The most common arrhythmia in the aging population is atrial fibrillation (AF), which carries an estimated lifetime risk of 25% after the age of 40 years. Cellular senescence is a stress response that is characterized by an irreversible loss of proliferative capacity, accompanied by a complex senescence-associated secretory phenotype (SASP) that can have profound effects on neighboring cells in the tissue. Our research plan is based on the following premises: Cellular senescence of atrial myocytes (AMs) and atrial cardiac fibroblasts (ACMFs) plays an important role in fibrosis, inflammation and arrhythmogenesis. The overarching hypothesis of our proposal is that atrial cell senescence is an important component of atrial aging and the increase incidence of AF. Specifically, we postulate that in the aging human (and rabbit) atrium, the interplay between aging and senescent AMs that have a lower threshold for arrhythmogenic activity and together with senescent ACMFs leads to fibrosis and the triggering of AF. This R21 proposal brings together several investigators with very different expertise to investigate mechanisms of AF in the aging heart, using a novel age-appropriate large animal model (rabbit), and human samples obtained from explanted hearts and right atrial appendage. In Aim 1 the Koren group will investigate the aging rabbit atria, as compared to the young atria, and correlate the arrhythmogenesis with molecular and cellular analysis of AMs and ACMFs. Senescence will be manipulated in vivo under Aim1 using pharmacologic approaches. Optical mapping of hearts ex vivo will be used to study arrhythmogenesis. In Aim 2 the group will study human explanted atria as well as tissue and AMs obtained from right atrial appendages during open heart surgery. In summary, we envision that by understanding the aging mechanisms that control cellular senescence we will be able to reduce fibrosis and the incidence of AF.