Zhang Cong, Cuervo Ana Maria
Department of Developmental and Molecular Biology, Marion Bessin Liver Research Center and Institute for Aging Research, 1300 Morris Park Avenue, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Nat Med. 2008 Sep;14(9):959-65. doi: 10.1038/nm.1851.
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.
伴侣介导的自噬（CMA）是一种在溶酶体中降解胞质蛋白的选择性机制，作为细胞质量控制系统的一部分，有助于清除异常蛋白。我们之前发现，CMA活性在衰老生物体中会下降，并提出细胞清除功能的这种缺陷可能导致异常蛋白的积累、细胞内稳态异常，最终导致衰老生物体特有的功能丧失。为了确定衰老的这些负面特征是否可以通过在生命后期维持有效的自噬活性来预防，在这项研究中，我们纠正了老年啮齿动物的CMA缺陷。我们构建了一种双转基因小鼠模型，其中CMA的溶酶体受体数量（之前已证明其丰度会随年龄增长而降低）可以被调节。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下降的后果。我们在此表明，如果受体丰度的下降得到阻止，CMA活性可以维持到高龄，并且自噬活性的保留与受损蛋白在细胞内的积累减少、处理蛋白损伤的能力增强以及器官功能改善有关。
