A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short‐lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA , mainly due to post‐transcriptional mechanisms that account for over 40% of the age‐regulated proteins. These changes cause a progressive loss of stoichiometry in several protein complexes, including ribosomes, which show impaired assembly/disassembly and are enriched in protein aggregates in old brains. Mechanistically, we show that reduction of proteasome activity is an early event during brain aging and is sufficient to induce proteomic signatures of aging and loss of stoichiometry in vivo . Using longitudinal transcriptomic data, we show that the magnitude of early life decline in proteasome levels is a major risk factor for mortality. Our work defines causative events in the aging process that can be targeted to prevent loss of protein homeostasis and delay the onset of age‐related neurodegeneration.

中文翻译：

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衰老大脑中蛋白酶体活性降低导致核糖体化学计量损失和聚集。

蛋白质稳态的逐渐丧失是衰老的特征，也是神经退行性变的驱动因素。为了定量研究这一过程，我们结合转录组学和蛋白质组学，对短命脊椎动物Nothobranchius Furzeri的大脑衰老过程中的蛋白质组动力学进行了表征。我们检测到蛋白质和 mRNA 之间的相关性逐渐降低，这主要是由于占年龄调节蛋白 40% 以上的转录后机制所致。这些变化导致包括核糖体在内的几种蛋白质复合物的化学计量逐渐丧失，核糖体的组装/分解受损，并且在老大脑中富含蛋白质聚集体。从机制上讲，我们表明蛋白酶体活性的降低是大脑衰老过程中的早期事件，并且足以诱导衰老的蛋白质组学特征和体内化学计量的丧失。使用纵向转录组数据，我们表明生命早期蛋白酶体水平下降的幅度是死亡的主要危险因素。我们的工作定义了衰老过程中的致病事件，可以有针对性地防止蛋白质稳态丧失并延缓与年龄相关的神经退行性变的发生。