In Need of Age-Appropriate Cardiac Models: Impact of Cell Age on Extracellular Matrix Therapy Outcomes

Aging is the main risk factor for cardiovascular disease (CVD). As the worlds population ages rapidly and CVD rates rise, there is a growing need for physiologically relevant models of aging hearts to better understand cardiac aging. Translational research relies heavily on young animal models, however, these models correspond to early ages in human life, therefore cannot fully capture the pathophysiology of age-related CVD. Here, we chronologically aged human induced pluripotent stem cell-derived cardiomyocytes (iCMs) and compared in vitro iCM aging to native human cardiac tissue aging. We showed that 14-month-old advanced aged iCMs had an aging profile similar to the aged human heart and recapitulated age-related disease hallmarks. We then used aged iCMs to study the effect of cell age on the young extracellular matrix (ECM) therapy, an emerging approach for myocardial infarction (MI) treatment and prevention. Young ECM decreased oxidative stress, improved survival, and post-MI beating in aged iCMs. In the absence of stress, young ECM improved beating and reversed aging-associated expressions in 3-month-old iCMs while causing the opposite effect on 14-month-old iCMs. The same young ECM treatment surprisingly increased SASP and impaired beating in advanced aged iCMs. Overall, we showed that young ECM therapy had a positive effect on post-MI recovery, however, cell age was determinant in the treatment outcomes without any stress conditions. Therefore, "one-size-fits-all" approaches to ECM treatments fail, and cardiac tissue engineered models with age-matched human iCMs are valuable in translational basic research for determining the appropriate treatment, particularly for the elderly.