Pub Date : 2025-12-11DOI: 10.1038/s43587-025-01038-2
Sheng Fong, Woon-Puay Koh, Jan Gruber
Biological aging clocks predict health outcomes, including morbidity and mortality, more accurately than chronological age alone, yet defining true biological age remains contentious. We propose ‘risk-equivalent’ age as an operationally defined metric that reflects an individual’s position on a continuum of clinically meaningful risk. Reconceptualizing biological age as a dynamic, risk-based vital sign may facilitate the use of aging clocks in clinical practice.
{"title":"Reframing biological age as risk-equivalent age","authors":"Sheng Fong, Woon-Puay Koh, Jan Gruber","doi":"10.1038/s43587-025-01038-2","DOIUrl":"10.1038/s43587-025-01038-2","url":null,"abstract":"Biological aging clocks predict health outcomes, including morbidity and mortality, more accurately than chronological age alone, yet defining true biological age remains contentious. We propose ‘risk-equivalent’ age as an operationally defined metric that reflects an individual’s position on a continuum of clinically meaningful risk. Reconceptualizing biological age as a dynamic, risk-based vital sign may facilitate the use of aging clocks in clinical practice.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"2-5"},"PeriodicalIF":19.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746471","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}
One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.
{"title":"Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation","authors":"Bingjie Guan, Mantang Zhou, Weixing Dai, Jing Zhang, Bowen Xie, Yushuai Mi, Xin Zhang, Ping Wei, Youdong Liu, Shanbao Li, Haonan Guan, Xiaoming Zhang, Sanjun Cai, Dawei Li, Dongwang Yan, Senlin Zhao","doi":"10.1038/s43587-025-01023-9","DOIUrl":"10.1038/s43587-025-01023-9","url":null,"abstract":"One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2449-2465"},"PeriodicalIF":19.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145672947","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 : 2025-12-02DOI: 10.1038/s43587-025-01041-7
To the best of our knowledge, this study provides the first comprehensive proteogenomic map of cerebral small vessel disease, identifying proteins and pathways involved in its pathophysiology and highlighting potential biomarkers and therapeutic targets for this extremely common and disabling condition, which is a leading cause of stroke and dementia.
{"title":"Proteogenomics uncovers biological fingerprints of small vessel disease","authors":"","doi":"10.1038/s43587-025-01041-7","DOIUrl":"10.1038/s43587-025-01041-7","url":null,"abstract":"To the best of our knowledge, this study provides the first comprehensive proteogenomic map of cerebral small vessel disease, identifying proteins and pathways involved in its pathophysiology and highlighting potential biomarkers and therapeutic targets for this extremely common and disabling condition, which is a leading cause of stroke and dementia.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2376-2377"},"PeriodicalIF":19.4,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663217","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 : 2025-11-26DOI: 10.1038/s43587-025-01021-x
Anna Krepelova, Mahdi Rasa, Francesco Annunziata, Jing Lu, Chiara Giannuzzi, Omid Omrani, Elisabeth Wyart, Paolo Ettore Porporato, Ihab Ansari, Dor Bilenko, Yehudit Bergman, Francesco Neri
Epigenetic drift is a key feature of aging and is associated with age-related diseases including cancer, yet the underlying molecular mechanisms remain unclear. Here, by analyzing DNA methylation and gene expression data from healthy and cancerous human colon samples, we identify an aging and colon cancer-associated DNA methylation (DNAm) drift. We find evidence that this drift is conserved in the mouse intestinal epithelium, where we demonstrate its origin within intestinal stem cells and identify its cell-intrinsic and non-mitotic characteristics, finding that its expansion is regulated via crypt clonality and fission. Mechanistically, we find that this drift is driven by age-related inflammation and reduced Wnt signaling, which dysregulate iron metabolism and impair TET activity. Despite CpG-level heterogeneity, we find that DNAm changes are consistent at the gene level, suggesting potential functionality. Our findings shed light on the epigenetic mechanisms of aging and provide a mechanistic basis for the hypermethylation observed in cancer. Krepelova and colleagues identify an aging- and colon cancer-associated DNA methylation drift in healthy and cancerous human colon samples, echoed in the mouse intestinal epithelium. They show it expands via intestinal cell clonality and is driven by dysregulated iron metabolism.
{"title":"Iron homeostasis and cell clonality drive cancer-associated intestinal DNA methylation drift in aging","authors":"Anna Krepelova, Mahdi Rasa, Francesco Annunziata, Jing Lu, Chiara Giannuzzi, Omid Omrani, Elisabeth Wyart, Paolo Ettore Porporato, Ihab Ansari, Dor Bilenko, Yehudit Bergman, Francesco Neri","doi":"10.1038/s43587-025-01021-x","DOIUrl":"10.1038/s43587-025-01021-x","url":null,"abstract":"Epigenetic drift is a key feature of aging and is associated with age-related diseases including cancer, yet the underlying molecular mechanisms remain unclear. Here, by analyzing DNA methylation and gene expression data from healthy and cancerous human colon samples, we identify an aging and colon cancer-associated DNA methylation (DNAm) drift. We find evidence that this drift is conserved in the mouse intestinal epithelium, where we demonstrate its origin within intestinal stem cells and identify its cell-intrinsic and non-mitotic characteristics, finding that its expansion is regulated via crypt clonality and fission. Mechanistically, we find that this drift is driven by age-related inflammation and reduced Wnt signaling, which dysregulate iron metabolism and impair TET activity. Despite CpG-level heterogeneity, we find that DNAm changes are consistent at the gene level, suggesting potential functionality. Our findings shed light on the epigenetic mechanisms of aging and provide a mechanistic basis for the hypermethylation observed in cancer. Krepelova and colleagues identify an aging- and colon cancer-associated DNA methylation drift in healthy and cancerous human colon samples, echoed in the mouse intestinal epithelium. They show it expands via intestinal cell clonality and is driven by dysregulated iron metabolism.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2432-2448"},"PeriodicalIF":19.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01021-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644157","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 : 2025-11-26DOI: 10.1038/s43587-025-00992-1
Katherine I. Kim, Natalie A. Bello, Liisa A. M. Galea, Vadim N. Gladyshev, Grazyna Jasienska, Kara L. McKinley, Eliza C. Miller, W. Tony Parks, Anna Z. Pollack, Egle Bytautiene Prewit, Janet Rich-Edwards, Calen P. Ryan, Jamie Slaughter-Acey, Anna E. Stanhewicz, Junie P. Warrington, Yousin Suh
In November 2023, the Division of Aging Biology of the National Institute on Aging held a workshop to discuss the long-term effects of pregnancy on aging. A synthesis of these discussions and a set of considerations are presented in this Meeting Report.
{"title":"A National Institute on Aging workshop on the long-term effects of pregnancy on aging","authors":"Katherine I. Kim, Natalie A. Bello, Liisa A. M. Galea, Vadim N. Gladyshev, Grazyna Jasienska, Kara L. McKinley, Eliza C. Miller, W. Tony Parks, Anna Z. Pollack, Egle Bytautiene Prewit, Janet Rich-Edwards, Calen P. Ryan, Jamie Slaughter-Acey, Anna E. Stanhewicz, Junie P. Warrington, Yousin Suh","doi":"10.1038/s43587-025-00992-1","DOIUrl":"10.1038/s43587-025-00992-1","url":null,"abstract":"In November 2023, the Division of Aging Biology of the National Institute on Aging held a workshop to discuss the long-term effects of pregnancy on aging. A synthesis of these discussions and a set of considerations are presented in this Meeting Report.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2372-2375"},"PeriodicalIF":19.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644098","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 : 2025-11-26DOI: 10.1038/s43587-025-01016-8
Yunhe Wang, Sihao Xiao, Bowen Liu, Rongtao Jiang, Yuxi Liu, Yian Hang, Li Chen, Runsen Chen, Michael V. Vitiello, Derrick Bennett, Baihan Wang, Jun Lv, Canqing Yu, Danielle E. Haslam, Qianyan Zheng, Robert E. Gerszten, Yanping Bao, Jie Shi, Junqing Xie, Lin Lu, Liming Li, Cornelia M. van Duijn, Dong D. Wang, Zhengming Chen, Andrew T. Chan
Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer’s disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations. Wang, Xiao and colleagues develop and validate organ-specific proteomic aging clocks across large population cohorts in the UK, the USA and China, which show strong performance in tracking organ aging and predicting the risk of morbidity and mortality.
{"title":"Organ-specific proteomic aging clocks predict disease and longevity across diverse populations","authors":"Yunhe Wang, Sihao Xiao, Bowen Liu, Rongtao Jiang, Yuxi Liu, Yian Hang, Li Chen, Runsen Chen, Michael V. Vitiello, Derrick Bennett, Baihan Wang, Jun Lv, Canqing Yu, Danielle E. Haslam, Qianyan Zheng, Robert E. Gerszten, Yanping Bao, Jie Shi, Junqing Xie, Lin Lu, Liming Li, Cornelia M. van Duijn, Dong D. Wang, Zhengming Chen, Andrew T. Chan","doi":"10.1038/s43587-025-01016-8","DOIUrl":"10.1038/s43587-025-01016-8","url":null,"abstract":"Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer’s disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations. Wang, Xiao and colleagues develop and validate organ-specific proteomic aging clocks across large population cohorts in the UK, the USA and China, which show strong performance in tracking organ aging and predicting the risk of morbidity and mortality.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"162-180"},"PeriodicalIF":19.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01016-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644168","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 : 2025-11-26DOI: 10.1038/s43587-025-01033-7
Jiahn Choi
Epigenetic drift is well known for aging phenotypes, but the underlying mechanisms are yet to be understood. A study by Krepelova and colleagues demonstrates that epigenetic drift is induced by dysregulation of iron metabolism in the intestinal stem cells, which leads to accumulating gene hypermethylation that propagates through crypt fission as the organism ages.
{"title":"Revealing epigenetic drift in intestinal pathogenesis with age","authors":"Jiahn Choi","doi":"10.1038/s43587-025-01033-7","DOIUrl":"10.1038/s43587-025-01033-7","url":null,"abstract":"Epigenetic drift is well known for aging phenotypes, but the underlying mechanisms are yet to be understood. A study by Krepelova and colleagues demonstrates that epigenetic drift is induced by dysregulation of iron metabolism in the intestinal stem cells, which leads to accumulating gene hypermethylation that propagates through crypt fission as the organism ages.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2367-2368"},"PeriodicalIF":19.4,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145644123","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 : 2025-11-25DOI: 10.1038/s43587-025-01022-w
Onur Eskiocak, Joseph Gewolb, Vyom Shah, James A. Rouse, Saria Chowdhury, Erdogan O. Akyildiz, Inés Fernández-Maestre, Jacob A. Boyer, Aveline Filliol, Alexander S. Harris, Raditya Utama, Guangran Guo, Carolina Castro-Hernández, Emmanuella Nnuji-John, Charlie Chung, Arianna Anderson, Sara Flowers, Jill Habel, Paul B. Romesser, Ross L. Levine, Scott W. Lowe, Michel Sadelain, Semir Beyaz, Corina Amor
Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms. uPAR is a senescence-associated protein, and CAR T cells targeting uPAR exert senolysis. Here Eskiocak et al. identify uPAR+ cells as key targets of intestinal aging and show that CAR T-mediated elimination prevents and restores age-related decline in intestinal regeneration and barrier function.
肠干细胞（ISCs）驱动肠上皮的快速再生。然而，随着年龄的增长，它们的再生能力减弱，可能是通过衰老和慢性炎症，尽管人们对肠道中与衰老相关的功能障碍是如何产生的知之甚少。我们之前发现尿激酶纤溶酶原激活物受体（uPAR）是一种衰老相关蛋白，并开发了能够有效靶向它的CAR - T细胞。利用它们，我们在衰老的肠道中发现了大多数上皮upar阳性细胞的积累，并揭示了它们在衰老过程中对ISC功能的有害影响。因此，抗upar CAR - T细胞的治疗性和预防性治疗均可改善老年小鼠的屏障功能、再生能力、炎症、粘膜免疫功能和微生物组组成。总的来说，这些发现揭示了upar阳性细胞对体内肠道衰老的有害作用，并为靶向免疫细胞疗法增强衰老生物体组织再生的潜力提供了概念证明。
{"title":"Anti-uPAR CAR T cells reverse and prevent aging-associated defects in intestinal regeneration and fitness","authors":"Onur Eskiocak, Joseph Gewolb, Vyom Shah, James A. Rouse, Saria Chowdhury, Erdogan O. Akyildiz, Inés Fernández-Maestre, Jacob A. Boyer, Aveline Filliol, Alexander S. Harris, Raditya Utama, Guangran Guo, Carolina Castro-Hernández, Emmanuella Nnuji-John, Charlie Chung, Arianna Anderson, Sara Flowers, Jill Habel, Paul B. Romesser, Ross L. Levine, Scott W. Lowe, Michel Sadelain, Semir Beyaz, Corina Amor","doi":"10.1038/s43587-025-01022-w","DOIUrl":"10.1038/s43587-025-01022-w","url":null,"abstract":"Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium. However, during aging, their regenerative capacity wanes, possibly through senescence and chronic inflammation, albeit little is known about how aging-associated dysfunction arises in the intestine. We previously identified the urokinase plasminogen activator receptor (uPAR) as a senescence-associated protein and developed CAR T cells able to efficiently target it. Harnessing them, here, we identify the accumulation of mostly epithelial uPAR-positive cells in the aging gut and uncover their detrimental impact on ISC function in aging. Thus, both therapeutic and prophylactic treatment with anti-uPAR CAR T cells improved barrier function, regenerative capacity, inflammation, mucosal immune function and microbiome composition in aged mice. Overall, these findings reveal the deleterious role of uPAR-positive cells on intestinal aging in vivo and provide proof of concept for the potential of targeted immune-based cell therapies to enhance tissue regeneration in aging organisms. uPAR is a senescence-associated protein, and CAR T cells targeting uPAR exert senolysis. Here Eskiocak et al. identify uPAR+ cells as key targets of intestinal aging and show that CAR T-mediated elimination prevents and restores age-related decline in intestinal regeneration and barrier function.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"108-126"},"PeriodicalIF":19.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01022-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145608107","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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