Cardiovascular diseases are the leading cause of death worldwide and their occurrence is highly associated with age. However, lack of knowledge in cardiac tissue aging is a major roadblock in devising novel therapies. Here, we studied the effects of cell and cardiac extracellular matrix (ECM) aging on the induced pluripotent stem cell (iPSC)-derived cardiomyocyte cell state, function, as well as response to myocardial infarction (MI)-mimicking stress conditions in vitro. Within 3-weeks, young ECM promoted proliferation and drug responsiveness in young cells, and induced cell cycle re-entry, and protection against stress in the aged cells. Adult ECM improved cardiac function, while aged ECM accelerated the aging phenotype, and impaired cardiac function and stress defense machinery of the cells. In summary, we have gained a comprehensive understanding of cardiac aging and highlighted the importance of cell-ECM interactions. This study is the first to investigate the individual effects of cellular and environmental aging and identify the biochemical changes that occur upon cardiac aging.

心血管疾病是全球范围内主要的死亡原因，其发生与年龄高度相关。然而，缺乏对心脏组织衰老的知识是设计新疗法的主要障碍。在这里，我们研究了细胞和心脏细胞外基质（ECM）老化对诱导多能干细胞（iPSC）衍生的心肌细胞状态，功能以及对体外模拟心肌梗塞（MI）的反应的影响。在3周内，年轻的ECM促进了年轻细胞的增殖和药物反应性，并诱导了细胞周期的重新进入，并保护了衰老细胞免受压力。成人ECM可改善心脏功能，而老年ECM则可加速衰老表型，并损害细胞的心脏功能和压力防御机制。总之，我们对心脏衰老有了全面的了解，并强调了细胞与ECM相互作用的重要性。这项研究是第一个研究细胞和环境衰老的个体影响并鉴定心脏衰老后发生的生化变化的研究。