老龄化相关的转录延伸变化影响长寿

SCI 10 May 2023

Ageing-associated changes in transcriptional elongation influence longevity

 (Nature IF: 49.96)

Debès C, Papadakis A, Grönke S, Karalay Ö, Tain LS, Mizi A, Nakamura S, Hahn O, Weigelt C, Josipovic N, Zirkel A, Brusius I, Sofiadis K, Lamprousi M, Lu YX, Huang W, Esmaillie R, Kubacki T, Späth MR, Schermer B, Benzing T, Müller RU, Antebi A, Partridge L, Papantonis A, Beyer A. Ageing-associated changes in transcriptional elongation influence longevity. Nature. 2023 Apr;616(7958):814-821. doi: 10.1038/s41586-023-05922-y. Epub 2023 Apr 12. PMID: 37046086; PMCID: PMC10132977.

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing. 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 and flies 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. 

由于转录和RNA剪接等细胞过程的损伤，生理平衡在老龄化过程中受到损害。然而，导致转录保真度丧失的分子机制，以及防止其丧失的方法，至今仍是未知数。在此，我们分析了不同生物体内转录过程的全基因组、与衰老有关的变化：线虫、果蝇、小鼠、大鼠和人类。所有五个物种的平均转录延伸速度（RNA聚合酶II速度）都随着年龄的增长而增加。伴随着这些延伸速度的变化，我们观察到剪接的变化，包括未剪接的转录本的减少和更多圆形RNA的形成。两种延长寿命的干预措施，即限制饮食和降低胰岛素-IGF信号，都逆转了这些与衰老有关的大部分变化。RNA聚合酶II的遗传变体降低了蠕虫和苍蝇的速度，使它们的寿命延长。同样，通过过度表达组蛋白成分来降低RNA聚合酶II的速度，以对抗与年龄相关的核糖体定位变化，也能延长苍蝇的寿命和人类细胞的分裂潜力。我们的研究结果揭示了动物衰老和延长寿命干预措施的基本分子机制，并指出了可能的预防措施。

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