Nature agingPub Date : 2025-05-01DOI: 10.1038/s43587-025-00856-8
Sarah Hoelzl, Tim P Hasenbein, Stefan Engelhardt, Daniel Andergassen
{"title":"Aging promotes reactivation of the Barr body at distal chromosome regions.","authors":"Sarah Hoelzl, Tim P Hasenbein, Stefan Engelhardt, Daniel Andergassen","doi":"10.1038/s43587-025-00856-8","DOIUrl":"https://doi.org/10.1038/s43587-025-00856-8","url":null,"abstract":"<p><p>Decades ago, evidence of age-related reactivation of a single gene on the female inactive X chromosome was observed in mice. While stable silencing of the Barr body is crucial for balancing gene dosage between sexes, it remains unclear whether silencing is maintained during aging. Here we used allele-specific multi-omics approaches to capture a comprehensive catalog of genes escaping X chromosome inactivation throughout mouse development and aging. We found substantially elevated escape rates during aging across organs, occurring in multiple distinct cell types and concentrated at distal chromosome regions. Consistently, chromatin accessibility was increased across multiple megabases at chromosome ends, affecting regulatory elements of escapees. As several age-specific escapees are linked to human diseases, their elevated expression in females might contribute to sex-biased disease progression observed during aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-30DOI: 10.1038/s43587-025-00855-9
Gonzalo Soto-Heredero, Enrique Gabandé-Rodríguez, Elisa Carrasco, José Ignacio Escrig-Larena, Manuel M Gómez de Las Heras, Sandra Delgado-Pulido, Isaac Francos-Quijorna, Eva M Blanco, Álvaro Fernández-Almeida, David Abia, María Josefa Rodríguez, Cristina M Fernández-Díaz, María Beatriz Álvarez-Flores, Ana Ramírez de Molina, Sascha Jung, Antonio Del Sol, Virginia Zorita, Fátima Sánchez-Cabo, Carlos Torroja, María Mittelbrunn
{"title":"KLRG1 identifies regulatory T cells with mitochondrial alterations that accumulate with aging.","authors":"Gonzalo Soto-Heredero, Enrique Gabandé-Rodríguez, Elisa Carrasco, José Ignacio Escrig-Larena, Manuel M Gómez de Las Heras, Sandra Delgado-Pulido, Isaac Francos-Quijorna, Eva M Blanco, Álvaro Fernández-Almeida, David Abia, María Josefa Rodríguez, Cristina M Fernández-Díaz, María Beatriz Álvarez-Flores, Ana Ramírez de Molina, Sascha Jung, Antonio Del Sol, Virginia Zorita, Fátima Sánchez-Cabo, Carlos Torroja, María Mittelbrunn","doi":"10.1038/s43587-025-00855-9","DOIUrl":"https://doi.org/10.1038/s43587-025-00855-9","url":null,"abstract":"<p><p>Recent studies using single-cell RNA sequencing technology have uncovered several subpopulations of CD4<sup>+</sup> T cells that accumulate with aging. These age-associated T cells are emerging as relevant players in the onset of inflammaging and tissue senescence. Here, based on information provided by single-cell RNA sequencing data, we present a flow cytometry panel that allows the identification of age-associated T cell subsets in systematic larger analysis in mice. We use this panel to evaluate at the single-cell level mitochondrial and senescence marks in the different age-associated CD4<sup>+</sup> T cell subpopulations. Our analysis identifies a subpopulation of regulatory T (T<sub>reg</sub>) cells that is characterized by the extracellular expression of the co-inhibitory molecule killer cell lectin-like receptor subfamily G member 1 (KLRG1) and accumulates with aging in humans and mice. KLRG1-expressing T<sub>reg</sub> cells display senescence features such as mitochondrial alterations, increased expression of cell-cycle regulators and genomic DNA damage. Functionally, KLRG1<sup>+</sup> T<sub>reg</sub> cells show a reduced suppressive activity in vivo accompanied by a pro-inflammatory phenotype.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-28DOI: 10.1038/s43587-025-00868-4
Mouna Sawan, Saman Khalatbari-Soltani, Anita van Zwieten, Suraj Samtani, Jo-An Occhipinti, J Jaime Miranda
{"title":"Valuing caregiving is a prerequisite for the wellbeing economy and mental wealth.","authors":"Mouna Sawan, Saman Khalatbari-Soltani, Anita van Zwieten, Suraj Samtani, Jo-An Occhipinti, J Jaime Miranda","doi":"10.1038/s43587-025-00868-4","DOIUrl":"https://doi.org/10.1038/s43587-025-00868-4","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-22DOI: 10.1038/s43587-025-00852-y
Thomas W P Wood, William S Henriques, Harrison B Cullen, Mayra Romero, Cecilia S Blengini, Shreya Sarathy, Julia Sorkin, Hilina Bekele, Chen Jin, Seungsoo Kim, Xifan Wang, Raphaelle Laureau, Alexei Chemiakine, Rishad C Khondker, José V V Isola, Michael B Stout, Vincenzo A Gennarino, Binyam Mogessie, Devanshi Jain, Karen Schindler, Yousin Suh, Blake Wiedenheft, Luke E Berchowitz
{"title":"The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity.","authors":"Thomas W P Wood, William S Henriques, Harrison B Cullen, Mayra Romero, Cecilia S Blengini, Shreya Sarathy, Julia Sorkin, Hilina Bekele, Chen Jin, Seungsoo Kim, Xifan Wang, Raphaelle Laureau, Alexei Chemiakine, Rishad C Khondker, José V V Isola, Michael B Stout, Vincenzo A Gennarino, Binyam Mogessie, Devanshi Jain, Karen Schindler, Yousin Suh, Blake Wiedenheft, Luke E Berchowitz","doi":"10.1038/s43587-025-00852-y","DOIUrl":"https://doi.org/10.1038/s43587-025-00852-y","url":null,"abstract":"<p><p>Almost half of the human genome consists of retrotransposons-'parasitic' sequences that insert themselves into the host genome via an RNA intermediate. Although most of these sequences are silenced or mutationally deactivated, they can present opportunities for evolutionary innovation: mutation of a deteriorating retrotransposon can result in a gene that provides a selective advantage to the host in a process termed 'domestication'<sup>1-3</sup>. The PNMA family of gag-like capsid genes was domesticated from an ancient vertebrate retrotransposon of the Metaviridae clade at least 100 million years ago<sup>4,5</sup>. PNMA1 and PNMA4 are positively regulated by the master germ cell transcription factors MYBL1 and STRA8, and their transcripts are bound by the translational regulator DAZL during gametogenesis<sup>6</sup>. This developmental regulation of PNMA1 and PNMA4 expression in gonadal tissue suggested to us that they might serve a reproductive function. Through the analysis of donated human ovaries, genome-wide association studies (GWASs) and mouse models, we found that PNMA1 and PNMA4 are necessary for the maintenance of a normal reproductive lifespan. These proteins self-assemble into capsid-like structures that exit human cells, and we observed large PNMA4 particles in mouse male gonadal tissue that contain RNA and are consistent with capsid formation.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-11DOI: 10.1038/s43587-025-00851-z
Nimrod Madrer, Shani Vaknine-Treidel, Tamara Zorbaz, Yonat Tzur, Estelle R Bennett, Paz Drori, Nitzan Suissa, David S Greenberg, Eitan Lerner, Eyal Soreq, Iddo Paldor, Hermona Soreq
{"title":"Pre-symptomatic Parkinson's disease blood test quantifying repetitive sequence motifs in transfer RNA fragments.","authors":"Nimrod Madrer, Shani Vaknine-Treidel, Tamara Zorbaz, Yonat Tzur, Estelle R Bennett, Paz Drori, Nitzan Suissa, David S Greenberg, Eitan Lerner, Eyal Soreq, Iddo Paldor, Hermona Soreq","doi":"10.1038/s43587-025-00851-z","DOIUrl":"https://doi.org/10.1038/s43587-025-00851-z","url":null,"abstract":"<p><p>Early, efficient Parkinson's disease (PD) tests may facilitate pre-symptomatic diagnosis and disease-modifying therapies. Here we report elevated levels of PD-specific transfer RNA fragments carrying a conserved sequence motif (RGTTCRA-tRFs) in the substantia nigra, cerebrospinal fluid and blood of patients with PD. A whole blood qPCR test detecting elevated RGTTCRA-tRFs and reduced mitochondrial-originated tRFs (MT-tRFs) segregated pre-symptomatic patients with PD from controls (area under the receiver operating characteristic curve (ROC-AUC) of 0.75 versus 0.71 based on traditional clinical scoring). Strengthening PD relevance, patients carrying PD-related mutations presented higher blood RGTTCRA-tRFs/MT-tRFs ratios than mutation-carrying non-symptomatic controls, and RGTTCRA-tRF levels decreased in patients' blood after deep brain stimulation. Furthermore, RGTTCRA-tRFs complementarity to ribosomal RNA and the translation-supporting LeuCAG3-tRF might aggravate PD via translational inhibition, as reflected by disrupted ribosomal association of RGTTCRA-tRFs in depolarized neuroblastoma cells. Our findings show tRF involvement in PD and suggest a potential simple and safe blood test that may aid clinicians in pre-symptomatic PD diagnosis after validation in larger independent cohorts.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-10DOI: 10.1038/s43587-025-00854-w
Rongcan Luo, Jin-Tai Yu
{"title":"New biomarkers for early-stage tau pathology in Alzheimer's disease.","authors":"Rongcan Luo, Jin-Tai Yu","doi":"10.1038/s43587-025-00854-w","DOIUrl":"https://doi.org/10.1038/s43587-025-00854-w","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144046790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nature agingPub Date : 2025-04-10DOI: 10.1038/s43587-025-00842-0
Yifei Cheng, Bingxin Liu, Junyi Xin, Xiaobin Wu, Wenchao Li, Jinwei Shang, Jiajin Wu, Zhengdong Zhang, Bin Xu, Mulong Du, Gong Cheng, Meilin Wang
{"title":"Single-cell and spatial RNA sequencing identify divergent microenvironments and progression signatures in early- versus late-onset prostate cancer.","authors":"Yifei Cheng, Bingxin Liu, Junyi Xin, Xiaobin Wu, Wenchao Li, Jinwei Shang, Jiajin Wu, Zhengdong Zhang, Bin Xu, Mulong Du, Gong Cheng, Meilin Wang","doi":"10.1038/s43587-025-00842-0","DOIUrl":"https://doi.org/10.1038/s43587-025-00842-0","url":null,"abstract":"<p><p>The clinical and pathological outcomes differ between early-onset (diagnosed in men ≤55 years of age) and late-onset prostate cancer, potentially attributed to the changes in hormone levels and immune activities associated with aging. Exploring the heterogeneity therein holds potential for developing age-specific precision interventions. Here, through single-cell and spatial transcriptomic analyses of prostate cancer tissues, we identified that an androgen response-related transcriptional meta-program (AR-MP) might underlie the age-related heterogeneity of tumor cells and microenvironment. APOE<sup>+</sup> tumor-associated macrophages infiltrated AR-MP-activated tumor cells in early-onset prostate cancer, potentially facilitating tumor progression and immunosuppression. By contrast, inflammatory cancer-associated fibroblasts in late-onset prostate cancer correlated with downregulation of AR-MP of tumor cells and increased epithelial-to-mesenchymal transition and pre-existing castration resistance, which may also be linked to smoking. This study provides potential insights for tailoring precision treatments by age groups, emphasizing interventions that include targeting AR and tumor-associated macrophages in young patients but anchoring epithelial-to-mesenchymal transition and inflammatory cancer-associated fibroblasts in old counterparts.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":17.0,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056171","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}