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Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses

Author

Listed:
  • Maria Chiara Barbera

    (Via Mario Negri 2
    University of Milano-Bicocca)

  • Luca Guarrera

    (Via Mario Negri 2)

  • Andrea David Re Cecconi

    (Via Mario Negri 2)

  • Giada Andrea Cassanmagnago

    (Via Mario Negri 2
    Institute of Oncology Research
    Faculty of Biomedical Sciences)

  • Arianna Vallerga

    (Via Mario Negri 2)

  • Martina Lunardi

    (Via Mario Negri 2)

  • Francesca Checchi

    (Via Mario Negri 2
    Via Celoria 26)

  • Laura Rito

    (Via Mario Negri 2)

  • Margherita Romeo

    (Via Mario Negri 2)

  • Sarah Natalia Mapelli

    (IRCCS Humanitas Research Hospital)

  • Benedikt Schoser

    (Ludwig-Maximilians University)

  • Edward V. Generozov

    (Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency)

  • Rick Jansen

    (Amsterdam UMC location Vrije Universiteit Amsterdam
    Mental Health Program
    Sleep & Stress Program)

  • Eco J. C. Geus

    (Vrije Universiteit Amsterdam)

  • Brenda Penninx

    (Amsterdam UMC location Vrije Universiteit Amsterdam
    Mental Health Program
    Sleep & Stress Program)

  • Jenny Dongen

    (Vrije Universiteit Amsterdam)

  • Ilaria Craparotta

    (Via Mario Negri 2)

  • Rosanna Piccirillo

    (Via Mario Negri 2)

  • Ildus I. Ahmetov

    (Liverpool John Moores University
    Plekhanov Russian University of Economics
    Kazan State Medical University)

  • Marco Bolis

    (Via Mario Negri 2
    Institute of Oncology Research
    Faculty of Biomedical Sciences
    Bioinformatics Core Unit)

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.

Suggested Citation

  • Maria Chiara Barbera & Luca Guarrera & Andrea David Re Cecconi & Giada Andrea Cassanmagnago & Arianna Vallerga & Martina Lunardi & Francesca Checchi & Laura Rito & Margherita Romeo & Sarah Natalia Map, 2025. "Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56918-3
    DOI: 10.1038/s41467-025-56918-3
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    References listed on IDEAS

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    1. Sevval Nur Bilgic & Aylin Domaniku & Batu Toledo & Samet Agca & Bahar Z. C. Weber & Dilsad H. Arabaci & Zeynep Ozornek & Pascale Lause & Jean-Paul Thissen & Audrey Loumaye & Serkan Kir, 2023. "EDA2R–NIK signalling promotes muscle atrophy linked to cancer cachexia," Nature, Nature, vol. 617(7962), pages 827-834, May.
    2. Yiwei Lai & Ignacio Ramírez-Pardo & Joan Isern & Juan An & Eusebio Perdiguero & Antonio L. Serrano & Jinxiu Li & Esther García-Domínguez & Jessica Segalés & Pengcheng Guo & Vera Lukesova & Eva Andrés , 2024. "Multimodal cell atlas of the ageing human skeletal muscle," Nature, Nature, vol. 629(8010), pages 154-164, May.
    3. Hamilton Se-Hwee Oh & Jarod Rutledge & Daniel Nachun & Róbert Pálovics & Olamide Abiose & Patricia Moran-Losada & Divya Channappa & Deniz Yagmur Urey & Kate Kim & Yun Ju Sung & Lihua Wang & Jigyasha T, 2023. "Organ aging signatures in the plasma proteome track health and disease," Nature, Nature, vol. 624(7990), pages 164-172, December.
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