Aging and Autophagy in the Heart

Abstract

The aging population is increasing in developed countries. Since 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 accumulation of misfolded proteins and dysfunctional organelles. On the other hand, 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.

The role of mitochondria in cardiac development and protection

“…Adult cardiomyocytes not only contain a large mitochondrial mass, they also maintain a high basal levels of mitochondrial biogenesis, as the intensive oxidative metabolism requires the constant degradation and replacement of damaged mitochondria [46]. Thus the turnover rate, the average lifespan of a mitochondrion, in mature heart is only six days [1].…”

“…The mitochondrial network is under constant remodeling by fusion and fission. Mitochondrial fission, budding off parts of the mitochondrial network, is essential for the identification of dysfunctional and senescent parts of the mitochondrial network and their removal by autophagy [46,73]. In addition, mitochondrial fusion is required for mitochondrial maintenance; it is not only essential for cardiomyocyte differentiation [74], but also for the healthy function of an adult heart [4,75].…”

“…The reported benefits of autophagy are not only mitochondria-related as it is also required for the clearance of stress fibers associated with myocardial injury, preventing pathological remodeling of the heart after ischemia-reperfusion [45]. Chronic exposure to elevated ROS not only increases autophagy [46][47][48], but also impairs the coupling of excitation-contraction and induces cardiac hypertrophy through apoptosis, necrosis and fibrosis [18]. Again, the distinction between acute and chronic effects is important.…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…Indeed, inhibiting autophagy confers cellular deficits related to aging (Blagosklonny, 2010; Rubinsztein et al ., 2011). Furthermore, autophagy declines during normal aging in Drosophila muscle (Demontis & Perrimon, 2010), mouse lung (Shirakabe et al ., 2016), and human brain (Lipinski et al ., 2010), and the mitochondrial autophagy (mitophagy) inducer PINK1 is transcriptionally downregulated during aging in mouse lung (Sosulski et al ., 2015). It was previously proposed that IIS pathway activity is deleterious to old organisms via inhibition of autophagy (Blagosklonny, 2010; Gems & de la Guardia, 2012).…”

“…Autophagy declines during normal aging in Drosophila muscle (Demontis & Perrimon, 2010), rat liver (Del Roso et al ., 2003); mouse lung (Shirakabe et al ., 2016), and human brain (Keller et al ., 2004; Lipinski et al ., 2010). Finally, the mitophagy inducer PINK1 is transcriptionally downregulated during aging in mouse lung (Sosulski et al ., 2015).…”