Endicott S Joseph
Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence, (AIM CoBRE), University of New Mexico Health Sciences Center, Albuquerque, NM, United States.
Front Aging. 2024 Dec 2;5:1509400. doi: 10.3389/fragi.2024.1509400. eCollection 2024.
Chaperone-mediated autophagy (CMA) is the lysosomal degradation of individually selected proteins, independent of vesicle fusion. CMA is a central part of the proteostasis network in vertebrate cells. However, CMA is also a negative regulator of anabolism, and it degrades enzymes required for glycolysis, lipogenesis, and translation at the cytoplasmic ribosome. Recently, CMA has gained attention as a possible modulator of rodent aging. Two mechanistic models have been proposed to explain the relationship between CMA and aging in mice. Both of these models are backed by experimental data, and they are not mutually exclusionary. Model 1, the "Longevity Model," states that lifespan-extending interventions that decrease signaling through the INS/IGF1 signaling axis also increase CMA, which degrades (and thereby reduces the abundance of) several proteins that negatively regulate vertebrate lifespan, such as MYC, NLRP3, ACLY, and ACSS2. Therefore, enhanced CMA, in early and midlife, is hypothesized to slow the aging process. Model 2, the "Aging Model," states that changes in lysosomal membrane dynamics with age lead to age-related losses in the essential CMA component LAMP2A, which in turn reduces CMA, contributes to age-related proteostasis collapse, and leads to overaccumulation of proteins that contribute to age-related diseases, such as Alzheimer's disease, Parkinson's disease, cancer, atherosclerosis, and sterile inflammation. The objective of this review paper is to comprehensively describe the data in support of both of these explanatory models, and to discuss the strengths and limitations of each.
伴侣介导的自噬（CMA）是单个选定蛋白质的溶酶体降解过程，不依赖于囊泡融合。CMA是脊椎动物细胞蛋白质稳态网络的核心组成部分。然而，CMA也是合成代谢的负调节因子，它会降解糖酵解、脂肪生成以及细胞质核糖体上翻译所需的酶。最近，CMA作为啮齿动物衰老的一种可能调节因子而受到关注。已经提出了两种机制模型来解释CMA与小鼠衰老之间的关系。这两种模型都有实验数据支持，且并非相互排斥。模型1，即“长寿模型”，指出通过INS/IGF1信号轴减少信号传导的寿命延长干预措施也会增加CMA，CMA会降解（从而降低其丰度）几种负调节脊椎动物寿命的蛋白质，如MYC、NLRP3、ACLY和ACSS2。因此，假设在生命早期和中期增强CMA可减缓衰老过程。模型2，即“衰老模型”，指出溶酶体膜动力学随年龄的变化会导致关键CMA组分LAMP2A出现与年龄相关的损失，进而减少CMA，导致与年龄相关的蛋白质稳态崩溃，并导致与年龄相关疾病（如阿尔茨海默病、帕金森病、癌症、动脉粥样硬化和无菌性炎症）相关的蛋白质过度积累。这篇综述文章的目的是全面描述支持这两种解释模型的数据，并讨论每种模型的优缺点。
