Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses
Abstract Intensive efforts have been made to identify features that could serve as biomarkers of aging. Yet, drug-based interventions aimed at lessening the detrimental effects of getting older are lacking. This is largely attributable to tissue-specificity, sex-related differences, and to the diffi...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56918-3 |
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| author | Maria Chiara Barbera Luca Guarrera Andrea David Re Cecconi Giada Andrea Cassanmagnago Arianna Vallerga Martina Lunardi Francesca Checchi Laura Di Rito Margherita Romeo Sarah Natalia Mapelli Benedikt Schoser Edward V. Generozov Molecular Genetics Group Rick Jansen Eco J. C. de Geus Brenda Penninx Jenny van Dongen Ilaria Craparotta Rosanna Piccirillo Ildus I. Ahmetov Marco Bolis |
| author_facet | Maria Chiara Barbera Luca Guarrera Andrea David Re Cecconi Giada Andrea Cassanmagnago Arianna Vallerga Martina Lunardi Francesca Checchi Laura Di Rito Margherita Romeo Sarah Natalia Mapelli Benedikt Schoser Edward V. Generozov Molecular Genetics Group Rick Jansen Eco J. C. de Geus Brenda Penninx Jenny van Dongen Ilaria Craparotta Rosanna Piccirillo Ildus I. Ahmetov Marco Bolis |
| author_sort | Maria Chiara Barbera |
| collection | DOAJ |
| description | Abstract Intensive efforts have been made to identify features that could serve as biomarkers of aging. Yet, drug-based interventions aimed at lessening the detrimental effects of getting older are lacking. This is largely attributable to tissue-specificity, sex-related differences, and to the difficulty of identifying actionable targets, which continues to pose a significant challenge. Here, we implement a bioinformatics approach revealing that aging-associated increase of the transmembrane Ectodysplasin-A2-Receptor is a prominent tissue-independent alteration occurring in humans and other species, and is particularly pronounced in models of accelerated aging. We show that strengthening of the Ectodysplasin-A2-Receptor signalling axis in myogenic precursors and differentiated myotubes suffices to trigger potent parainflammatory responses, mirroring aspects of aging-driven sarcopenia. Intriguingly, obesity, insulin-resistance, and aging-related comorbidities, such as type-2-diabetes, result in heightened levels of the Ectodysplasin-A2 ligand. Our findings suggest that targeting the Ectodysplasin-A2 surface receptor represents a promising pharmacological strategy to mitigate the development of aging-associated phenotypes. |
| format | Article |
| id | doaj-art-4cb422e260344dd7bba9d63579f126fa |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4cb422e260344dd7bba9d63579f126fa2025-08-20T02:15:06ZengNature PortfolioNature Communications2041-17232025-02-0116111110.1038/s41467-025-56918-3Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responsesMaria Chiara Barbera0Luca Guarrera1Andrea David Re Cecconi2Giada Andrea Cassanmagnago3Arianna Vallerga4Martina Lunardi5Francesca Checchi6Laura Di Rito7Margherita Romeo8Sarah Natalia Mapelli9Benedikt Schoser10Edward V. Generozov11Molecular Genetics GroupRick Jansen12Eco J. C. de Geus13Brenda Penninx14Jenny van Dongen15Ilaria Craparotta16Rosanna Piccirillo17Ildus I. Ahmetov18Marco Bolis19Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Laboratory of Muscle Pathophysiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Laboratory of Muscle Pathophysiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Computational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Laboratory of Human Pathology in Model Organism, Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Department of Research in Inflammation and Immunology, IRCCS Humanitas Research HospitalFriedrich-Baur-Institute, Department of Neurology, LMU Klinikum, Ludwig-Maximilians UniversityDepartment of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological AgencyDepartment of Psychiatry, Amsterdam UMC location Vrije Universiteit AmsterdamDepartment of Biological Psychology, Vrije Universiteit AmsterdamDepartment of Psychiatry, Amsterdam UMC location Vrije Universiteit AmsterdamDepartment of Biological Psychology, Vrije Universiteit AmsterdamComputational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Laboratory of Muscle Pathophysiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Research Institute for Sport and Exercise Sciences, Liverpool John Moores UniversityComputational Oncology Unit, Department of Oncology, Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS, Via Mario Negri 2Abstract Intensive efforts have been made to identify features that could serve as biomarkers of aging. Yet, drug-based interventions aimed at lessening the detrimental effects of getting older are lacking. This is largely attributable to tissue-specificity, sex-related differences, and to the difficulty of identifying actionable targets, which continues to pose a significant challenge. Here, we implement a bioinformatics approach revealing that aging-associated increase of the transmembrane Ectodysplasin-A2-Receptor is a prominent tissue-independent alteration occurring in humans and other species, and is particularly pronounced in models of accelerated aging. We show that strengthening of the Ectodysplasin-A2-Receptor signalling axis in myogenic precursors and differentiated myotubes suffices to trigger potent parainflammatory responses, mirroring aspects of aging-driven sarcopenia. Intriguingly, obesity, insulin-resistance, and aging-related comorbidities, such as type-2-diabetes, result in heightened levels of the Ectodysplasin-A2 ligand. Our findings suggest that targeting the Ectodysplasin-A2 surface receptor represents a promising pharmacological strategy to mitigate the development of aging-associated phenotypes.https://doi.org/10.1038/s41467-025-56918-3 |
| spellingShingle | Maria Chiara Barbera Luca Guarrera Andrea David Re Cecconi Giada Andrea Cassanmagnago Arianna Vallerga Martina Lunardi Francesca Checchi Laura Di Rito Margherita Romeo Sarah Natalia Mapelli Benedikt Schoser Edward V. Generozov Molecular Genetics Group Rick Jansen Eco J. C. de Geus Brenda Penninx Jenny van Dongen Ilaria Craparotta Rosanna Piccirillo Ildus I. Ahmetov Marco Bolis Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses Nature Communications |
| title | Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses |
| title_full | Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses |
| title_fullStr | Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses |
| title_full_unstemmed | Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses |
| title_short | Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses |
| title_sort | increased ectodysplasin a2 receptor eda2r is a ubiquitous hallmark of aging and mediates parainflammatory responses |
| url | https://doi.org/10.1038/s41467-025-56918-3 |
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