Nature agingPub Date : 2025-04-01Epub Date: 2025-03-13DOI: 10.1038/s43587-025-00816-2
Shirin Schneeberger, Seung Joon Kim, Maria N Geesdorf, Ekaterina Friebel, Pascale Eede, Marina Jendrach, Anastasiya Boltengagen, Caroline Braeuning, Torben Ruhwedel, Andreas J Hülsmeier, Niclas Gimber, Marlene Foerster, Juliane Obst, Myrto Andreadou, Sarah Mundt, Jan Schmoranzer, Stefan Prokop, Wiebke Kessler, Tanja Kuhlmann, Wiebke Möbius, Klaus-Armin Nave, Thorsten Hornemann, Burkhard Becher, Julia M Edgar, Nikos Karaiskos, Christine Kocks, Nikolaus Rajewsky, Frank L Heppner
{"title":"Interleukin-12 signaling drives Alzheimer's disease pathology through disrupting neuronal and oligodendrocyte homeostasis.","authors":"Shirin Schneeberger, Seung Joon Kim, Maria N Geesdorf, Ekaterina Friebel, Pascale Eede, Marina Jendrach, Anastasiya Boltengagen, Caroline Braeuning, Torben Ruhwedel, Andreas J Hülsmeier, Niclas Gimber, Marlene Foerster, Juliane Obst, Myrto Andreadou, Sarah Mundt, Jan Schmoranzer, Stefan Prokop, Wiebke Kessler, Tanja Kuhlmann, Wiebke Möbius, Klaus-Armin Nave, Thorsten Hornemann, Burkhard Becher, Julia M Edgar, Nikos Karaiskos, Christine Kocks, Nikolaus Rajewsky, Frank L Heppner","doi":"10.1038/s43587-025-00816-2","DOIUrl":"10.1038/s43587-025-00816-2","url":null,"abstract":"<p><p>Neuroinflammation including interleukin (IL)-12/IL-23-signaling is central to Alzheimer's disease (AD) pathology. Inhibition of p40, a subunit of IL-12/IL-23, attenuates pathology in AD-like mice; however, its signaling mechanism and expression pattern remained elusive. Here we show that IL-12 receptors are predominantly expressed in neurons and oligodendrocytes in AD-like APPPS1 mice and in patients with AD, whereas IL-23 receptor transcripts are barely detectable. Consistently, deletion of the IL-12 receptor in neuroectodermal cells ameliorated AD pathology in APPPS1 mice, whereas removal of IL-23 receptors had no effect. Genetic ablation of IL-12 signaling alone reverted the loss of mature oligodendrocytes, restored myelin homeostasis, rescued the amyloid-β-dependent reduction of parvalbumin-positive interneurons and restored phagocytosis-related changes in microglia of APPPS1 mice. Furthermore, IL-12 protein expression was increased in human AD brains compared to healthy age-matched controls, and human oligodendrocyte-like cells responded profoundly to IL-12 stimulation. We conclude that oligodendroglial and neuronal IL-12 signaling, but not IL-23 signaling, are key in orchestrating AD-related neuroimmune crosstalk and that IL-12 represents an attractive therapeutic target in AD.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"622-641"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627337","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}
Nature agingPub Date : 2025-04-01Epub Date: 2025-03-03DOI: 10.1038/s43587-025-00824-2
Lina Cui, Xichen Nie, Yixuan Guo, Pengcheng Ren, Yifei Guo, Xiaoyan Wang, Ran Li, James M Hotaling, Bradley R Cairns, Jingtao Guo
{"title":"Single-cell transcriptomic atlas of the human testis across the reproductive lifespan.","authors":"Lina Cui, Xichen Nie, Yixuan Guo, Pengcheng Ren, Yifei Guo, Xiaoyan Wang, Ran Li, James M Hotaling, Bradley R Cairns, Jingtao Guo","doi":"10.1038/s43587-025-00824-2","DOIUrl":"10.1038/s43587-025-00824-2","url":null,"abstract":"<p><p>Testicular aging is associated with declining reproductive health, but the molecular mechanisms are unclear. Here we generate a dataset of 214,369 single-cell transcriptomes from testicular cells of 35 individuals aged 21-69, offering a resource for studying testicular aging and physiology. Machine learning analysis reveals a stronger aging response in somatic cells compared to germ cells. Two waves of aging-related changes are identified: the first in peritubular cells of donors in their 30s, marked by increased basement membrane thickness, indicating a priming state for aging. In their 50s, testicular cells exhibit functional changes, including altered steroid metabolism in Leydig cells and immune responses in macrophages. Further analyses reveal the impact of body mass index on spermatogenic capacity as age progresses, particularly after age 45. Altogether, our findings illuminate molecular alterations during testis aging and their relationship with body mass index, providing a foundation for future research and offering potential diagnostic markers and therapeutic targets.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"658-674"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545478","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}
Nature agingPub Date : 2025-04-01Epub Date: 2025-03-17DOI: 10.1038/s43587-025-00836-y
Zhuoer Lin, Yuting Qian, Thomas M Gill, Xiaohui Hou, Heather Allore, Shanquan Chen, Xi Chen
{"title":"Absence of care among community-dwelling older adults with dementia and functional limitations.","authors":"Zhuoer Lin, Yuting Qian, Thomas M Gill, Xiaohui Hou, Heather Allore, Shanquan Chen, Xi Chen","doi":"10.1038/s43587-025-00836-y","DOIUrl":"10.1038/s43587-025-00836-y","url":null,"abstract":"<p><p>Assistance with daily activities is crucial for persons living with dementia and functional limitations, yet many face substantial challenges in accessing adequate care and support. Using harmonized longitudinal survey data (2012-2018) from the United States, England, 18 European countries, Israel and China, we found that at least one-fifth of persons with dementia and functional limitations received no personal assistance for basic activities of daily living or instrumental activities of daily living, regardless of regional development level. Care gaps were widespread across both basic activities of daily living or instrumental activities of daily living limitations, as well as for informal and formal care. Disparities were evident, with less educated people more likely to lack formal care, whereas those living alone often lacked informal support, resulting in the absence of any care. Alarmingly, care availability showed no improvement over time. Our findings underscore the urgent need for policies to address inequities and ensure critical access to care services for this vulnerable population worldwide.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"548-557"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652908","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}
Nature agingPub Date : 2025-04-01Epub Date: 2025-02-19DOI: 10.1038/s43587-025-00813-5
Yun-Hee Youm, Christy Gliniak, Yuan Zhang, Tamara Dlugos, Philipp E Scherer, Vishwa Deep Dixit
{"title":"Enhanced paracrine action of FGF21 in stromal cells delays thymic aging.","authors":"Yun-Hee Youm, Christy Gliniak, Yuan Zhang, Tamara Dlugos, Philipp E Scherer, Vishwa Deep Dixit","doi":"10.1038/s43587-025-00813-5","DOIUrl":"10.1038/s43587-025-00813-5","url":null,"abstract":"<p><p>Age-related thymic involution precedes aging of all other organs in vertebrates and initiates the process of declining T cell diversity, which leads to eventual immune dysfunction. Whether FGF21, a liver-derived pro-longevity hormone that is also produced in thymic stroma, including by adipocytes, controls the mechanism of thymic demise is incompletely understood. Here, we demonstrate that elevation of FGF21 in thymic epithelial cells (TECs) and in adipocytes protects against thymic aging, whereas conditional hepatic overexpression did not impact thymic biology in aged mice. Notably, elevation of thymic FGF21 increased naïve CD8 T cells in aged animals and extended healthspan. Mechanistically, thymic FGF21 overexpression elevated TECs and reduced fibroadipogenic cells. Ablation of β-klotho, the obligatory co-receptor for FGF21 in Foxn1<sup>+</sup> TECs, accelerated thymic aging, suggesting regulation of TECs by FGF21 is partially required for thymic lymphopoiesis. These findings establish that paracrine FGF21 improves thymic function and delays immune aging.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"576-587"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12003152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460901","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}
Nature agingPub Date : 2025-04-01DOI: 10.1038/s43587-025-00832-2
Nir Barzilai, Risa Starr, Eric Verdin, Laura J Niedernhofer, André Bertram, Gordon J Lithgow, Andrea B Maier
{"title":"Accelerating the promise of geroscience through The Academy of Health & Lifespan Research.","authors":"Nir Barzilai, Risa Starr, Eric Verdin, Laura J Niedernhofer, André Bertram, Gordon J Lithgow, Andrea B Maier","doi":"10.1038/s43587-025-00832-2","DOIUrl":"10.1038/s43587-025-00832-2","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"529-531"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588909","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 : 2025-04-01Epub Date: 2025-03-31DOI: 10.1038/s43587-025-00840-2
Dongeun Heo, Anya A Kim, Björn Neumann, Valerie N Doze, Yu Kang T Xu, Yevgeniya A Mironova, Jared Slosberg, Loyal A Goff, Robin J M Franklin, Dwight E Bergles
{"title":"Transcriptional profiles of mouse oligodendrocyte precursor cells across the lifespan.","authors":"Dongeun Heo, Anya A Kim, Björn Neumann, Valerie N Doze, Yu Kang T Xu, Yevgeniya A Mironova, Jared Slosberg, Loyal A Goff, Robin J M Franklin, Dwight E Bergles","doi":"10.1038/s43587-025-00840-2","DOIUrl":"10.1038/s43587-025-00840-2","url":null,"abstract":"<p><p>Oligodendrocyte progenitor cells (OPCs) are highly dynamic, widely distributed glial cells of the central nervous system responsible for generating myelinating oligodendrocytes throughout life. However, the rates of OPC proliferation and differentiation decline dramatically with aging, which may impair homeostasis, remyelination and adaptive myelination during learning. To determine how aging influences OPCs, we generated a transgenic mouse line (Matn4-mEGFP) and performed single-cell RNA sequencing, providing enhanced resolution of transcriptional changes during key transitions from quiescence to proliferation and differentiation across the lifespan. We found that aging induces distinct transcriptomic changes in OPCs in different states, including enhanced activation of HIF-1α and WNT pathways. Pharmacological inhibition of these pathways in aged OPCs was sufficient to increase their ability to differentiate in vitro. Ultimately, Matn4-mEGFP mouse line and the sequencing dataset of cortical OPCs across ages will help to define the molecular changes guiding OPC behavior in various physiological and pathological contexts.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"675-690"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756955","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 : 2025-04-01DOI: 10.1038/s43587-025-00848-8
{"title":"Pathways that limit differentiation of oligodendrocyte progenitors in the aging brain.","authors":"","doi":"10.1038/s43587-025-00848-8","DOIUrl":"10.1038/s43587-025-00848-8","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"544-545"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Large-scale proteomic analyses of incident Parkinson's disease reveal new pathophysiological insights and potential biomarkers.","authors":"Yi-Han Gan, Ling-Zhi Ma, Yi Zhang, Jia You, Yu Guo, Yu He, Lin-Bo Wang, Xiao-Yu He, Yu-Zhu Li, Qiang Dong, Jian-Feng Feng, Wei Cheng, Jin-Tai Yu","doi":"10.1038/s43587-025-00818-0","DOIUrl":"10.1038/s43587-025-00818-0","url":null,"abstract":"<p><p>The early pathophysiology of Parkinson's disease (PD) is poorly understood. We analyzed 2,920 Olink-measured plasma proteins in 51,804 UK Biobank participants, identifying 859 incident PD cases after 14.45 years. We found 38 PD-related proteins, with six of the top ten validated in the Parkinson's Progression Markers Initiative (PPMI) cohort. ITGAV, HNMT and ITGAM showed consistent significant association (hazard ratio: 0.11-0.57, P = 6.90 × 10<sup>-24</sup> to 2.10 × 10<sup>-11</sup>). Lipid metabolism dysfunction was evident 15 years before PD onset, and levels of BAG3, HPGDS, ITGAV and PEPD continuously decreased before diagnosis. These proteins were linked to prodromal symptoms and brain measures. Mendelian randomization suggested ITGAM and EGFR as potential causes of PD. A predictive model using machine learning combined the top 16 proteins and demographics, achieving high accuracy for 5-year (area under the curve (AUC) = 0.887) and over-5-year PD prediction (AUC = 0.816), outperforming demographic-only models. It was externally validated in PPMI (AUC = 0.802). Our findings reveal early peripheral pathophysiological changes in PD crucial for developing early biomarkers and precision therapies.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"642-657"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470356","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 : 2025-04-01DOI: 10.1038/s43587-025-00837-x
Dorsa Toghani, Sanika Gupte, Sharon Zeng, Elmir Mahammadov, Edie I Crosse, Negar Seyedhassantehrani, Christian Burns, David Gravano, Stefan Radtke, Hans-Peter Kiem, Sonia Rodriguez, Nadia Carlesso, Amogh Pradeep, Alexis Georgiades, Fabienne Lucas, Nicola K Wilson, Sarah J Kinston, Berthold Göttgens, Le Zong, Isabel Beerman, Bongsoo Park, Derek H Janssens, Daniel Jones, Ali Toghani, Claus Nerlov, Eric M Pietras, Marion Mesnieres, Christa Maes, Atsushi Kumanogoh, Thomas Worzfeld, Jin-Gyu Cheong, Steven Z Josefowicz, Peter Kharchenko, David T Scadden, Antonio Scialdone, Joel A Spencer, Lev Silberstein
{"title":"Author Correction: Niche-derived Semaphorin 4A safeguards functional identity of myeloid-biased hematopoietic stem cells.","authors":"Dorsa Toghani, Sanika Gupte, Sharon Zeng, Elmir Mahammadov, Edie I Crosse, Negar Seyedhassantehrani, Christian Burns, David Gravano, Stefan Radtke, Hans-Peter Kiem, Sonia Rodriguez, Nadia Carlesso, Amogh Pradeep, Alexis Georgiades, Fabienne Lucas, Nicola K Wilson, Sarah J Kinston, Berthold Göttgens, Le Zong, Isabel Beerman, Bongsoo Park, Derek H Janssens, Daniel Jones, Ali Toghani, Claus Nerlov, Eric M Pietras, Marion Mesnieres, Christa Maes, Atsushi Kumanogoh, Thomas Worzfeld, Jin-Gyu Cheong, Steven Z Josefowicz, Peter Kharchenko, David T Scadden, Antonio Scialdone, Joel A Spencer, Lev Silberstein","doi":"10.1038/s43587-025-00837-x","DOIUrl":"10.1038/s43587-025-00837-x","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"720"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470354","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 : 2025-04-01DOI: 10.1038/s43587-025-00838-w
Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J Hastings, Alexander Tyshkovskiy, Sara Hägg, John C Earls, Christian E Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S Tsang, Riccardo E Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S Gootenberg, Omar O Abudayyeh, M Austin Argentieri, Raymond H Mak, Lynne S Cox, Andrew S Brack, Gordan Lauc, David Furman, Jason D Buenrostro, Björn Schumacher, Jamie N Justice, Tina Woods, David Gobel, Viviana I Perez, David A Sinclair, Andrea B Maier, Nir Barzilai, Michael P Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev
{"title":"Invigorating discovery and clinical translation of aging biomarkers.","authors":"Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J Hastings, Alexander Tyshkovskiy, Sara Hägg, John C Earls, Christian E Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S Tsang, Riccardo E Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S Gootenberg, Omar O Abudayyeh, M Austin Argentieri, Raymond H Mak, Lynne S Cox, Andrew S Brack, Gordan Lauc, David Furman, Jason D Buenrostro, Björn Schumacher, Jamie N Justice, Tina Woods, David Gobel, Viviana I Perez, David A Sinclair, Andrea B Maier, Nir Barzilai, Michael P Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev","doi":"10.1038/s43587-025-00838-w","DOIUrl":"10.1038/s43587-025-00838-w","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":"539-543"},"PeriodicalIF":17.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756840","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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