Ageing-associated changes in transcriptional elongation influence longevity

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.

Rapid and synchronous chemical induction of replicative-like senescence via a small molecule inhibitor

“…Cells maintained in RS long-term (i.e., "deep" senescence) display even more pronounced changes in 3D genome organization, mostly compaction of chromosomal arms and changes between compartments of active and inactive chromatin 21 to suppress gene expression and activate transposable elements 22 . This is in line with spurious 23 and accelerated transcription in senescence 24 , with an overall compromised ability to transcribe 20 , as well as with a transcription-dependent reorganization of chromatin loops 25 .…”

“…We plotted 1-D Micro-C signal around CTCF peaks and found that, despite an overall signal decrease in ICM-induced cells, nucleosomes were positioned in better defined arrays following ICM treatment (Fig 6l). Nucleosome signal decrease is characteristic of senescence 24 , while the more defined positioning is reminiscent of what was seen following depletion of RNAPII in human cells 58 . Thus, also as regards 3D genome reorganization, ICM-induced senescence aligns well with RS entry.…”

“…When splice junctions were detected within introns, we further subdivided those introns accordingly. The slope of the intronic coverage was calculated in these introns across all samples as described 24 . To avoid artefacts due to the different numbers of introns used per sample, we always contrasted the same sets of introns for each comparison of different conditions, only using slopes that were negative across all samples.…”

Liquid Metal–Polymer Conductor-Based Conformal Cyborg Devices

“…LM-based cyborg devices may potentially be used to overexpress transcription factors for cell reprogramming, rejuvenating aged cells by restoring vitality, epigenetic marks, and erasing cellular damage markers, thereby reversing age-related cellular phenotypes . Additionally, molecules such as RNA polymerase II, may become potential targets for LM-based devices …”

“…367 Additionally, molecules such as RNA polymerase II, may become potential targets for LM-based devices. 368 Because LM can be compatible with various materials, including polymers, silicon, and metals, making it suitable for preparing flexible electronic skin. This electronic skin can be used to monitor physiological signals of the human body, such as heart rate and body temperature, and can transmit this information to external devices.…”