Autophagy may be triggered by the accumulation of intracellular protein aggregation (48), nutrient deprivation (49), or various intracellular signals. The process initiates with a highly regulated activation step that forms a double membrane autophagosome, which engulfs damaged proteins and organelles. Autophagosomes then fuse with the lysosome, which contain proteases to digest the engulfed content. Aging increases the cardiomyocyte’s need for autopahgy to maintain intracellular homeostasis, but simultaneously reduces the activity of lysosomes and thereby inhibits autophagic flux. Figure illustration by Craig Skaggs.