Cardiovascular diseases (CVDs) such as myocardial infarction are the primary cause of death worldwide. The current clinical approach after MI is reoxygenating the infarct heart tissue, however, this may lead to further damage due to the oxidative stress created, causing reperfusion injury (RI). Occurrence of CVDs and the related mortality drastically increases with age; over 69% of patients who die of such diseases are age 65 or older. Therefore, having a thorough understanding of the pathophysiology of CVDs in the elderly population is crucial. Most studies, however, use animal models such as mice or rats that are 8-12 weeks old. Thus, the drastic differences brought by age and interspecies differences lead to poor success in translating treatments to the clinical settings, showing the immense need for a more pathologically relevant tissue/disease model. Using tissue engineering, highly controlled yet complex tissue level 3-dimensional systems can be developed. Such systems can be incorporated with human induced pluripotent stem cell (hiPSC)-derived cells to fabricate fully human-origin, personalized platforms.The main goal of this dissertation was to develop physiologically relevant, aged human-origin myocardial tissue models to study the pathology of RI. Towards that goal, we first determined the characteristics of aging on the tissue level and observed that aging is not just the sum of cellular failures, but it is an emergent event that manifests due to the interdependency of the cells within the tissue. We then designed and fabricated myocardial model tissues using hiPSC-derived endothelial cells (ECs) and cardiomyocytes (CMs) from rats to study pathophysiology and potential ameliorations of RI. We showed that EC-CM interactions and hypoxia inducible factor 1 expression in ECs is crucial for myocardial survival under RI. Using whole genome transcriptome analysis, we showed that this protective effect is governed by EC-driven stabilization of mitochondrial complexes, suppression of oxidative phosphorylation, and activation of Rap1 signaling pathway. Finally, we developed the first in vitro aged engineered myocardium which shows molecular and functional characteristics resembling aged mammalian heart. This novel platform showing age-appropriate physiology and pathology is promising for investigating CVDs or other age-related diseases in a time and cost-effective manner.