Researchers here make inroads into mapping a relationship between EDA2R expression and age-related inflammation. They show that EDA2R expression robustly increases with age and correlates with inflammation in multiple tissues types in mice as well as in muscle biopsies from a human study. When overexpressing EDA2R in cells in culture, those cells become more inflammatory. The next step is to established a way to reduce the expression of EDA2R or inhibit its activity and assess in aged mice the degree to which this approach to therapy can reduce inflammation and improve function. No small molecule is known to target EDA2R's interactions in a useful way, so the fastest path ahead to mouse data is likely RNA interference to reduce EDA2R expression.
Ectodysplasin A2 Receptor (EDA2R) is a member of the tumor necrosis factor receptor (TNFR) superfamily which selectively binds to Ectodysplasin-A2 (EDA-A2), a protein encoded by an alternative splicing isoform of EDA (Ectodysplasin A) gene. EDA2R receptor has been recognized as a target of TP53, and EDA2R/EDA-A2 signaling has been observed to mediate activation of JNK, NF-kB pathways and to promote apoptosis and cell death. Moreover, EDA2R messenger RNA expression was reported to be elevated in the aging lungs, and several studies indicated that polymorphisms in the EDA2R gene locus are linked with age-associated androgenetic alopecia (AGA).
Despite these observations, the broader role of EDA2R in aging remains poorly understood. Here, we implement a bioinformatics approach revealing that aging-associated increase of the transmembrane EDA2R 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 EDA2R 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 EDA-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.
Link: https://doi.org/10.1038/s41467-025-56918-3
View the full article at FightAging
