Scientists have discovered an inflammatory gene that accelerates aging
Extracellular dysplasia A2 receptor (EDA2R) is a member of the tumor necrosis factor receptor (TNFR) superfamily that selectively binds to EDA-A2.
The EDA2R receptor is considered to be the target of TP53, and EDA2R/EDA-A2 signaling mediates the activation of JNK, NF-kB pathways, and promotes apoptosis and cell death.
Other studies have found that the expression of EDA2R mRNA increases in aging lungs, and the polymorphism of EDA2R gene loci is associated with age-related androgenic alopecia (AGA).
The broader role of EDA2R in aging is still poorly understood.
In February 2025, The team of Professor Marco Bolis from the Bellinzona Institute of Oncology in Switzerland published a paper in the journal Nature Communications entitled "Increased ectodysplasin-A2-receptor EDA2R is a ubiquitous hallmark of aging and mediates parainflammatory responses ".
Our analysis of multi-tissue transcriptome data shows that EDA2R is a key tissue-independent marker of aging.
The EDA2R/EDA-A2 axis is highlighted as a promising pharmacological target for improving age-related phenotypes.
To identify genes positively associated with an individual's aging, the researchers selectively screened for transcriptional changes that occurred in a tissue-independent manner in the Genotype-Tissue Expression Database (GTEX) and found that EDA2R was the most significant outlier in the analysis.
Further analysis of transcriptome data in a mouse model of progeria syndrome (HGPS) revealed that EDA2R remained one of the most significantly upregulated genes in HGPS mice compared to age-matched wild-type mice.
Subsequent research found that in cellular models, EDA2R overexpression triggers inflammatory signals and disrupts muscle health pathways, mimicking a key feature of aging-driven sarcopenia, namely the gradual loss of muscle mass and strength.
In contrast, EDA2R inhibition mitigated these adverse effects.
Finally, the analysis of two large population cohorts, the Dutch Depression and Anxiety Study (NESDA, n= 2064) and the Dutch Twin Register (NTR, n= 3164), found a strong correlation between EDA2R expression and systemic inflammation, such as C-reactive protein.
The results reveal that EDA2R appears as a significant age-related feature in solid tissue and has functional relevance in skeletal muscle.
Currently, there are no identified antagonists that specifically target EDA2R, which limits direct pharmacological intervention.
Thus, the EDA2R/EDA-A2 axis may represent a new target for the development of compounds that offer new therapeutic avenues for inflammation and related conditions associated with aging phenotypes and subsequent age-related decline.
References: https://www.nature.com/articles/s41467-025-56918-3
