Loeffler David A
Beaumont Research Institute, Department of Neurology, Beaumont Health, Royal Oak, MI, United States.
Front Aging Neurosci. 2019 Mar 11;11:49. doi: 10.3389/fnagi.2019.00049. eCollection 2019.
Misfolded proteins are pathological findings in some chronic neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Aging is a major risk factor for these disorders, suggesting that the mechanisms responsible for clearing misfolded proteins from the brain, the ubiquitin-proteasome system and the autophagy-lysosomal pathway, may decline with age. Although autophagic mechanisms have been found to decrease with age in many experimental models, whether they do so in the brain is unclear. This review examines the literature with regard to age-associated changes in macroautophagy and chaperone-mediated autophagy (CMA) in the central nervous system (CNS). Beclin 1, LC3-II, and the LC3-II/LC3-I ratio have frequently been used to examine changes in macroautophagic activity, while lamp2a and HSPA8 (also known as hsc70) have been used to measure CMA activity. Three gene expression analyses found evidence for an age-related downregulation of macroautophagy in human brain, but no published studies were found of age-related changes in CMA in human brain, although cerebrospinal fluid concentrations of HSPA8 were reported to decrease with age. Most studies of age-related changes in brain autophagy in experimental animals have found age-related declines in macroautophagy, and macroautophagy is necessary for normal lifespan in , and mice. However, the few studies of age-related changes in brain CMA in experimental animals have produced conflicting results. Investigations of the influence of aging on macroautophagy in experimental animals in systems other than the CNS have generally found an age-related decrease in Beclin 1, but conflicting results for LC3-II and the LC3-II/LC3-I ratio, while CMA decreases with age in most models. CONCLUSION: while indirect evidence suggests that brain autophagy may decrease with normal aging, this issue has not been investigated sufficiently, particularly in human brain. Measuring autophagic activity in the brain can be challenging because of differences in basal autophagic activity between experimental models, and the inability to include lysosomal inhibitors when measuring the LC3-II/LC3-I ratio in postmortem specimens. If autophagy does decrease in the brain with aging, then pharmacological interventions and/or lifestyle alterations to slow this decline could reduce the risk of developing age-related neurodegenerative disorders.
错误折叠的蛋白质是一些慢性神经退行性疾病（包括阿尔茨海默病、帕金森病和亨廷顿病）的病理学特征。衰老为这些疾病的主要风险因素，这表明负责从大脑清除错误折叠蛋白质的机制，即泛素 - 蛋白酶体系统和自噬 - 溶酶体途径，可能会随着年龄增长而衰退。尽管在许多实验模型中已发现自噬机制会随着年龄增长而减少，但在大脑中是否如此尚不清楚。本综述研究了有关中枢神经系统（CNS）中巨自噬和伴侣介导的自噬（CMA）与年龄相关变化的文献。Beclin 1、LC3 - II以及LC3 - II/LC3 - I比率经常被用于检测巨自噬活性的变化，而lamp2a和HSPA8（也称为hsc70）已被用于测量CMA活性。三项基因表达分析发现了人类大脑中巨自噬与年龄相关下调的证据，但未发现有关人类大脑中CMA与年龄相关变化的已发表研究，尽管据报道脑脊液中HSPA8的浓度会随着年龄增长而降低。大多数关于实验动物大脑自噬与年龄相关变化的研究发现巨自噬存在与年龄相关的衰退，并且巨自噬对于线虫和小鼠的正常寿命是必需的。然而，少数关于实验动物大脑CMA与年龄相关变化的研究得出了相互矛盾的结果。在中枢神经系统以外的系统中对实验动物衰老对巨自噬影响的研究通常发现Beclin 1存在与年龄相关的减少，但LC3 - II和LC3 - II/LC3 - I比率的结果相互矛盾，而在大多数模型中CMA会随着年龄增长而减少。结论：虽然间接证据表明大脑自噬可能会随着正常衰老而减少，但这个问题尚未得到充分研究，尤其是在人类大脑中。由于实验模型之间基础自噬活性存在差异，并且在测量死后标本中的LC3 - II/LC3 - I比率时无法使用溶酶体抑制剂，因此测量大脑中的自噬活性可能具有挑战性。如果大脑中的自噬确实会随着衰老而减少，那么减缓这种衰退的药物干预和/或生活方式改变可能会降低患年龄相关神经退行性疾病的风险。
