We report that increased mRNA-expression of Ectodysplasin-A2-Receptor (EDA2R) is the most remarkable aging-associated transcriptional perturbation in humans, and that its induction is confirmed in murine-models of Hutchinson-Gilford progeria syndrome and in other species. Up-regulation of EDA2R occurs in all solid-tissues and is complemented by the progressive transcriptional increase of its ligand in bloodstream. Strengthening of EDA2R/EDA-A2 signaling may exacerbate inflammation in ageing individuals which might be prevented by EDA2R/EDA-A2 blockade.