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 PMID:37046086  

Ageing-associated changes in transcriptional elongation influence longevity.

Cédric Debès | Antonios Papadakis | Sebastian Grönke | Özlem Karalay | Luke S Tain | Athanasia Mizi | Shuhei Nakamura | Oliver Hahn | Carina Weigelt | Natasa Josipovic | Anne Zirkel | Isabell Brusius | Konstantinos Sofiadis | Mantha Lamprousi | Yu-Xuan Lu | Wenming Huang | Reza Esmaillie | Torsten Kubacki | Martin R Späth | Bernhard Schermer | Thomas Benzing | Roman-Ulrich Müller | Adam Antebi | Linda Partridge | Argyris Papantonis | Andreas Beyer
Nature | 2023

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1-4. However, the molecular mechanisms leading to the loss of transcriptional fidelity are so far elusive, as are ways of preventing it. Here we profiled and analysed genome-wide, ageing-related changes in transcriptional processes across different organisms: nematodes, fruitflies, mice, rats and humans. The average transcriptional elongation speed (RNA polymerase II speed) increased with age in all five species. Along with these changes in elongation speed, we observed changes in splicing, including a reduction of unspliced transcripts and the formation of more circular RNAs. Two lifespan-extending interventions, dietary restriction and lowered insulin-IGF signalling, both reversed most of these ageing-related changes. Genetic variants in RNA polymerase II that reduced its speed in worms5 and flies6 increased their lifespan. Similarly, reducing the speed of RNA polymerase II by overexpressing histone components, to counter age-associated changes in nucleosome positioning, also extended lifespan in flies and the division potential of human cells. Our findings uncover fundamental molecular mechanisms underlying animal ageing and lifespan-extending interventions, and point to possible preventive measures.

Pubmed ID: 37046086

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Addgene (tool)

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Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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