Cardiac Aging: From Molecular Mechanisms to Significance in Human Health and Disease
Cardiovascular diseases (CVDs) are the major causes of death in the western world. The incidence of cardiovascular disease as well as the rate of cardiovascular mortality and morbidity increase exponentially in the elderly population, suggesting that age per se is a major risk factor of CVDs. The physiologic changes of human cardiac aging mainly include left ventricular hypertrophy, diastolic dysfunction, valvular degeneration, increased cardiac fibrosis, increased prevalence of atrial fibrillation, and decreased maximal exercise capacity. Many of these changes are closely recapitulated in animal models commonly used in an aging study, including rodents, flies, and monkeys. The application of genetically modified aged mice has provided direct evidence of several critical molecular mechanisms involved in cardiac aging, such as mitochondrial oxidative stress, insulin/insulin-like growth factor/PI3K pathway, adrenergic and renin angiotensin II signaling, and nutrient signaling pathways. This article also reviews the central role of mitochondrial oxidative stress in CVDs and the plausible mechanisms underlying the progression toward heart failure in the susceptible aging hearts. Finally, the understanding of the molecular mechanisms of cardiac aging may support the potential clinical application of several “anti-aging” strategies that treat CVDs and improve healthy cardiac aging. I. Introduction II. Aging and Epidemiology of CVDs III. Physiology of Cardiac Aging A. Ventricular changes B. Valvular changes IV. Animal Models of Cardiac Aging A. Rodents B. Drosophila C. Canines D. Nonhuman primates V. Mitochondria and the Free Radical Theory of Aging A. ROS and aging B. Pleiotropy of ROS C. Mitochondrial hormesis in aging D. Mitochondrial turnover in aging VI. Molecular Mechanisms of Cardiac Aging A. Mitochondrial oxidative stress in cardiac aging B. Neurohormonal regulation of cardiac aging 1. Renin-angiotensin system in cardiac aging 2. B-adrenergic signaling 3. Insulin/insulin-like growth factor 1/PI3K signaling 4. Natriuretic peptides signaling C. Nutrient signaling in cardiac aging D. Cardiac stem cell aging and telomeres VII. Aging, Oxidative Stress, and CVDs A. Oxidative stress and mitochondria in CVDs 1. The central role of mitochondrial oxidative stress and redox status in hypertension and heart failure 2. The role of mitochondria and oxidative stress in IR injury B. Mechanisms of progression to heart failure in the aged hypertrophic heart 1. Increased cardiomyocyte death 2. ECM remodeling 3. Alteration of calcium handling proteins 4. Hypoxic response and angiogenesis 5. Mitochondrial dysfunction and abnormalities in energetics VIII. Exercise, Cardiovascular Risks, and Cardiac Aging IX. Emerging “Anti-Aging” Interventional Strategies for Cardiac Aging and CVDs A. Dietary restriction B. Antioxidant interventions 1. Nontargeted antioxidants 2. Mitochondrial-targeted antioxidants a. TPP+conjugated antioxidants b. Szeto-schiller peptides C. Resveratrol and SIRTs activators X. Conclusion and Future Directions