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

Autor: Malik Y; School of Biosciences, University of Kent, Canterbury, United Kingdom., Kulaberoglu Y; Institute of Healthy Ageing, Research Department of Genetics Evolution and Environment, University College London, London, United Kingdom., Anver S; Institute of Healthy Ageing, Research Department of Genetics Evolution and Environment, University College London, London, United Kingdom., Javidnia S; Institute of Healthy Ageing, Research Department of Genetics Evolution and Environment, University College London, London, United Kingdom., Borland G; School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Rivera R; School of Biosciences, University of Kent, Canterbury, United Kingdom., Cranwell S; Institute of Healthy Ageing, Research Department of Genetics Evolution and Environment, University College London, London, United Kingdom., Medelbekova D; Institute of Healthy Ageing, Research Department of Genetics Evolution and Environment, University College London, London, United Kingdom., Svermova T; Institute of Healthy Ageing, Research Department of Genetics Evolution and Environment, University College London, London, United Kingdom., Thomson J; School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Broughton S; Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom., von der Haar T; School of Biosciences, University of Kent, Canterbury, United Kingdom., Selman C; School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom., Tullet JMA; School of Biosciences, University of Kent, Canterbury, United Kingdom., Alic N; Institute of Healthy Ageing, Research Department of Genetics Evolution and Environment, University College London, London, United Kingdom.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2024 Oct 22; Vol. 22 (10), pp. e3002853. Date of Electronic Publication: 2024 Oct 22 (Print Publication: 2024).
DOI: 10.1371/journal.pbio.3002853
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Malik et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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