Disruption of tRNA biogenesis enhances proteostatic resilience, improves later-life health, and promotes longevity

tRNAs are evolutionarily ancient molecular decoders essential for protein translation. In eukaryotes, tRNAs and other short, noncoding RNAs are transcribed by RNA polymerase (Pol) III, an enzyme that promotes ageing in yeast, worms, and flies. Here, we show that a partial reduction in Pol III activi...

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Bibliographic Details
Published in:PLoS biology 2024-10, Vol.22 (10), p.e3002853
Main Authors: Malik, Yasir, Kulaberoglu, Yavuz, Anver, Shajahan, Javidnia, Sara, Borland, Gillian, Rivera, Rene, Cranwell, Stephen, Medelbekova, Danel, Svermova, Tatiana, Thomson, Jackie, Broughton, Susan, von der Haar, Tobias, Selman, Colin, Tullet, Jennifer M A, Alic, Nazif
Format: Article
Language:English
Subjects:
Aging
Aging - genetics
Aging - metabolism
Animals
Biological research
Biology and life sciences
Biology, Experimental
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Drosophila melanogaster - genetics
Drosophila melanogaster - metabolism
Genetic aspects
Genetic transcription
Longevity
Longevity - genetics
Male
Mice
Physiological aspects
Proteostasis
Research and Analysis Methods
RNA
RNA Polymerase III - genetics
RNA Polymerase III - metabolism
RNA, Transfer - genetics
RNA, Transfer - metabolism
Synthesis
Transfer RNA
Unfolded Protein Response
Veterinary physiology
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Summary:tRNAs are evolutionarily ancient molecular decoders essential for protein translation. In eukaryotes, tRNAs and other short, noncoding RNAs are transcribed by RNA polymerase (Pol) III, an enzyme that promotes ageing in yeast, worms, and flies. Here, we show that a partial reduction in Pol III activity specifically disrupts tRNA levels. This effect is conserved across worms, flies, and mice, where computational models indicate that it impacts mRNA decoding. In all 3 species, reduced Pol III activity increases proteostatic resilience. In worms, it activates the unfolded protein response (UPR) and direct disruption of tRNA metabolism is sufficient to recapitulate this. In flies, decreasing Pol III's transcriptional initiation on tRNA genes by a loss-of-function in the TFIIIC transcription factor robustly extends lifespan, improves proteostatic resilience and recapitulates the broad-spectrum benefits to late-life health seen following partial Pol III inhibition. We provide evidence that a partial reduction in Pol III activity impacts translation, quantitatively or qualitatively, in both worms and flies, indicating a potential mode of action. Our work demonstrates a conserved and previously unappreciated role of tRNAs in animal ageing.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3002853