The Roles of EDA2R in Ageing and Disease

Farrington, G, Tonge, L, Branagan, T, Sudirman, S ORCID: 0000-0003-4083-0810, Fang, C, Luk, L, Kir, S ORCID: 0000-0001-8722-9913, Bolis, M, Ahmetov, II ORCID: 0000-0002-6335-4020 and Ross, K ORCID: 0000-0003-0252-1152 (2025) The Roles of EDA2R in Ageing and Disease. Aging Cell. pp. 1-19. ISSN 1474-9718

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Abstract

Ageing is a complex biological process driven, in part, by inflammaging. Recent research identifies the ectodysplasin A2 receptor (EDA2R) as a key regulator of inflammaging and a novel biomarker of ageing, with its expression increasing with age across diverse tissues in humans and animal models. Elevated EDA2R gene expression is associated with accelerated ageing, cellular senescence, frailty, obesity, acne, radiation response and increased levels of inflammatory, renal, cardiac and vascular biomarkers. Similarly, elevated EDA2R protein levels, a critical component of the proteomic ageing clock, are associated with a wide range of conditions, including cardiovascular diseases, dementia, Parkinson's disease, mood disorders, post-traumatic stress disorder, various cancers, osteoarthritis, digestive diseases, diabetes, obesity, chronic obstructive pulmonary disease, ear and eye diseases, renal impairment, systemic autoimmune diseases, anaemia, bacterial infections, myositis, frailty, accelerated biological ageing, shorter telomere length, decreased healthspan and longevity, higher all-cause mortality and overall poor health. Beyond serving as a biomarker, EDA2R actively drives ageing, as its overexpression induces inflammation and tissue damage, whereas its inhibition mitigates these effects. Mechanistically, EDA2R activates non-canonical and canonical NF-κB signalling, promoting pro-inflammatory and catabolic processes that accelerate ageing phenotypes. Genetic variants of EDA2R are linked to alopecia, facial ageing, lipid profiles and prostate cancer. This review explores the structure and function of the EDA2R gene and protein, its role in tissue-specific ageing, and its therapeutic potential for multiple diseases. Although specific EDA2R antagonists are not yet available, interventions like calorie restriction, physical activity and specific supplements show promise in lowering EDA2R levels.

Item Type:	Article
Uncontrolled Keywords:	06 Biological Sciences; 11 Medical and Health Sciences; Developmental Biology; 31 Biological sciences; 32 Biomedical and clinical sciences
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics
Divisions:	Computer Science and Mathematics Pharmacy and Biomolecular Sciences Sport and Exercise Sciences
Publisher:	Wiley and The Anatomical Society
Date of acceptance:	18 October 2025
Date of first compliant Open Access:	4 November 2025
Date Deposited:	04 Nov 2025 11:43
Last Modified:	04 Nov 2025 11:45
DOI or ID number:	10.1111/acel.70282
URI:	https://researchonline.ljmu.ac.uk/id/eprint/27482

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