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 () and Andreas Beyer ()
Additional contact information
Cédric Debès: University of Cologne
Antonios Papadakis: University of Cologne
Sebastian Grönke: Max Planck Institute for Biology of Ageing
Özlem Karalay: Max Planck Institute for Biology of Ageing
Luke S. Tain: Max Planck Institute for Biology of Ageing
Athanasia Mizi: University Medical Centre Göttingen
Shuhei Nakamura: Max Planck Institute for Biology of Ageing
Oliver Hahn: University of Cologne
Carina Weigelt: Max Planck Institute for Biology of Ageing
Natasa Josipovic: University Medical Centre Göttingen
Anne Zirkel: University of Cologne, Faculty of Medicine and University Hospital Cologne
Isabell Brusius: University of Cologne
Konstantinos Sofiadis: University Medical Centre Göttingen
Mantha Lamprousi: University Medical Centre Göttingen
Yu-Xuan Lu: Max Planck Institute for Biology of Ageing
Wenming Huang: Max Planck Institute for Biology of Ageing
Reza Esmaillie: University of Cologne
Torsten Kubacki: University of Cologne, Faculty of Medicine and University Hospital Cologne
Martin R. Späth: University of Cologne
Bernhard Schermer: University of Cologne
Thomas Benzing: University of Cologne
Roman-Ulrich Müller: University of Cologne
Adam Antebi: University of Cologne
Linda Partridge: University of Cologne
Argyris Papantonis: University Medical Centre Göttingen
Andreas Beyer: University of Cologne

Nature, 2023, vol. 616, issue 7958, 814-821

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-05922-y

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