Altered translation elongation contributes to key hallmarks of aging in the killifish brain

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-07-31 DOI:10.1126/science.adk3079

Domenico Di Fraia, Antonio Marino, Jae Ho Lee, Erika Kelmer Sacramento, Mario Baumgart, Sara Bagnoli, Till Balla, Felix Schalk, Stephan Kamrad, Rui Guan, Cinzia Caterino, Chiara Giannuzzi, Pedro Tomaz da Silva, Amit Kumar Sahu, Hanna Gut, Giacomo Siano, Max Tiessen, Eva Terzibasi-Tozzini, Eugenio F. Fornasiero, Julien Gagneur, Christoph Englert, Kiran R. Patil, Clara Correia-Melo, Danny D. Nedialkova, Judith Frydman, Alessandro Cellerino, Alessandro Ori

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Abstract

Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain’s biology—the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.

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翻译延伸的改变是鳉鱼大脑衰老的关键标志

衰老是神经退行性疾病的主要危险因素，具有多种细胞和分子特征。为了了解这些特征的起源，我们研究了衰老对短命鳉鱼大脑中转录组、翻译组和蛋白质组的影响。我们确定了一系列事件，其中异常翻译暂停导致独立于转录调节的蛋白质丰度改变。特别是，衰老导致核糖体失速增加和富含碱性氨基酸的蛋白质的广泛消耗。这些发现揭示了衰老大脑生物学中潜在的脆弱点——基本DNA和RNA结合蛋白的生物发生。这种脆弱性可能代表了一个统一的原则，它连接了各种衰老特征，包括基因组完整性、蛋白质平衡和大分子的生物合成。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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