Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function

Aging is the major risk factor for neurodegenerative diseases that are also associated with impaired proteostasis, resulting in abnormal accumulation of protein aggregates. However, the role of aging in development and progression of disease remains elusive. Here, we used <i>Caenorhabditis elegans</i> models to show that aging-promoting genetic variations accelerated the rate of cell-to-cell transmission of SNCA/α-synuclein aggregates, hallmarks of Parkinson disease, and the progression of disease phenotypes, such as nerve degeneration, behavioral deficits, and reduced life span. Genetic and pharmacological anti-aging manipulations slowed the spread of aggregates and the associated phenotypes. Lysosomal degradation was significantly impaired in aging models, while anti-aging treatments reduced the impairment. Transgenic expression of <i>hlh-30p::hlh-30</i>, the master controller of lysosomal biogenesis, alleviated intercellular transmission of aggregates in the aging model. Our results demonstrate that the rate of aging closely correlates with the rate of aggregate propagation and that general anti-aging treatments can slow aggregate propagation and associated disease progression by restoring lysosomal function.

衰老是神经退行性疾病的主要危险因素，此类疾病常伴随蛋白稳态（proteostasis）受损，进而导致蛋白质聚集体的异常蓄积。然而，衰老在疾病发生发展中的具体作用仍不明晰。本研究借助秀丽隐杆线虫（Caenorhabditis elegans）模型展开实验，结果显示，促衰老的遗传变异会加速α-突触核蛋白（SNCA/α-synuclein）聚集体的细胞间传播速率——此类聚集体是帕金森病的标志性病理特征——同时还会加快疾病表型的进展，包括神经退行性变、行为缺陷以及寿命缩短。遗传与药理学抗衰老干预手段可延缓聚集体的扩散及其相关表型的进展。衰老模型中的溶酶体降解（lysosomal degradation）功能显著受损，而抗衰老处理可缓解这一损伤。溶酶体生物发生的主调控因子hlh-30p::hlh-30的转基因表达，可缓解衰老模型中聚集体的细胞间传播。本研究结果证实，衰老速率与聚集体的传播速率密切相关，而常规抗衰老处理可通过恢复溶酶体功能，延缓聚集体的传播及其伴随的疾病进展。