The authors observed that atrial tissues in older AF patients, as reproduced in aged mice and senescent human atrial fibroblasts, displayed severe AF and correlated to higher levels of EP300, acetylated TP53, SMAD3, and other phosphorylated SMADs, as well as higher levels of pro-fibrotic factors (e.g., COL1A1/3A1, MMP-2/9, and TGFβ). This evidence concerns the gene SMAD3 and atrial fibrillation.