EDA2R is Upregulated with Aging and Promotes Inflammatory Signaling
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.
" 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."
Not sure if I go along with this.
A "small molecule " is a low molecular weight organic compound, typically involved in a biological process as a substrate or product. Metabolomics usually studies small molecules within a mass range of 50 - 1500 daltons, which covers most polyphenols.
There is quite a lot of work showing that polyphenols can have significant impact on ectodysplacins.
eg. this work with grape seed proanthocyanidins:
https://doi.org/10.3892/ijmm.2017.3162
"This was associated with a significantly increased expression of the pro-apoptosis regulator BAX protein and a significantly decreased expression of the anti-apoptosis regulator Bcl-2 protein at 100 µg/ml GSPs. In addition, at non-toxic concentrations GSPs significantly inhibited the secretion of matrix metalloproteinase-2 (MMP-2) and MMP-9 from Tca8113 cells, as well as their migration and invasion. Furthermore, it was demonstrated that GSPs significantly inhibited the phosphorylation of protein kinase B (Akt) and IκB kinase, as well as the translocation of nuclear factor-κB (NF-κB) into the nucleus of Tca8113 cells. Taken together, these results suggest that GSPs inhibit the proliferation, migration and invasion of Tca8113 cells through suppression of the Akt/NF-κB signaling pathway. This indicates that GSPs may be developed as a novel potential chemopreventive agent against TSCC.
or indeed against most tumours of ectoderm eg skin.
In this study they used grape seed proanthocyanidins ( GSP). Pretty close to that, and probably better, is delphinidin ( molar weight 301 daltons). Aronia berries are paticularly high in delphinidin and quit nice to eat.
Vastly cheaper than anything from big pharma and not patentable.