Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses
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.
Authors
- Laura Di Rito (ORCID: https://orcid.org/0000-0003-4155-6753)
- Andrea David Re Cecconi (ORCID: https://orcid.org/0000-0003-1502-9108)
- Rick Jansen (ORCID: https://orcid.org/0000-0002-3333-6737)
- Luca Guarrera (ORCID: https://orcid.org/0000-0001-7475-3345)
- Giada Andrea Cassanmagnago (ORCID: https://orcid.org/0000-0001-8803-5344)
- Sarah N. Mapelli (ORCID: https://orcid.org/0000-0002-0129-2055)
- Ekaterina A. Semenova (ORCID: https://orcid.org/0000-0003-1248-2855)
- Nikolay A. Kulemin (ORCID: https://orcid.org/0000-0002-8588-3206)
- Martina Lunardi (ORCID: https://orcid.org/0000-0003-2011-5131)
- Benedikt G. H. Schoser (ORCID: https://orcid.org/0000-0002-2757-8131)
- Alexandra Kanygina (ORCID: https://orcid.org/0000-0003-4993-9492)
- Marco Bolis
- Brenda W.J.H. Penninx (ORCID: https://orcid.org/0000-0001-7779-9672)
- Edward V. Generozov (ORCID: https://orcid.org/0000-0002-6314-4883)
- Margherita Romeo (ORCID: https://orcid.org/0000-0002-3020-8545)
- Rinat Sultanov (ORCID: https://orcid.org/0000-0003-3918-708X)
- Ildus I. Ahmetov (ORCID: https://orcid.org/0000-0002-6335-4020)
- Jenny van Dongen (ORCID: https://orcid.org/0000-0003-2063-8741)
- Eco J. C. de Geus (ORCID: https://orcid.org/0000-0001-6022-2666)
- Ilaria Craparotta (ORCID: https://orcid.org/0000-0002-0846-9634)
- Arianna Vallerga (ORCID: https://orcid.org/0000-0002-5623-2412)
- Rosanna Piccirillo (ORCID: https://orcid.org/0000-0002-1613-9352)
- Maria Chiara Barbera (ORCID: https://orcid.org/0000-0003-1627-0032)
- Francesca Checchi
Institutions
- Plekhanov Russian University of Economics (RU)
- SIB Swiss Institute of Bioinformatics (CH)
- Kazan State Medical University (RU)
- University of Milan (IT)
- Mario Negri Institute for Pharmacological Research (IT)
- LMU Klinikum (DE)
- Institute of Oncology Research (CH)
- Amsterdam Neuroscience (NL)
- GGD Amsterdam (NL)
- Amsterdam University Medical Centers (NL)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- IRCCS Humanitas Research Hospital (IT)
- Volga Region State Academy of Physical Culture, Sports and Tourism (RU)
- Università della Svizzera italiana (CH)
- Liverpool John Moores University (GB)
- Federal Medical-Biological Agency (RU)
- University of Milano-Bicocca (IT)
- Ludwig-Maximilians-Universität München (DE)
- Vrije Universiteit Amsterdam (NL)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-23
- DOI
- https://doi.org/10.1038/s41467-025-56918-3
- Citations
- 19
- Primary Topic
- dental development and anomalies
- Type
- article
- Field-Weighted Citation Impact
- 15.31