Abstract
Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.
Highlights
It is estimated that older individuals (≥65 years of age) will comprise 20% of the United States (US) population by 2030
Knowledge is evolving with regard to the contribution from and the potential for interaction among autophagy-lysosomal protein degradation pathways during the inevitable process of aging
The balance of available evidence indicates that age-associated proteotoxicity contributes to cardiac dysfunction in the mammalian heart and that this is precipitated by a defect in one or more of these highly conserved intracellular protein degradation processes together with mitophagy [5,100,115,177,178]
Summary
It is estimated that older individuals (≥65 years of age) will comprise 20% of the United States (US) population by 2030. Targeting protein and mitochondria quality control systems might be a viable therapeutic strategy to delay the onset, attenuate the severity, or even prevent aging-associated cardiac dysfunction. Aging is a stress over which we have no control During this physiological process there is a disruption of cardiovascular homeostasis that can lead to structural and functional changes in the heart, a topic comprehensively reviewed elsewhere [3,4,5,6,7]. Because misfolded/damaged proteins accumulate during the aging process, a widely held hypothesis is that an imbalance between protein synthesis and protein degradation precipitates age-associated cardiac pathologies. We review current understanding of: (1) protein and mitochondria quality control pathways in the heart; (Figure 1) (2) aging-associated disruptions of protein and mitochondria degradation pathways in the heart (Figure 2); and (3) current “therapies”. Interventions that target cardiac protein and mitochondrial quality control pathways (Figure 3)
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