Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function.
Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function.
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伴侣介导的自噬 (CMA) 是溶酶体中胞浆蛋白降解的一种选择性机制，有助于去除改变的蛋白质，作为细胞质量控制系统的一部分。我们之前发现衰老生物体中的 CMA 活性下降，并提出细胞清除的失败可能导致改变蛋白质的积累、细胞稳态异常，并最终导致衰老生物体特征的功能丧失。为了确定是否可以通过维持有效的自噬活性直至晚年来预防衰老的这些负面特征，在这项工作中，我们纠正了老年啮齿动物的 CMA 缺陷。我们已经建立了一个双转基因小鼠模型，其中可以调节 CMA 溶酶体受体的数量（之前显示其丰度随着年龄的增长而减少）。我们在该模型中分析了在细胞和器官水平上防止老年啮齿动物受体丰度随年龄而减少的后果。我们在此表明，如果阻止受体丰度的下降，CMA 活性将维持到高龄，并且自噬活性的保留与受损蛋白质的细胞内积累较低、处理蛋白质损伤的能力更强以及器官功能的改善有关。
Chaperone-mediated autophagy (CMA), a selective mechanism for degradation of cytosolic proteins in lysosomes, contributes to the removal of altered proteins as part of the cellular quality-control systems. We have previously found that CMA activity declines in aged organisms and have proposed that this failure in cellular clearance could contribute to the accumulation of altered proteins, the abnormal cellular homeostasis and, eventually, the functional loss characteristic of aged organisms. To determine whether these negative features of aging can be prevented by maintaining efficient autophagic activity until late in life, in this work we have corrected the CMA defect in aged rodents. We have generated a double transgenic mouse model in which the amount of the lysosomal receptor for CMA, previously shown to decrease in abundance with age, can be modulated. We have analyzed in this model the consequences of preventing the age-dependent decrease in receptor abundance in aged rodents at the cellular and organ levels. We show here that CMA activity is maintained until advanced ages if the decrease in the receptor abundance is prevented and that preservation of autophagic activity is associated with lower intracellular accumulation of damaged proteins, better ability to handle protein damage and improved organ function.