Pub Date : 2025-11-04DOI: 10.1038/s43587-025-00986-z
Emily G. Shuldiner, Saswati Karmakar, Min K. Tsai, Jess D. Hebert, Yuning J. Tang, Laura Andrejka, Maggie R. Robertson, Minwei Wang, Colin R. Detrick, Hongchen Cai, Rui Tang, Christian A. Kunder, David M. Feldser, Dmitri A. Petrov, Monte M. Winslow
Most cancers are diagnosed in people over 60 years of age, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation (widely understood to contribute to cancer risk) it is associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses oncogenic KRAS-driven tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K–AKT pathway, weakened disproportionately. Single-cell transcriptomic analysis revealed that neoplastic cells in aged mice retain age-related transcriptomic changes, showing that the impact of age persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings underscore the interconnectedness of the pathways involved in aging and tumorigenesis and document tumor-suppressive effects of aging that may contribute to the deceleration in cancer incidence with age. The mechanisms that impact tumorigenesis during aging are incompletely understood. Here Shuldiner et al. show that in mice, aging represses KRAS-driven lung tumorigenesis and dampens the impact of inactivating many tumor suppressor genes, which may contribute to the deceleration in cancer incidence with extreme age in humans.
{"title":"Aging represses oncogenic KRAS-driven lung tumorigenesis and alters tumor suppression","authors":"Emily G. Shuldiner, Saswati Karmakar, Min K. Tsai, Jess D. Hebert, Yuning J. Tang, Laura Andrejka, Maggie R. Robertson, Minwei Wang, Colin R. Detrick, Hongchen Cai, Rui Tang, Christian A. Kunder, David M. Feldser, Dmitri A. Petrov, Monte M. Winslow","doi":"10.1038/s43587-025-00986-z","DOIUrl":"10.1038/s43587-025-00986-z","url":null,"abstract":"Most cancers are diagnosed in people over 60 years of age, but little is known about how age impacts tumorigenesis. While aging is accompanied by mutation accumulation (widely understood to contribute to cancer risk) it is associated with numerous other cellular and molecular changes likely to impact tumorigenesis. Moreover, cancer incidence decreases in the oldest part of the population, suggesting that very old age may reduce carcinogenesis. Here we show that aging represses oncogenic KRAS-driven tumor initiation and growth in genetically engineered mouse models of human lung cancer. Moreover, aging dampens the impact of inactivating many tumor suppressor genes with the impact of inactivating PTEN, a negative regulator of the PI3K–AKT pathway, weakened disproportionately. Single-cell transcriptomic analysis revealed that neoplastic cells in aged mice retain age-related transcriptomic changes, showing that the impact of age persists through oncogenic transformation. Furthermore, the consequences of PTEN inactivation were strikingly age-dependent, with PTEN deficiency reducing signatures of aging in cancer cells and the tumor microenvironment. Our findings underscore the interconnectedness of the pathways involved in aging and tumorigenesis and document tumor-suppressive effects of aging that may contribute to the deceleration in cancer incidence with age. The mechanisms that impact tumorigenesis during aging are incompletely understood. Here Shuldiner et al. show that in mice, aging represses KRAS-driven lung tumorigenesis and dampens the impact of inactivating many tumor suppressor genes, which may contribute to the deceleration in cancer incidence with extreme age in humans.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2263-2278"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-00986-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446992","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 : 2025-11-04DOI: 10.1038/s43587-025-01010-0
Reproductive aging involves a decline in oocyte chromosome cohesion and various other developmental conditions that are difficult to study in isolation. We developed a mouse system that enables rapid manipulation of chromosome cohesion, which revealed that centromere dysfunction is a key driver of age-related chromosomal errors in mammalian eggs.
{"title":"A synthetic oocyte aging method for uncovering the molecular origins of egg aneuploidy","authors":"","doi":"10.1038/s43587-025-01010-0","DOIUrl":"10.1038/s43587-025-01010-0","url":null,"abstract":"Reproductive aging involves a decline in oocyte chromosome cohesion and various other developmental conditions that are difficult to study in isolation. We developed a mouse system that enables rapid manipulation of chromosome cohesion, which revealed that centromere dysfunction is a key driver of age-related chromosomal errors in mammalian eggs.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2158-2159"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446972","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 : 2025-11-04DOI: 10.1038/s43587-025-00984-1
Adrienne Parsons, Esther Sauras Colón, Meghana Manjunath, Hanyun Zhang, Julia Chen, Milos Spasic, Beyza Koca, Busem Binboga Kurt, Rachel A. Freedman, Elizabeth A. Mittendorf, Alexander Swarbrick, Peter van Galen, Sandra S. McAllister
Aging is associated with increased breast cancer risk, and the oldest and youngest patients have worse outcomes, irrespective of subtype. It is unknown how age affects cells in the breast tumor microenvironment or how they contribute to age-related pathology. Here we discover age-associated differences in cell states in human estrogen receptor-positive and triple-negative breast cancers using analyses of existing bulk and single-cell transcriptomic data. We generate and apply an Age-Specific Program ENrichment (ASPEN) analysis pipeline, revealing age-related changes, including increased tumor cell epithelial–mesenchymal transition and cancer-associated fibroblast inflammatory responses in triple-negative breast cancer. Estrogen receptor-positive breast cancer displays increased ESR1 expression and reduced vascular and immune cell metabolism with age. Cell interactome analysis reveals candidate signaling pathways that drive age-related cell states. Spatial analyses across independent clinical cohorts support the computational findings. This work identifies potential targets for age-adapted therapeutic interventions for breast cancer. Parsons and colleagues characterize age-associated changes in the tumor microenvironment of triple-negative and estrogen receptor-positive breast cancer using computational analysis of transcriptomic data, paired with immunostaining of independently collected samples.
{"title":"Cell populations in human breast cancers are molecularly and biologically distinct with age","authors":"Adrienne Parsons, Esther Sauras Colón, Meghana Manjunath, Hanyun Zhang, Julia Chen, Milos Spasic, Beyza Koca, Busem Binboga Kurt, Rachel A. Freedman, Elizabeth A. Mittendorf, Alexander Swarbrick, Peter van Galen, Sandra S. McAllister","doi":"10.1038/s43587-025-00984-1","DOIUrl":"10.1038/s43587-025-00984-1","url":null,"abstract":"Aging is associated with increased breast cancer risk, and the oldest and youngest patients have worse outcomes, irrespective of subtype. It is unknown how age affects cells in the breast tumor microenvironment or how they contribute to age-related pathology. Here we discover age-associated differences in cell states in human estrogen receptor-positive and triple-negative breast cancers using analyses of existing bulk and single-cell transcriptomic data. We generate and apply an Age-Specific Program ENrichment (ASPEN) analysis pipeline, revealing age-related changes, including increased tumor cell epithelial–mesenchymal transition and cancer-associated fibroblast inflammatory responses in triple-negative breast cancer. Estrogen receptor-positive breast cancer displays increased ESR1 expression and reduced vascular and immune cell metabolism with age. Cell interactome analysis reveals candidate signaling pathways that drive age-related cell states. Spatial analyses across independent clinical cohorts support the computational findings. This work identifies potential targets for age-adapted therapeutic interventions for breast cancer. Parsons and colleagues characterize age-associated changes in the tumor microenvironment of triple-negative and estrogen receptor-positive breast cancer using computational analysis of transcriptomic data, paired with immunostaining of independently collected samples.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 12","pages":"2546-2563"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-00984-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446951","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 : 2025-11-04DOI: 10.1038/s43587-025-01005-x
Qiyuan Zhuang, Yihan Hu, Dang Wei, Chenxi Qin, Kejia Hu, Junyi Zhang, Lida Chen, Zhelun Yang, Weimin Ye, Karin Wirdefeldt, Xiang Zou, Ying Mao, Sara Hägg, Fang Fang
Infectious diseases are known to trigger acute seizures, but their long-term impact on epilepsy, especially in later life, is unclear. We conducted nested case–control studies of newly diagnosed epilepsy after age 50 in the UK Biobank (2,486 cases; 12,430 controls) and Swedish registers (56,266 cases; 281,330 controls), including a sibling comparison. Previous hospital-treated infections were associated with a persistently elevated epilepsy risk (for example, >10 years after infection: odds ratio (OR) 1.68, 95% confidence interval: 1.39–2.04 in UK Biobank; 1.46, 1.41–1.51 in Sweden). Associations were robust in sibling analyses and across infection types and sites. We further found that infections, together with a high cardiovascular genetic risk (OR 2.62, 2.22–3.08), a high cardiovascular risk score (OR 3.14, 2.68–3.68) or cardiovascular disease history (OR 4.77, 4.64–4.91), were associated with the highest epilepsy risk. Hospital-treated infections exert prolonged impact on epilepsy risk in older age, especially when in combination with cardiovascular risk factors. Infectious diseases can cause acute seizures. Here the authors investigate their long-term impact on the risk of epilepsy for older adults. They find that hospital-treated infectious diseases have a lasting impact on the development of epilepsy in older age, and that cardiovascular risk factors may exacerbate this impact.
{"title":"Hospital-treated infectious diseases and the risk of epilepsy in older age","authors":"Qiyuan Zhuang, Yihan Hu, Dang Wei, Chenxi Qin, Kejia Hu, Junyi Zhang, Lida Chen, Zhelun Yang, Weimin Ye, Karin Wirdefeldt, Xiang Zou, Ying Mao, Sara Hägg, Fang Fang","doi":"10.1038/s43587-025-01005-x","DOIUrl":"10.1038/s43587-025-01005-x","url":null,"abstract":"Infectious diseases are known to trigger acute seizures, but their long-term impact on epilepsy, especially in later life, is unclear. We conducted nested case–control studies of newly diagnosed epilepsy after age 50 in the UK Biobank (2,486 cases; 12,430 controls) and Swedish registers (56,266 cases; 281,330 controls), including a sibling comparison. Previous hospital-treated infections were associated with a persistently elevated epilepsy risk (for example, >10 years after infection: odds ratio (OR) 1.68, 95% confidence interval: 1.39–2.04 in UK Biobank; 1.46, 1.41–1.51 in Sweden). Associations were robust in sibling analyses and across infection types and sites. We further found that infections, together with a high cardiovascular genetic risk (OR 2.62, 2.22–3.08), a high cardiovascular risk score (OR 3.14, 2.68–3.68) or cardiovascular disease history (OR 4.77, 4.64–4.91), were associated with the highest epilepsy risk. Hospital-treated infections exert prolonged impact on epilepsy risk in older age, especially when in combination with cardiovascular risk factors. Infectious diseases can cause acute seizures. Here the authors investigate their long-term impact on the risk of epilepsy for older adults. They find that hospital-treated infectious diseases have a lasting impact on the development of epilepsy in older age, and that cardiovascular risk factors may exacerbate this impact.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2188-2196"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01005-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446988","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 : 2025-11-04DOI: 10.1038/s43587-025-01004-y
Liang-Kung Chen, Fei-Yuan Hsiao, Masahiro Akishita, Prasert Assantachai, Wei-Ju Lee, Wee Shiong Lim, Weerasak Muangpaisan, Miji Kim, Reshma Aziz Merchant, Li-Ning Peng, Maw Pin Tan, Chang Won Won, Minoru Yamada, Jean Woo, Hidenori Arai
The Asian Working Group for Sarcopenia (AWGS) presents an updated 2025 consensus reframing sarcopenia management through a life-course approach to muscle health promotion. While aligning with the Global Leadership Initiative in Sarcopenia (GLIS), this update provides healthcare providers with Asia-specific guidance. The consensus introduces three key refinements: first, expanding sarcopenia diagnosis to middle-aged adults (50‒64 years) with validated diagnostic thresholds; second, simplifying the diagnostic algorithm to require only concurrent low muscle mass and strength, with physical performance as an outcome measure; and third, introducing an enhanced muscle health framework recognizing skeletal muscle as vital for healthy longevity, emphasizing cross-talk with brain, bone, adipose tissue and immune systems. This framework leverages the World Health Organization’s Integrated Care for Older People (ICOPE) implementation for enhanced case-finding through natural overlap between muscle health and ICOPE’s intrinsic capacity domains. The consensus provides evidence-based recommendations for multimodal interventions that combine resistance exercise with nutritional supplementation, representing advancement toward proactive muscle health promotion and establishing a framework for reducing age-related decline in Asian populations. The Asian Working Group for Sarcopenia updates its consensus on sarcopenia, highlighting the need to extend diagnosis to middle-aged adults and use the World Health Organization’s Integrated Care for Older People to promote muscle health. Multimodal interventions involving exercise and nutrition are recommended to prevent age-related decline in Asian populations.
{"title":"A focus shift from sarcopenia to muscle health in the Asian Working Group for Sarcopenia 2025 Consensus Update","authors":"Liang-Kung Chen, Fei-Yuan Hsiao, Masahiro Akishita, Prasert Assantachai, Wei-Ju Lee, Wee Shiong Lim, Weerasak Muangpaisan, Miji Kim, Reshma Aziz Merchant, Li-Ning Peng, Maw Pin Tan, Chang Won Won, Minoru Yamada, Jean Woo, Hidenori Arai","doi":"10.1038/s43587-025-01004-y","DOIUrl":"10.1038/s43587-025-01004-y","url":null,"abstract":"The Asian Working Group for Sarcopenia (AWGS) presents an updated 2025 consensus reframing sarcopenia management through a life-course approach to muscle health promotion. While aligning with the Global Leadership Initiative in Sarcopenia (GLIS), this update provides healthcare providers with Asia-specific guidance. The consensus introduces three key refinements: first, expanding sarcopenia diagnosis to middle-aged adults (50‒64 years) with validated diagnostic thresholds; second, simplifying the diagnostic algorithm to require only concurrent low muscle mass and strength, with physical performance as an outcome measure; and third, introducing an enhanced muscle health framework recognizing skeletal muscle as vital for healthy longevity, emphasizing cross-talk with brain, bone, adipose tissue and immune systems. This framework leverages the World Health Organization’s Integrated Care for Older People (ICOPE) implementation for enhanced case-finding through natural overlap between muscle health and ICOPE’s intrinsic capacity domains. The consensus provides evidence-based recommendations for multimodal interventions that combine resistance exercise with nutritional supplementation, representing advancement toward proactive muscle health promotion and establishing a framework for reducing age-related decline in Asian populations. The Asian Working Group for Sarcopenia updates its consensus on sarcopenia, highlighting the need to extend diagnosis to middle-aged adults and use the World Health Organization’s Integrated Care for Older People to promote muscle health. Multimodal interventions involving exercise and nutrition are recommended to prevent age-related decline in Asian populations.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2164-2175"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145447008","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 : 2025-11-04DOI: 10.1038/s43587-025-00987-y
Kejun Ying, Seth Paulson, Alec Eames, Alexander Tyshkovskiy, Siyuan Li, Nir Eynon, Macsue Jacques, Robin Grolaux, Kirsten Seale, Erik Jacques, Ludger J. E. Goeminne, Andrea Cipriano, Martin Perez-Guevara, Mehrnoosh Emamifar, Maximiliano Casas Martínez, Dayoon Kwon, Anna Kosheleva, Michael Snyder, Dane Gobel, Chiara Herzog, Daniel L. McCartney, Riccardo E. Marioni, Jessica Lasky-Su, Jesse R. Poganik, Mahdi Moqri, Vadim N. Gladyshev
Aging biomarkers are essential tools for quantifying biological aging, but systematic validation has been hindered by methodological inconsistencies and fragmented datasets. Here we show that the ability of traditional aging clocks to predict chronological age does not correlate with mortality prediction capacity (R = 0.12, P = 0.67), suggesting that these metrics capture distinct biological processes. We developed Biolearn, an open-source framework enabling standardized evaluation of 39 biomarkers across over 20,000 individuals from diverse cohorts. The Horvath skin and blood clock achieved the highest chronological age accuracy (R2 = 0.88), while GrimAge2 demonstrated the strongest mortality association (hazard ratio = 2.57) and healthspan prediction (hazard ratio = 2.00). Our systematic evaluation reveals considerable heterogeneity in biomarker performance across different clinical outcomes, with optimal biomarkers varying according to specific application. Biolearn provides unified data processing pipelines with quality control and cell-type deconvolution capabilities, establishing a foundation for reproducible aging research and facilitating development of robust aging biomarkers. Ying, Paulson and collagues have developed an open-source framework, Biolearn, to harmonize and systematically evaluate 39 aging biomarkers across diverse populations, enabling standardized validation and facilitating development of robust aging biomarkers.
衰老生物标志物是量化生物衰老的重要工具，但系统验证一直受到方法不一致和数据集碎片化的阻碍。本研究表明，传统衰老时钟预测实足年龄的能力与预测死亡率的能力不相关（R = 0.12, P = 0.67），这表明这些指标捕捉了不同的生物过程。我们开发了biollearn，这是一个开源框架，可以对来自不同群体的20,000多名个体的39种生物标志物进行标准化评估。Horvath皮肤和血液时钟获得了最高的实足年龄准确性（R2 = 0.88），而GrimAge2显示出最强的死亡率相关性（风险比= 2.57）和健康寿命预测（风险比= 2.00）。我们的系统评估显示，生物标志物在不同临床结果中的表现存在相当大的异质性，最佳生物标志物根据具体应用而变化。biollearn提供统一的数据处理管道，具有质量控制和细胞类型反褶积能力，为可重复的衰老研究奠定了基础，并促进了强大的衰老生物标志物的开发。
{"title":"A unified framework for systematic curation and evaluation of aging biomarkers","authors":"Kejun Ying, Seth Paulson, Alec Eames, Alexander Tyshkovskiy, Siyuan Li, Nir Eynon, Macsue Jacques, Robin Grolaux, Kirsten Seale, Erik Jacques, Ludger J. E. Goeminne, Andrea Cipriano, Martin Perez-Guevara, Mehrnoosh Emamifar, Maximiliano Casas Martínez, Dayoon Kwon, Anna Kosheleva, Michael Snyder, Dane Gobel, Chiara Herzog, Daniel L. McCartney, Riccardo E. Marioni, Jessica Lasky-Su, Jesse R. Poganik, Mahdi Moqri, Vadim N. Gladyshev","doi":"10.1038/s43587-025-00987-y","DOIUrl":"10.1038/s43587-025-00987-y","url":null,"abstract":"Aging biomarkers are essential tools for quantifying biological aging, but systematic validation has been hindered by methodological inconsistencies and fragmented datasets. Here we show that the ability of traditional aging clocks to predict chronological age does not correlate with mortality prediction capacity (R = 0.12, P = 0.67), suggesting that these metrics capture distinct biological processes. We developed Biolearn, an open-source framework enabling standardized evaluation of 39 biomarkers across over 20,000 individuals from diverse cohorts. The Horvath skin and blood clock achieved the highest chronological age accuracy (R2 = 0.88), while GrimAge2 demonstrated the strongest mortality association (hazard ratio = 2.57) and healthspan prediction (hazard ratio = 2.00). Our systematic evaluation reveals considerable heterogeneity in biomarker performance across different clinical outcomes, with optimal biomarkers varying according to specific application. Biolearn provides unified data processing pipelines with quality control and cell-type deconvolution capabilities, establishing a foundation for reproducible aging research and facilitating development of robust aging biomarkers. Ying, Paulson and collagues have developed an open-source framework, Biolearn, to harmonize and systematically evaluate 39 aging biomarkers across diverse populations, enabling standardized validation and facilitating development of robust aging biomarkers.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2323-2339"},"PeriodicalIF":19.4,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446966","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 : 2025-11-03DOI: 10.1038/s43587-025-00997-w
Jiyeon Leem, Tom Lemonnier, Ani Khutsaidze, Lei Tian, Xiaojun Xing, Suxia Bai, Timothy Nottoli, Binyam Mogessie
Female reproductive aging is accompanied by a sharp increase in egg aneuploidy rates. Premature loss of chromosome cohesion proteins and early separation of chromosomes are thought to cause high aneuploidy rates during maternal aging. However, because cohesion loss occurs gradually throughout a woman’s reproductive lifespan, and because cytoskeletal defects alone can lead to chromosomal abnormalities, the main causes of the rapid rise in aneuploidy at older reproductive ages are still unclear. In this study, we created a versatile and tunable cohesion manipulation system that enables rapid, dose-dependent degradation of the meiotic cohesin REC8 in live mouse oocytes. By coupling this system with quantitative high-resolution live imaging, we directly observed cohesion protein behavior during meiosis and tested the longstanding threshold model of aneuploidy development. Our results show that premature sister chromatid separation sharply increases only when REC8 levels drop below a critical threshold, supporting the idea of a nonlinear, vulnerability-triggering cohesion limit. We also used our system to examine how other age-related issues, such as cytoskeletal disruption and partial centromere dysfunction, can exacerbate chromatid separation in the context of weakened cohesion. This work provides a tractable oocyte platform for modeling and dissecting the multifactorial mechanisms driving female reproductive age-related egg aneuploidy. To study pathways that lead to aneuploidy during aging, the authors provide a system that enables cohesion protein depletion in mouse oocytes, mimicking effects that occur during aging. They uncover a threshold for cohesion loss driving chromosome errors and show that actin and centromere defects amplify aneuploidy.
{"title":"A versatile cohesion manipulation system probes female reproductive age-related egg aneuploidy","authors":"Jiyeon Leem, Tom Lemonnier, Ani Khutsaidze, Lei Tian, Xiaojun Xing, Suxia Bai, Timothy Nottoli, Binyam Mogessie","doi":"10.1038/s43587-025-00997-w","DOIUrl":"10.1038/s43587-025-00997-w","url":null,"abstract":"Female reproductive aging is accompanied by a sharp increase in egg aneuploidy rates. Premature loss of chromosome cohesion proteins and early separation of chromosomes are thought to cause high aneuploidy rates during maternal aging. However, because cohesion loss occurs gradually throughout a woman’s reproductive lifespan, and because cytoskeletal defects alone can lead to chromosomal abnormalities, the main causes of the rapid rise in aneuploidy at older reproductive ages are still unclear. In this study, we created a versatile and tunable cohesion manipulation system that enables rapid, dose-dependent degradation of the meiotic cohesin REC8 in live mouse oocytes. By coupling this system with quantitative high-resolution live imaging, we directly observed cohesion protein behavior during meiosis and tested the longstanding threshold model of aneuploidy development. Our results show that premature sister chromatid separation sharply increases only when REC8 levels drop below a critical threshold, supporting the idea of a nonlinear, vulnerability-triggering cohesion limit. We also used our system to examine how other age-related issues, such as cytoskeletal disruption and partial centromere dysfunction, can exacerbate chromatid separation in the context of weakened cohesion. This work provides a tractable oocyte platform for modeling and dissecting the multifactorial mechanisms driving female reproductive age-related egg aneuploidy. To study pathways that lead to aneuploidy during aging, the authors provide a system that enables cohesion protein depletion in mouse oocytes, mimicking effects that occur during aging. They uncover a threshold for cohesion loss driving chromosome errors and show that actin and centromere defects amplify aneuploidy.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2215-2227"},"PeriodicalIF":19.4,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-00997-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145440310","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 : 2025-10-31DOI: 10.1038/s43587-025-00999-8
Evandro F. Fang, Yuan Fang, Guobing Chen, He-Ling Wang, Jianying Zhang, Chenkai Wu, Jing Liao, Chenglong Xie, Xiaoting Liu, Kan Wang, Yang Liu, Guang Yang, Qian Wang, Long-Tao He, Jun Li, Hou-Zao Chen, Lin Kang, Yawen Jiang, Huanxing Su, Hong Jiang, Na He, Jun Tao, Sean Xiao Leng, Richard C. Siow, Chunrong Liu, Hafiz T. A. Khan, Yuanli Liu, Hisaya Kato, Takashi Sasaki, Jong In Kim, Andrea Britta Maier, Lin Zhang, Lene Juel Rasmussen, Jean Woo, Jing Wu, Huachun Zou
Despite its rapid economic rise over the past four decades, China now grapples with the challenge of accommodating and supporting its expanding aging population. In 2020, 18% of its population were over age 60, and 2.5% were over age 80, projected to rise to 39% and 10%, respectively, by 2050. This demographic shift places China at the forefront of diverse individual, familial and societal challenges. Here, we review these challenges in the context of emerging breakthroughs in basic and translational research, shifts in healthcare paradigms, evolving socioeconomic and political dynamics, and policy innovations. We synthesize China’s current policies toward promoting healthy longevity in the general population, focusing on social health insurance, long-term care insurance, community and home-based care and palliative care, as well as gerontological research, public health prevention, nutritional and medical interventions, while identifying strengths and gaps. Finally, we propose suggestions to promote a more inclusive, resilient and happier aging society within China’s distinctive sociopolitical and cultural context. China’s dramatic demographic shift toward population aging raises challenges at the individual, familial and societal levels. Fang et al. review these challenges and emerging policies designed to promote healthy longevity in China.
{"title":"Adapting health, economic and social policies to address population aging in China","authors":"Evandro F. Fang, Yuan Fang, Guobing Chen, He-Ling Wang, Jianying Zhang, Chenkai Wu, Jing Liao, Chenglong Xie, Xiaoting Liu, Kan Wang, Yang Liu, Guang Yang, Qian Wang, Long-Tao He, Jun Li, Hou-Zao Chen, Lin Kang, Yawen Jiang, Huanxing Su, Hong Jiang, Na He, Jun Tao, Sean Xiao Leng, Richard C. Siow, Chunrong Liu, Hafiz T. A. Khan, Yuanli Liu, Hisaya Kato, Takashi Sasaki, Jong In Kim, Andrea Britta Maier, Lin Zhang, Lene Juel Rasmussen, Jean Woo, Jing Wu, Huachun Zou","doi":"10.1038/s43587-025-00999-8","DOIUrl":"10.1038/s43587-025-00999-8","url":null,"abstract":"Despite its rapid economic rise over the past four decades, China now grapples with the challenge of accommodating and supporting its expanding aging population. In 2020, 18% of its population were over age 60, and 2.5% were over age 80, projected to rise to 39% and 10%, respectively, by 2050. This demographic shift places China at the forefront of diverse individual, familial and societal challenges. Here, we review these challenges in the context of emerging breakthroughs in basic and translational research, shifts in healthcare paradigms, evolving socioeconomic and political dynamics, and policy innovations. We synthesize China’s current policies toward promoting healthy longevity in the general population, focusing on social health insurance, long-term care insurance, community and home-based care and palliative care, as well as gerontological research, public health prevention, nutritional and medical interventions, while identifying strengths and gaps. Finally, we propose suggestions to promote a more inclusive, resilient and happier aging society within China’s distinctive sociopolitical and cultural context. China’s dramatic demographic shift toward population aging raises challenges at the individual, familial and societal levels. Fang et al. review these challenges and emerging policies designed to promote healthy longevity in China.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2176-2187"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145423683","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 : 2025-10-31DOI: 10.1038/s43587-025-00996-x
Dominic Denk, Anurag Singh, Herbert G. Kasler, Davide D’Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M. Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J. Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R. Greten
Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day−1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 . Immune aging fosters multimorbidity and compromises control of infection and cancer. In a phase 1 randomized controlled trial in middle-aged adults, Denk and colleagues administer the mitophagy inducer urolithin A and profile cellular and metabolic aspects of immune aging.
{"title":"Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial","authors":"Dominic Denk, Anurag Singh, Herbert G. Kasler, Davide D’Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M. Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J. Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R. Greten","doi":"10.1038/s43587-025-00996-x","DOIUrl":"10.1038/s43587-025-00996-x","url":null,"abstract":"Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day−1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 . Immune aging fosters multimorbidity and compromises control of infection and cancer. In a phase 1 randomized controlled trial in middle-aged adults, Denk and colleagues administer the mitophagy inducer urolithin A and profile cellular and metabolic aspects of immune aging.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2309-2322"},"PeriodicalIF":19.4,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-00996-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145423681","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 : 2025-10-29DOI: 10.1038/s43587-025-00976-1
Min Gao, Jing Bai, Fangzhou Lou, Yang Sun, Zhikai Wang, Xiaojie Cai, Yan Li, Fengjiao Zhang, Jihuan Liang, Xiangxiao Li, Yue Wu, Ziyang Zhang, Li Fan, Xinping Jin, Honglin Wang
Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer’s disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD. Gao, Bai and colleagues identify peroxisomal MFE-2 as an essential regulator for microglial homeostasis in Alzheimer’s disease, showing that maintaining MFE-2 reduces neuroinflammation and slows Alzheimer’s disease progression, making it a potential therapeutic target.
{"title":"Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer’s pathogenesis","authors":"Min Gao, Jing Bai, Fangzhou Lou, Yang Sun, Zhikai Wang, Xiaojie Cai, Yan Li, Fengjiao Zhang, Jihuan Liang, Xiangxiao Li, Yue Wu, Ziyang Zhang, Li Fan, Xinping Jin, Honglin Wang","doi":"10.1038/s43587-025-00976-1","DOIUrl":"10.1038/s43587-025-00976-1","url":null,"abstract":"Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer’s disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD. Gao, Bai and colleagues identify peroxisomal MFE-2 as an essential regulator for microglial homeostasis in Alzheimer’s disease, showing that maintaining MFE-2 reduces neuroinflammation and slows Alzheimer’s disease progression, making it a potential therapeutic target.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 11","pages":"2279-2296"},"PeriodicalIF":19.4,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145402986","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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