Project Summary/Abstract Cardiovascular drugs are primarily prescribed to older people (>65 years of age) since the prevalence of chronic heart failure and fibrillation increases with age. The incidence of other diseases, including cancer and neurological disorders, increases with age, too. Any medications hold potential risks to cause adverse events. Therefore, the risks of medications in older people also increase with age. While cardiac safety of drugs is one of the primary concerns among drug developers and regulatory agencies, potential new drugs are tested using animal models of normal age. Limited progress has been made in developing a tool to predict potential cardiac safety issues in aging heart, representing a significant unmet need in drug discovery industry. The United States will have 73 million aging population, (>65 years of age) in 2030. The development of a computational model that can predict potential cardiac safety reactions is a plausible step towards preparing the drug discovery industry for a rapidly approaching era of longevity. This Phase I proposal will validate and improve a computational model that incorporate potential age-related changes in regulators of excitation contraction coupling (ECC) of cardiomyocytes (CMs) and contribution of fibroblasts (FBs) that are known to increase their population in aging hearts. The specific Aims are 1) to develop and refine a computational model representing coupled FBs and CMs to simulate electrophysiology and calcium handling of aging human heart tissue, 2) to establish human engineered heart tissues by incorporating aging cardiac FBs and applying environmental stress that known to induce cardiac aging. These Aims are proposed to optimize a computational model, Wisdom Heart (WH) that mimics age-associated changes in cardiac ECC of myocardium with increasing number of FBs. The quality of WH model will be evaluated and improved against experimental data obtained from myocardium models. The established model will be shared with the consortium organized by HESI (hesiglobal.org) with FDA, industry, and academia that is trying to improve cardiac safety issues. The model will be incorporated to our services for conducting contract research projects of cardiac safety assessments and drug discovery for heart failure. We have active contracts with FDA research scientists at the National Center for Toxicological Research.