Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases. Senescent cells (SCs) accumulate with age, but how the immune system regulates their burden is unclear. Here we show that CD4 T cells differentiate into Eomesodermin (Eomes)+CCL5+ T lymphocytes (CD4-Eomes) in a SC-rich environment and that a reduction in the SC load, achieved using senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4-Eomes cells at advanced age by selectively deleting the Eomes transcription factor in CD4 T cells results in increased accumulation of SCs, profound physical deterioration and a decreased lifespan. In liver cirrhosis, a model of localized chronic inflammation, CD4-Eomes cell elimination increased fibrosis, SC load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4-Eomes cells in modulating tissue senescence, with implications for age-related diseases and longevity. Elyahu and colleagues describe the reciprocal interplay between senescent cells (SCs) and a helper T cell population that accumulates during aging. They show that selective depletion of this T cell population increases SC accumulation, accelerates frailty and limits lifespan in mice.
{"title":"CD4 T cells acquire Eomesodermin to modulate cellular senescence and aging","authors":"Yehezqel Elyahu, Ilana Feygin, Ekaterina Eremenko, Noa Pinkas, Alon Zemer, Amit Shicht, Omer Berner, Roni Avigdory-Meiri, Anna Nemirovsky, Keren Reshef, Lior Roitman, Valery Krizhanovsky, Alon Monsonego","doi":"10.1038/s43587-025-00953-8","DOIUrl":"10.1038/s43587-025-00953-8","url":null,"abstract":"Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases. Senescent cells (SCs) accumulate with age, but how the immune system regulates their burden is unclear. Here we show that CD4 T cells differentiate into Eomesodermin (Eomes)+CCL5+ T lymphocytes (CD4-Eomes) in a SC-rich environment and that a reduction in the SC load, achieved using senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4-Eomes cells at advanced age by selectively deleting the Eomes transcription factor in CD4 T cells results in increased accumulation of SCs, profound physical deterioration and a decreased lifespan. In liver cirrhosis, a model of localized chronic inflammation, CD4-Eomes cell elimination increased fibrosis, SC load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4-Eomes cells in modulating tissue senescence, with implications for age-related diseases and longevity. Elyahu and colleagues describe the reciprocal interplay between senescent cells (SCs) and a helper T cell population that accumulates during aging. They show that selective depletion of this T cell population increases SC accumulation, accelerates frailty and limits lifespan in mice.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 10","pages":"1970-1982"},"PeriodicalIF":19.4,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145246046","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 : 2025-10-06DOI: 10.1038/s43587-025-00983-2
Michael S. Ringel, Yue Zhang, Wen Kin Lim
{"title":"Accelerating activity in the longevity biopharmaceutical sector","authors":"Michael S. Ringel, Yue Zhang, Wen Kin Lim","doi":"10.1038/s43587-025-00983-2","DOIUrl":"10.1038/s43587-025-00983-2","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2357-2358"},"PeriodicalIF":19.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240713","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 : 2025-10-06DOI: 10.1038/s43587-025-00988-x
Joe Swift, Angela Cucchi, Michael Chang, Richard G. A. Faragher, Carol A. Holland, Itziar Tueros, Matthew J. Dalby, Elizabeth G. Canty-Laird
On 12 February 2025, a joint meeting of the UK Aging Networks was held in Liverpool, UK. It was convened by the ECMage (extracellular matrix aging) network and EuroAgeNet, an initiative led by ECMage but involving four other UK aging networks — namely, the building links in aging science and translation network (BLAST), the cognitive frailty interdisciplinary network (CFIN), the aging and nutrient sensing network (AGENTS) and the food systems for older people (Food4Years) network — together with industrial and European partners. In this Meeting Report, we summarize the opinions of an industrial panel and round-table discussions on barriers and opportunities related to academic–industrial partnerships.
{"title":"Considerations for creating effective academic–industrial partnerships","authors":"Joe Swift, Angela Cucchi, Michael Chang, Richard G. A. Faragher, Carol A. Holland, Itziar Tueros, Matthew J. Dalby, Elizabeth G. Canty-Laird","doi":"10.1038/s43587-025-00988-x","DOIUrl":"10.1038/s43587-025-00988-x","url":null,"abstract":"On 12 February 2025, a joint meeting of the UK Aging Networks was held in Liverpool, UK. It was convened by the ECMage (extracellular matrix aging) network and EuroAgeNet, an initiative led by ECMage but involving four other UK aging networks — namely, the building links in aging science and translation network (BLAST), the cognitive frailty interdisciplinary network (CFIN), the aging and nutrient sensing network (AGENTS) and the food systems for older people (Food4Years) network — together with industrial and European partners. In this Meeting Report, we summarize the opinions of an industrial panel and round-table discussions on barriers and opportunities related to academic–industrial partnerships.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2153-2157"},"PeriodicalIF":19.4,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240747","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 : 2025-10-03DOI: 10.1038/s43587-025-00989-w
Nektarios Tavernarakis
Bai and colleagues show that specialized translation hubs called mitochondria-associated translation organelles (MATOs) form by liquid–liquid phase separation on the mitochondrial surface. MATOs congregate ribosomes and specific mRNAs to supply key proteins on-site and thereby uphold mitochondrial integrity and function. Persistent association of MATOs with mitochondria enhances stress resistance and extends lifespan.
{"title":"Phase separation meets energy generation to boost longevity","authors":"Nektarios Tavernarakis","doi":"10.1038/s43587-025-00989-w","DOIUrl":"10.1038/s43587-025-00989-w","url":null,"abstract":"Bai and colleagues show that specialized translation hubs called mitochondria-associated translation organelles (MATOs) form by liquid–liquid phase separation on the mitochondrial surface. MATOs congregate ribosomes and specific mRNAs to supply key proteins on-site and thereby uphold mitochondrial integrity and function. Persistent association of MATOs with mitochondria enhances stress resistance and extends lifespan.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 10","pages":"1936-1938"},"PeriodicalIF":19.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226540","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 : 2025-10-03DOI: 10.1038/s43587-025-00962-7
Philippe Jawinski, Helena Forstbach, Holger Kirsten, Frauke Beyer, Arno Villringer, A. Veronica Witte, Markus Scholz, Stephan Ripke, Sebastian Markett
Neuroimaging and machine learning are advancing research into the mechanisms of biological aging. In this field, ‘brain age gap’ has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual’s biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of 23–29% attributable to common genetic variants and highlighted 59 associated loci (39 novel). The leading locus encompasses MAPT, encoding the tau protein central to Alzheimer’s disease. Genetic correlations revealed relationships with mental health, physical health, lifestyle and socioeconomic traits, including depressed mood, diabetes, alcohol intake and income. Mendelian randomization indicated a causal role of high blood pressure and type 2 diabetes in accelerated brain aging. Our study highlights key genes and pathways related to neurogenesis, immune-system-related processes and small GTPase binding, laying the foundation for further mechanistic exploration. This genomic study of magnetic resonance imaging-based brain age in 56,348 people identifies 59 genetic loci, links brain aging to mental and physical health, and suggests high blood pressure and type 2 diabetes as causal factors of brain aging.
{"title":"Genome-wide analysis of brain age identifies 59 associated loci and unveils relationships with mental and physical health","authors":"Philippe Jawinski, Helena Forstbach, Holger Kirsten, Frauke Beyer, Arno Villringer, A. Veronica Witte, Markus Scholz, Stephan Ripke, Sebastian Markett","doi":"10.1038/s43587-025-00962-7","DOIUrl":"10.1038/s43587-025-00962-7","url":null,"abstract":"Neuroimaging and machine learning are advancing research into the mechanisms of biological aging. In this field, ‘brain age gap’ has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual’s biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of 23–29% attributable to common genetic variants and highlighted 59 associated loci (39 novel). The leading locus encompasses MAPT, encoding the tau protein central to Alzheimer’s disease. Genetic correlations revealed relationships with mental health, physical health, lifestyle and socioeconomic traits, including depressed mood, diabetes, alcohol intake and income. Mendelian randomization indicated a causal role of high blood pressure and type 2 diabetes in accelerated brain aging. Our study highlights key genes and pathways related to neurogenesis, immune-system-related processes and small GTPase binding, laying the foundation for further mechanistic exploration. This genomic study of magnetic resonance imaging-based brain age in 56,348 people identifies 59 genetic loci, links brain aging to mental and physical health, and suggests high blood pressure and type 2 diabetes as causal factors of brain aging.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 10","pages":"2086-2103"},"PeriodicalIF":19.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-00962-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226555","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 : 2025-09-30DOI: 10.1038/s43587-025-00968-1
Kefan Wang, Wei He, Zhe Gong, Jun Gao, Tianyou Gao, Nan Pan, Dongze Wu, Yijie Yang, Zhuang Li, Xing Zhao, Mingliang Ji, Shuying Shen
Osteoarthritis (OA) is a whole-joint disorder that interferes with the quality of life in older individuals. Here we report that ZDHHC11 is highly expressed in articular chondrocytes but is downregulated in the degenerated cartilage of aged mice and patients with OA. ZDHHC11 prevents chondrocyte senescence and promotes cartilage anabolism, culminating in an improved OA phenotype. The deletion of Zdhhc11 in mice (Zdhhc11fl/fl) exacerbates OA progression in a destabilized medial meniscus model. Specifically, we identify ZDHHC11 as a key palmitoyltransferase whose depletion leads to a GNB2-dependent E3 ubiquitin ligase-mediated proteasomal degradation of APOD. Mechanistically, ZDHHC11-mediated palmitoylation alleviates OA progression by deactivating the GATA4–P65 signaling pathway. We also propose an original lipid nanoparticle-based platform for Zdhhc11 mRNA delivery to rejuvenate impaired cartilage by specifically targeting chondrocytes in vivo. Collectively, ZDHHC11-dependent palmitoylation is essential for ameliorating OA, and the targeted delivery of ZDHHC11 may serve as a promising strategy for future OA treatment. Wang, He, Gong and colleagues identify an age-related decline in the palmitoyltransferase ZDHHC11 in chondrocytes that leads to senescence and the pathogenesis of osteoarthritis, highlighting the potential of targeted ZDHHC11 delivery as a therapeutic strategy for osteoarthritis.
{"title":"ZDHHC11-mediated palmitoylation alleviates chondrocyte senescence and serves as a therapeutic target for osteoarthritis","authors":"Kefan Wang, Wei He, Zhe Gong, Jun Gao, Tianyou Gao, Nan Pan, Dongze Wu, Yijie Yang, Zhuang Li, Xing Zhao, Mingliang Ji, Shuying Shen","doi":"10.1038/s43587-025-00968-1","DOIUrl":"10.1038/s43587-025-00968-1","url":null,"abstract":"Osteoarthritis (OA) is a whole-joint disorder that interferes with the quality of life in older individuals. Here we report that ZDHHC11 is highly expressed in articular chondrocytes but is downregulated in the degenerated cartilage of aged mice and patients with OA. ZDHHC11 prevents chondrocyte senescence and promotes cartilage anabolism, culminating in an improved OA phenotype. The deletion of Zdhhc11 in mice (Zdhhc11fl/fl) exacerbates OA progression in a destabilized medial meniscus model. Specifically, we identify ZDHHC11 as a key palmitoyltransferase whose depletion leads to a GNB2-dependent E3 ubiquitin ligase-mediated proteasomal degradation of APOD. Mechanistically, ZDHHC11-mediated palmitoylation alleviates OA progression by deactivating the GATA4–P65 signaling pathway. We also propose an original lipid nanoparticle-based platform for Zdhhc11 mRNA delivery to rejuvenate impaired cartilage by specifically targeting chondrocytes in vivo. Collectively, ZDHHC11-dependent palmitoylation is essential for ameliorating OA, and the targeted delivery of ZDHHC11 may serve as a promising strategy for future OA treatment. Wang, He, Gong and colleagues identify an age-related decline in the palmitoyltransferase ZDHHC11 in chondrocytes that leads to senescence and the pathogenesis of osteoarthritis, highlighting the potential of targeted ZDHHC11 delivery as a therapeutic strategy for osteoarthritis.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2228-2246"},"PeriodicalIF":19.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-00968-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145202592","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}
The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n = 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response. Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals. The contribution of the extracellular matrix and its degradation to the aging process is not well understood. Here, the authors show that degraded elastin fragments, which increase in the circulation with age, promote aging, while counteracting elastin fragment signals alleviates inflammation, promotes healthy aging and extends lifespan.
{"title":"Elastin-derived extracellular matrix fragments drive aging through innate immune activation","authors":"Junzhi Yi, Yixuan Wang, Hairu Sui, Zhichu Chen, Tianning Ye, Yuliang Zhong, Jingyi Qian, Bingbing Wu, Jiayun Huang, Tian Tian, Fangyuan Bao, Xuri Chen, Xiao Xiao, Jiasheng Wang, Jiajie Hu, Yujuan Xie, Hui Zhang, Pan Jin, Xiaoping Xia, Xudong Yao, Yishan Chen, Zi Yin, Weiliang Shen, Jing Zhou, Xiaohui Zou, Hua Liu, Hongwei Ouyang","doi":"10.1038/s43587-025-00961-8","DOIUrl":"10.1038/s43587-025-00961-8","url":null,"abstract":"The roles of cells in systemic aging have been systematically investigated, while the roles of the extracellular matrix (ECM) and its degradation have been largely overlooked. Herein, we show that the serum contents of elastin-, hyaluronic acid- and fibronectin-derived fragments are all positively correlated with age. Elastin-derived fragments exhibited the most potent lifespan-shortening effects in mice and a positive correlation with various aging indicators in a human cohort (n = 1,068). Mechanistically, the VGVAPG oligopeptide (E-motif) in elastin-derived fragments activated monocytes and macrophages through NEU1, a component of the elastin receptor complex, which consequently caused an inflammatory response. Therapeutically, a NEU1 inhibitor extended lifespan by up to 17% in wild-type naturally aged mice and alleviated aging-related phenotypes in wild-type mice, immune-humanized mice and pigs. This study uncovers that degraded ECM acts as a circulating driver of aging, providing an anti-aging intervention strategy focused on particular elastin fragment signals. The contribution of the extracellular matrix and its degradation to the aging process is not well understood. Here, the authors show that degraded elastin fragments, which increase in the circulation with age, promote aging, while counteracting elastin fragment signals alleviates inflammation, promotes healthy aging and extends lifespan.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2380-2398"},"PeriodicalIF":19.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-00961-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194233","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 : 2025-09-26DOI: 10.1038/s43587-025-00980-5
Takeshi Iwatsubo
{"title":"A Japanese registry for optimizing the safe use of anti-amyloid therapies for Alzheimer’s disease in Japan","authors":"Takeshi Iwatsubo","doi":"10.1038/s43587-025-00980-5","DOIUrl":"10.1038/s43587-025-00980-5","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 10","pages":"1917-1919"},"PeriodicalIF":19.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180742","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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