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During the past century, life expectancy has risen in Germany from 35.6 and 38.5 years in men and women (1871/1881) to 78.2 and 83.1 years (2013/2015). In recent years, the dominance of chronic diseases as major contributors to total global mortality has emerged. The incidence of cardiovascular diseases (CVD) increases in westernized societies and projected trends suggest that by 2030, CVD alone will also be responsible for more deaths in low-income countries than infectious diseases. The occurrence of CVD also seems to correlate to a further increase of biological age within westernized societies. Therefore, age-associated changes in the heart are an issue of high interest in cardiac surgery. The chronological age is a prognostic marker in some clinical scoring systems. However, it does not represent an adequate estimation of the biological age of patients or their perioperative risk. In fact, frailty might be a more powerful predictor for normal perioperative course or risk escalation. An unhealthy, sedentary lifestyle can induce premature aging of vessels and myocardium. Understanding the age-associated genetic, biochemical, and pathophysiological changes can help identify the therapeutic capability of aged myocardium. Future “therapeutic myocardial rejuvenation” may represent a powerful tool for the stabilization of the perioperative course in aged patients. In this review, we will focus on selected mediators or conditions with impact on age-associated myocardial changes with a major focus on obesity and discuss potential therapeutic strategies to utilize or modify these mediators.