Calorie restriction and calorie- restriction mimetics activate chaperone- mediated autophagy

• 成果类型: Article
• 署名作者: Jafari, Maryam; Macho-Gonzalez, Adrian; Diaz, Antonio; Lindenau, Kristen; Fernandez, Olaya Santiago-; Zeng, Mei; Massey, Ashish C.; de Cabo, Rafael; Kaushik, Susmita; Cuervo, Ana Maria
• 署名单位: Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine; Montefiore Medical Center; Albert Einstein College of Medicine; Yeshiva University; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA); Yeshiva University; Montefiore Medical Center; Albert Einstein College of Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13461
• DOI: 10.1073/pnas.2317945121
• 发表日期: 2024-06-25
• 关键词: glyceraldehyde-3-phosphate dehydrogenase; selective uptake; protein; degradation; receptor; AGE; spermidine; lysosomes; hallmarks; lipids

摘要

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.