Introduction
Aging has significant structural, metabolic and biochemical repercussions on a variety of tissues, including the heart. Many age-associated changes converge on mitochondria, which include disrupted morphology characterized by swollen organelles1, and functional impairments including declines in oxidative phosphorylation and elevations in reactive oxygen species (ROS) emission2. Mitochondrial maintenance throughout the lifespan is critical for cardiac health, which relies on the removal and degradation of dysfunctional mitochondria via the lysosomes through a selective form of autophagy, known as mitophagy.
Autophagy is a cytoprotective mechanism, and is often associated with pro-survival outcomes in the face of cellular stress, including ischemia-reperfusion (IR) insults3–7. Autophagy provides a pivotal step in determining cell fate, as damaged mitochondria that do not undergo mitophagy may initiate apoptosis or cell death8,9. It has been reported that autophagy decreases with age and this is thought to contribute to the aging phenotype10. The importance of autophagy in the heart has been demonstrated through loss- and gain-of-function animal models in which impaired autophagy has resulted in cardiomyopathy11,12, while enhanced autophagy has promoted longevity13. Therefore, it is important to understand how the intersection of age impacts the ability of the heart to respond to stress and injury, which in turn may allow a more tailored approach for interventions and therapies.
To better understand the role of age in implementing a pro-survival stress response in the heart, samples of the right atrial appendage were taken from patients prior to, and following cardioplegia during a coronary artery bypass grafting surgery (CABG), which is a model of ischemia-reperfusion14. As sampling ventricular tissue in humans poses a risk for patients, tissues harvested from the right atrial appendage are used as a surrogate for the molecular events taking place in the myocardium as a whole. Participants were selected based on age, with young subjects classified as being under the age of 50 years, while aged subjects were over the age of 70 years. We hypothesized that the young cohort would have a pronounced autophagic response following post-operative reperfusion compared to the aged patients. This would be associated with a pro-survival response, and could provide insight into how age influences the mechanisms involved in the stress response following an ischemia-reperfusion insult.