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

Barbera, MC, Guarrera, L, Re Cecconi, AD, Cassanmagnago, GA, Vallerga, A, Lunardi, M, Checchi, F, Di Rito, L, Romeo, M, Mapelli, SN, Schoser, B, Generozov, EV, Molecular Genetics Group, Jansen, R, de Geus, EJC, Penninx, B, van Dongen, J, Craparotta, I, Piccirillo, R, Ahmetov, II et al (2025) Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses. Nature Communications, 16. pp. 1-11. ISSN 2041-1723

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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.

Item Type:	Article
Subjects:	R Medicine > RC Internal medicine > RC1200 Sports Medicine R Medicine > RS Pharmacy and materia medica
Divisions:	Sport and Exercise Sciences
Publisher:	Nature Publishing Group
Date of acceptance:	29 January 2025
Date of first compliant Open Access:	24 February 2025
Date Deposited:	24 Feb 2025 12:06
Last Modified:	24 Feb 2025 12:15
DOI or ID number:	10.1038/s41467-025-56918-3
URI:	https://researchonline.ljmu.ac.uk/id/eprint/25703

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