Aging and Autophagy in the Heart

Abstract

The aging population is increasing in developed countries. Because the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as autophagy) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by the accumulation of misfolded proteins and dysfunctional organelles. On the contrary, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart. Increasing lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction, in various organisms. These results raise the exciting possibility that autophagy may play an important role in combating the adverse effects of aging in the heart. In this review, we discuss the role of autophagy in the heart during aging, how autophagy alleviates age-dependent changes in the heart, and how the level of autophagy in the aging heart can be restored.

Keywords: NAD; aging; autophagy; mitochondria; mitochondrial degradation; oxidative stress.

Figure 1. Regulation of cardiac aging by autophagy

Aging inhibits autophagy in cardiomyocytes through multiple mechanisms. Aging-induced suppression of autophagy induces accumulation of misfolded proteins and dysfunctional organelles, sterile infection caused by undigested mtDNA, inflammation, and lipotoxicity, thereby leading to a metabolically unhealthier environment, precipitous mitochondrial dysfunction and eventual cell death.

Figure 2. Mechanisms of mitochondrial autophagy in the heart

Molecular mechanisms mediating mitochondrial degradation are summarized. The contribution of each mechanism to the regulation of cardiac senescence at baseline and under stress remains to be elucidated.

Figure 3. Possible interventions to normalize autophagy during cardiac aging

Aging inhibits autophagy and mitophagy in cardiomyocytes. Interventions to normalize autophagy and mitophagy and to alleviate protein aggregates may attenuate aging of the heart and increase the resistance of the heart stress.