Role of protein homeostasis in cardiac aging

心力衰竭是一种典型的年龄相关性疾病。尽管心脏的增龄性改变可能是老年人心力衰竭的易感因素，但对心脏衰老的分子机制知之甚少。我们分析了小鼠心脏中与年龄相关的变化，以及抑制磷酸肌醇3-激酶活性的p110-α亚型改变心脏衰老的方式。老年小鼠的心脏功能下降与衰老标记物的表达有关。泛素化蛋白和脂褐素的积累，以及全面的基因表达谱，表明蛋白质质量控制的失调是心脏衰老的一个特征。抑制磷酸肌醇3-激酶可以保护心脏功能，并减弱与增强自噬相关的衰老标记物的表达。抑制雷帕霉素的靶点，磷酸肌醇3-激酶的下游效应物，也阻止了心脏中脂褐质的积累。总之，抑制磷酸肌醇3-激酶可以防止许多与年龄相关的心脏变化，并保护老年小鼠的心脏功能。

Heart failure is a typical age-associated disease. Although age-related changes of heart are likely to predispose aged people to heart failure, little is known about the molecular mechanism of cardiac aging. We analyzed age-associated changes in murine heart and the manner in which suppression of the p110-alpha isoform of phosphoinositide 3-kinase activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiquitinated protein and lipofuscin, as well as comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of phosphoinositide 3-kinase preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of phosphoinositide 3-kinase, also prevented lipofuscin accumulation in the heart. In conclusion, suppression of phosphoinositide 3-kinase prevented many age-associated changes in the heart and preserved cardiac function of aged mice.