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Ageing-associated changes in transcriptional elongation influence longevity

Debès, Cédric, Papadakis, Antonios, Grönke, Sebastian, Karalay, Özlem, Tain, Luke S., Mizi, Athanasia, Nakamura, Shuhei, Hahn, Oliver, Weigelt, Carina, Josipovic, Natasa, Zirkel, Anne, Brusius, Isabell, Sofiadis, Konstantinos, Lamprousi, Mantha, Lu, Yu-Xuan, Huang, Wenming, Esmaillie, Reza, Kubacki, Torsten, Späth, Martin R., Schermer, Bernhard, Benzing, Thomas, Müller, Roman-Ulrich, Antebi, Adam, Partridge, Linda, Papantonis, Argyris, Beyer, Andreas·2023·Nature
DOI 10.1038/s41586-023-05922-yPMC PMC10132977
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Abstract

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing 1–4 . 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 worms 5 and flies 6 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.

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  • Reduced production of senescent cells in long-lived mammals can be due to enhanced repair of cellular damage, such as double-stranded breaks.

    “Reduced production of senescent cells in long-lived mammals can be due to enhanced repair of cellular damage, such as double-stranded breaks3,9–11,58.”

    From A damage accumulation model identifies distinct aging regimes across species (2026) · cites this paper as [58]

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Metadata

Authors
Debès, C., Papadakis, A., Grönke, S., Karalay, Ö., Tain, L. S., Mizi, A., Nakamura, S., Hahn, O., Weigelt, C., Josipovic, N., Zirkel, A., Brusius, I., Sofiadis, K., Lamprousi, M., Lu, Y.-X., Huang, W., Esmaillie, R., Kubacki, T., Späth, M. R., Schermer, B., Benzing, T., Müller, R.-U., Antebi, A., Partridge, L., Papantonis, A., & Beyer, A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-04-12
Volume
616
Issue
7958
Pages
814-821
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/s41586-023-05922-y
PMC
PMC10132977
Cited by
214
References
19
Language
en
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