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标题：Cytosolic and mitochondrial tRNA synthetase inhibitors increase lifespan in a GCN4/ atf-4-dependent manner
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作者：Christine E. Robbins ; Bhumil Patel ; Danielle L. Sawyer 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：11
页码：1-19
DOI：10.1016/j.isci.2022.105410
语种：English
出版社：Elsevier
摘要：SummaryDeletion of genes encoding ribosomal proteins extends lifespan in yeast. This increases translation of the functionally conserved transcription factor Gcn4, and lifespan extension in these mutants isGCN4-dependent. Gcn4 is also translationally upregulated by uncharged tRNAs, as are itsCaenorhabditis elegansand mammalian functional orthologs. Here, we show that cytosolic tRNA synthetase inhibitors upregulate Gcn4 translation and extend yeast lifespan in a Gcn4-dependent manner. This cytosolic tRNA synthetase inhibitor is also able to extend the lifespan ofC.elegansin anatf-4-dependent manner. We show that mitochondrial tRNA synthetase inhibitors greatly extend the lifespan ofC.elegans, and this depends onatf-4. This suggests that perturbations of both cytosolic and mitochondrial translation may act in part via the same downstream pathway. These findings establishGCN4orthologs as conserved longevity factors and, as long-lived mice exhibit elevated ATF4, leave open the possibility that tRNA synthetase inhibitors could also extend lifespan in mammals.Graphical abstractDisplay OmittedHighlights•tRNA Synthetase inhibitors significantly extend lifespan•This lifespan extension is completely dependent onGCN4/atf-4•Other effects appear separable from lifespan extension•Lowered overall translation is not sufficient for the observed extensionBiological sciences; Biochemistry; Molecular biology;