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.