Ageing-associated changes in transcriptional elongation influence longevity

被引：96

作者：

Debes, Cedric ^{[1
]}

Papadakis, Antonios ^{[1
]}

Groenke, Sebastian ^{[2
]}

Karalay, Oezlem ^{[2
]}

Tain, Luke S. ^{[2
]}

Mizi, Athanasia ^{[3
]}

Nakamura, Shuhei ^{[2
]}

Hahn, Oliver ^{[1
,2
]}

Weigelt, Carina ^{[2
]}

Josipovic, Natasa ^{[3
,4
]}

Zirkel, Anne ^{[4
]}

Brusius, Isabell ^{[1
]}

Sofiadis, Konstantinos ^{[3
,4
]}

Lamprousi, Mantha ^{[3
]}

Lu, Yu-Xuan ^{[2
]}

Huang, Wenming ^{[2
]}

Esmaillie, Reza ^{[1
,4
,5
,6
]}

Kubacki, Torsten ^{[5
,6
]}

Spaeth, Martin R. ^{[1
,5
,6
]}

Schermer, Bernhard ^{[1
,5
,6
]}

Benzing, Thomas ^{[1
,4
,5
,6
]}

Mueller, Roman-Ulrich ^{[1
,5
,6
]}

Antebi, Adam ^{[1
,2
]}

Partridge, Linda ^{[1
,2
,7
]}

Papantonis, Argyris ^{[3
,4
]}

Beyer, Andreas ^{[1
,4
,8
]}

机构：

[1] Univ Cologne, Cluster Excellence Cellular Stress Responses Aging, Cologne, Germany

[2] Max Planck Inst Biol Ageing, Cologne, Germany

[3] Univ Med Ctr Gottingen, Inst Pathol, Gottingen, Germany

[4] Univ Cologne, Fac Med, Ctr Mol Med Cologne CMMC, Univ Hosp Cologne, Cologne, Germany

[5] Univ Cologne, Fac Med, Dept Internal Med 2, Cologne, Germany

[6] Univ Hosp Cologne, Cologne, Germany

[7] UCL, Inst Hlth Ageing, Dept Genet Evolut & Environm, London, England

[8] Univ Cologne, Inst Genet, Fac Math & Nat Sci, Cologne, Germany

来源：

NATURE | 2023年 / 616卷 / 7958期

基金：

欧洲研究理事会;

关键词：

RNA-POLYMERASE-II; LIFE-SPAN; NASCENT TRANSCRIPTION; INTRON RETENTION; EXPRESSION; PROTEIN; TRANSITION; LEVEL; RATES; AGE;

D O I：

10.1038/s41586-023-05922-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：814 / +

页数：28

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