiaoyong Lu, Jun Ping, Zichu Han, Shuo Zhang, Lixiao Liu, Muzhao Xiong, Yanling Fan, Jiaming Li, Xiaoyan Sun, Peng Yang, Kejie Zheng, Zheng-Kai Wang, Jiale Ping, Yu Xiong, Yuesheng Zuo, Min Zhang, Jingyi Li, Qi Wu, Qiaoran Wang, Dan-Dan Gao, Beier Jiang, Shuhui Sun, Shuai Ma, Si Wang, Jing Qu, Yun-Gui Yang, Feng Zhang, Guang-Hui Liu, Weiqi Zhang","doi":"10.1038/s43587-026-01181-4","DOIUrl":"https://doi.org/10.1038/s43587-026-01181-4","url":null,"abstract":"<p><p>The gut microbiome profoundly influences host aging, yet the specific microbes and mechanisms governing divergent aging trajectories remain elusive. In this study, we delineated enterotype-specific gut microbial remodeling during aging and developed a microbiome-based aging clock (MicroAge) to track biological aging trajectories. We identified Bifidobacterium pseudocatenulatum (B. pseudocatenulatum) as a candidate geroprotective species consistently depleted during aging across both sexes and multiple Chinese cohorts. In naturally aged mice, oral B. pseudocatenulatum monotherapy rescued intestinal homeostasis, mitigated multiorgan inflammaging, enhanced cognitive-motor performance and extended healthspan. Mechanistically, we characterized 5-aminovaleric acid betaine (5-AVAB) as a key B. pseudocatenulatum-derived metabolite whose levels decline physiologically in aging humans. 5-AVAB supplementation partially recapitulated a broad spectrum of the systemic benefits observed with B. pseudocatenulatum treatment, including improved cognitive and motor function and suppressed multiorgan inflammaging. Our findings identify the B. pseudocatenulatum-5-AVAB axis as a promising target for microbiome-based interventions to promote healthy aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820860","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 : 2026-08-25DOI: 10.1038/s43587-026-01206-y
John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova
{"title":"cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.","authors":"John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova","doi":"10.1038/s43587-026-01206-y","DOIUrl":"10.1038/s43587-026-01206-y","url":null,"abstract":"<p><p>Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820844","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 : 2026-08-20DOI: 10.1038/s43587-026-01189-w
Liqin Wang, Rene Bernards
{"title":"Turning CDK4/6 inhibitors against the dark side of senescence.","authors":"Liqin Wang, Rene Bernards","doi":"10.1038/s43587-026-01189-w","DOIUrl":"https://doi.org/10.1038/s43587-026-01189-w","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803845","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 : 2026-08-20DOI: 10.1038/s43587-026-01196-x
Adarsh Rajesh, Aaron P Havas, Rouven Arnold, Kathryn Lande, Xue Lei, Kelly Yichen Li, Armin Gandhi, Ana Catarina Franco, Seung-Hwa Woo, Anthony B Lagnado, Angela Liou, K Garrett Evensen, Linshan Laux, Maggie Klaers, Jake Kircher, Amirhossein Nayeri Rad, Hiroshi Tanaka, Marcos Garcia Teneche, Michael Alcaraz, Karl N Miller, Zoe Yao, Sviatlana Zaretski, Sainath Mamde, Qian Yang, Jessica Proulx, Andrew Davis, Laurence Haddadin, Carolina Cano Macip, Brightany Li, Nirmalya Dasgupta, Zong Ming Chua, Cedomir Stamenkovic, Gabriele Guarnaccia, Hideki Tanizawa, Charlene Miciano, Elizabeth Smoot, Allen Wang, Rebecca A Porritt, Alessandra Sacco, Ken-Ichi Noma, Jeffrey H Albrecht, Laura J Niedernhofer, Joao F Passos, April E Williams, Bing Ren, Kevin Y Yip, Peter D Adams
{"title":"Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.","authors":"Adarsh Rajesh, Aaron P Havas, Rouven Arnold, Kathryn Lande, Xue Lei, Kelly Yichen Li, Armin Gandhi, Ana Catarina Franco, Seung-Hwa Woo, Anthony B Lagnado, Angela Liou, K Garrett Evensen, Linshan Laux, Maggie Klaers, Jake Kircher, Amirhossein Nayeri Rad, Hiroshi Tanaka, Marcos Garcia Teneche, Michael Alcaraz, Karl N Miller, Zoe Yao, Sviatlana Zaretski, Sainath Mamde, Qian Yang, Jessica Proulx, Andrew Davis, Laurence Haddadin, Carolina Cano Macip, Brightany Li, Nirmalya Dasgupta, Zong Ming Chua, Cedomir Stamenkovic, Gabriele Guarnaccia, Hideki Tanizawa, Charlene Miciano, Elizabeth Smoot, Allen Wang, Rebecca A Porritt, Alessandra Sacco, Ken-Ichi Noma, Jeffrey H Albrecht, Laura J Niedernhofer, Joao F Passos, April E Williams, Bing Ren, Kevin Y Yip, Peter D Adams","doi":"10.1038/s43587-026-01196-x","DOIUrl":"10.1038/s43587-026-01196-x","url":null,"abstract":"<p><p>Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the senescence-associated secretory phenotype (SASP), including interferon-stimulated genes (ISGs). Here we confirm and extend previous observations that cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of nonproliferating senescent cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver. Further, palbociclib suppresses frailty and improves physical performance of aged mice. These findings demonstrate a role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising target for therapeutic repurposing.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803901","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 : 2026-08-19DOI: 10.1038/s43587-026-01192-1
Júlia Bonjoch, Paloma Solá, Sandra García-Mulero, Thomas Mortimer, Oscar Reina, Camille Stephan-Otto Attolini, Yekaterina A Miroshnikova, Sara A Wickström, Laura Álvarez, Salvador Aznar Benitah, Guiomar Solanas
{"title":"Noncircadian BMAL1-YAP activity amplifies persistent inflammation in aged epidermis.","authors":"Júlia Bonjoch, Paloma Solá, Sandra García-Mulero, Thomas Mortimer, Oscar Reina, Camille Stephan-Otto Attolini, Yekaterina A Miroshnikova, Sara A Wickström, Laura Álvarez, Salvador Aznar Benitah, Guiomar Solanas","doi":"10.1038/s43587-026-01192-1","DOIUrl":"https://doi.org/10.1038/s43587-026-01192-1","url":null,"abstract":"<p><p>Aging is characterized by persistent low-grade inflammation linked to impaired tissue homeostasis, yet the underlying molecular mechanisms remain poorly understood. The mammalian skin is a clinically relevant site of aging-driven inflammation associated with compromised barrier function, inefficient wound healing, elevated oxidative stress and DNA damage accumulation. Here we show that, in the murine epidermis, aging engages a previously uncharacterized BMAL1-YAP functional cooperation with enhanced binding at inflammation-related enhancers, amplifying target gene transcription. Independent of its circadian clock role, BMAL1 partners with the mechanosensitive cofactor YAP at enhancer regions to regulate epidermal identity genes. However, in aged skin, this cooperative binding undergoes a functional shift, enhancing the expression of inflammation-related genes, partially coregulated by NF-κB. In addition, aged pro-inflammatory IL-17 signaling activates YAP in a Hippo-independent manner. These findings unveil a transcriptional mechanism underlying epidermal aging, linking chromatin dynamics to inflammatory programs through rewiring of BMAL1-YAP-occupied enhancers, highlighting potential strategies to counteract chronic inflammation and restore tissue homeostasis during aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":25.0,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803922","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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