Lysosomes figure prominently in theories of aging as the proteolytic system most responsible for eliminating growing burdens of damaged proteins and organelles in aging neurons and other long lived cells. Newer evidence shows that diverse experimental measures known to extend lifespan in invertebrate aging models share the property of boosting lysosomal clearance of substrates through the autophagy pathway. Maintaining an optimal level of lysosome acidification is particularly crucial for these anti-aging effects. The exceptional dependence of neurons on fully functional lysosomes is reflected by the phenotypes seen in congenital lysosomal storage disorders, which commonly present as severe neurodevelopmental or neurodegenerative conditions even though lysosomal deficits are systemic. Similar connections are now being appreciated between risk for late age-onset neurodegenerative disorders and primary lysosomal deficits. In diseases such as Alzheimer's and Parkinson's, as in aging alone, primary lysosome dysfunction due to acidification impairment is emerging as a frequent theme, supported by the growing list of familial neurodegenerative disorders that involve primary vATPase dysfunction. The additional cellular roles played by intraluminal pH in sensing nutrient and stress and modulating cellular signaling have further expanded the possible ways that lysosomal pH dysregulation in aging and disease can disrupt neuronal function. Here, we consider the impact of cellular aging on lysosomes and how these changes may create the tipping point for disease emergence in major late-age onset neurodegenerative disorders.

中文翻译：

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老化溶酶体：迟发性神经退行性疾病的重要催化剂。

溶酶体在衰老理论中占有突出地位，是最有责任消除衰老神经元和其他长寿细胞中受损蛋白质和细胞器日益增加的负担的蛋白水解系统。新的证据表明，已知可延长无脊椎动物衰老模型寿命的各种实验措施都具有通过自噬途径促进底物溶酶体清除的特性。保持溶酶体酸化的最佳水平对于这些抗衰老作用尤其重要。先天性溶酶体贮积症的表型反映了神经元对全功能溶酶体的特殊依赖性，尽管溶酶体缺陷是全身性的，但通常表现为严重的神经发育或神经退行性疾病。现在人们正在认识到晚发性神经退行性疾病的风险与原发性溶酶体缺陷之间的类似联系。在阿尔茨海默氏症和帕金森氏症等疾病中，与单纯衰老一样，由于酸化损伤导致的原发性溶酶体功能障碍正在成为一个常见的主题，越来越多的家族性神经退行性疾病涉及原发性 vATPase 功能障碍，这也支持这一点。管腔内 pH 在感知营养和压力以及调节细胞信号传导方面发挥的额外细胞作用进一步扩展了溶酶体 pH 失调在衰老和疾病中破坏神经元功能的可能方式。在这里，我们考虑了细胞衰老对溶酶体的影响，以及这些变化如何为晚年发病的主要神经退行性疾病创造疾病出现的临界点。