Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
Acta Physiol (Oxf). 2018 Aug;223(4):e13074. doi: 10.1111/apha.13074. Epub 2018 May 7.
As average life expectancy continues to rise in the developed world, age-associated pathologies are increasing in prevalence. The hallmarks of cardiac ageing include cardiomyocyte loss, fibrosis and hypertrophy, all of which contribute to an increased incidence of cardiac disease. At the molecular level, cellular ageing is characterized by increased ROS production, mitochondrial dysfunction and the accumulation of damaged proteins and organelles. Cardiomyocytes and other senescent cell types rely upon autophagy, a lysosome-mediated degradation pathway, to remove potentially toxic protein aggregates and damaged organelles from the cellular milieu. However, increasing lines of evidence point to an age-associated decrease in cardiomyocyte autophagy, with predictably negative consequences for cardiac function and health. Conversely, stimulation of autophagy has been shown to improve cellular health and cardiac function and to increase lifespan in numerous model organisms. Clearly, autophagy represents a critical pathway for cellular vitality, as well as a promising therapeutic target for the treatment of age-related cardiac pathologies. In this review, we will discuss the mechanism of autophagy and its regulation in the cell, the role of autophagy in the ageing heart, and how the autophagy pathway might be targeted to improve cardiac health.
随着发达世界的平均预期寿命持续延长,与年龄相关的疾病的发病率也在增加。心脏衰老的特征包括心肌细胞丧失、纤维化和肥大,所有这些都导致心脏病发病率的增加。在分子水平上,细胞衰老的特征是活性氧(ROS)产生增加、线粒体功能障碍以及受损蛋白质和细胞器的积累。心肌细胞和其他衰老细胞类型依赖于自噬,这是一种溶酶体介导的降解途径,可从细胞环境中清除潜在的有毒蛋白聚集体和受损细胞器。然而,越来越多的证据表明,心肌细胞自噬与年龄相关的减少有关,这对心脏功能和健康产生了可预测的负面影响。相反,刺激自噬已被证明可以改善细胞健康和心脏功能,并在许多模式生物中延长寿命。显然,自噬代表了细胞活力的关键途径,也是治疗与年龄相关的心脏疾病的有前途的治疗靶点。在这篇综述中,我们将讨论自噬的机制及其在细胞中的调节、自噬在衰老心脏中的作用,以及自噬途径如何被靶向以改善心脏健康。