PDF(Pubmed)
Abstract：
Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and proteome changes required for the adaptation to stress. Loss of proteostasis is one of the hallmarks of aging. CMA decreases with age in multiple rodent tissues and human cell types. A decrease in lysosomal levels of the lysosome-associated membrane protein type 2A (LAMP2A), the CMA receptor, has been identified as a main reason for declined CMA in aging. Here, we report constitutive activation of CMA with calorie restriction (CR), an intervention that extends healthspan, in old rodent livers and in an in vitro model of CR with cultured fibroblasts. We found that CR-mediated upregulation of CMA is due to improved stability of LAMP2A at the lysosome membrane. We also explore the translational value of our observations using calorie-restriction mimetics (CRMs), pharmacologically active substances that reproduce the biochemical and functional effects of CR. We show that acute treatment of old mice with CRMs also robustly activates CMA in several tissues and that this activation is required for the higher resistance to lipid dietary challenges conferred by treatment with CRMs. We conclude that part of the beneficial effects associated with CR/CRMs could be a consequence of the constitutive activation of CMA mediated by these interventions.
摘要：
分子伴侣介导的自噬（CMA）是哺乳动物细胞蛋白质稳定网络的一部分，可确保蛋白质质量控制。维持蛋白质组稳态，和适应压力所需的蛋白质组变化。蛋白质的丧失是衰老的标志之一。在多种啮齿动物组织和人类细胞类型中，CMA随年龄而降低。溶酶体相关膜蛋白2A（LAMP2A）的溶酶体水平降低，CMA受体，已被确定为老化CMA下降的主要原因。这里,我们报道了CMA的组成型激活与热量限制（CR），延长健康跨度的干预措施，在老啮齿动物肝脏和培养成纤维细胞的CR体外模型中。我们发现CR介导的CMA上调是由于LAMP2A在溶酶体膜上的稳定性提高。我们还使用卡路里限制模拟物(CRM)探索我们的观察结果的翻译价值，复制CR的生化和功能作用的药理活性物质。我们表明，用CRMs对老年小鼠的急性治疗也能强烈激活几种组织中的CMA，并且这种激活是对CRMs治疗所赋予的脂质饮食挑战的更高抵抗力所必需的。我们得出结论，与CR/CRMs相关的部分有益作用可能是由这些干预措施介导的CMA组成性激活的结果。
