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Longevity Briefs: We May Age Because Our DNA Is Read Too Fast

Posted on 25 April 2023

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Our genome contains all the instructions necessary to build a fully functional human. Yet the 20-25 thousand genes sitting in the nucleus of each cell don’t do anything on their own – other molecules are needed to first read and transcribe a gene into a temporary template molecule called mRNA, which is then translated into a functional protein. The proteins are what actually determine how a cell functions.

As we age, the quality of our proteins declines for many reasons. One reason is that transcription – the process in which an mRNA molecule is produced – becomes less faithful. Even if the DNA sequence is correct, the process of transcription will introduce errors, some of which will alter the meaning of the code enough to change how the eventual protein product functions. Yet despite the apparent importance of these changes in the ageing process, we don’t know much about why transcription becomes more error-prone with age.

What did the researchers do: In this study, researchers looked at cells from five different organisms (including humans) and estimated how fast the DNA was being transcribed into RNA templates by a molecule called RNA polymerase II (Pol II). They were able to do this by destroying the cells and sequencing their mRNA. Because Pol II spends proportionally less time reading certain parts of a gene when it works faster, researchers were able to estimate its speed based on which part of the gene was being read when the transcription process was interrupted.

Researchers then looked at whether certain interventions known to extend lifespan in animal models had an effect on transcription speed.

Key takeaway(s) from this research:

  • Pol II speed increased with age in all species studied
  • Lifespan-extending interventions were associated with slower Pol II activity in model organisms
  • Genetically decreasing Pol II speed extended lifespan in worms and flies
  • Increasing the expression of DNA packaging proteins slowed Pol II speed in human cells and increased the maximum number of times they could divide
Percentage of surviving animals over time for slow Pol II mutants (yellow lines) and controls (black lines). Graphs show data for worms (left) and flies (right).
Ageing-associated changes in transcriptional elongation influence longevity

The study found that Pol II speed was correlated with age in all 5 species, and that this increase in speed was associated with detrimental changes in RNA splicing (the necessary step of cutting and re-joining pieces of RNA). Researchers then looked at the effects of two known lifespan-extending treatments in animal models – dietary restriction, and inhibiting the signalling pathway that involves the blood sugar control hormone and its cousin, insulin-like growth factor (IGF). With a few exceptions, dietary restriction and inhibiting insulin-IGF signalling was associated with slower Pol II speed compared to controls. 

Finally, researchers wanted to see if they could extend lifespan by slowing down Pol II. They introduced genetic variants of Pol II that would slow it down in worms and flies, and found that these changes extended median worm lifespan by 20% and median fruit fly lifespan by 10%. They also found that increasing the expression of histone proteins – proteins involved in packaging the DNA molecule – increased the maximum number of times human cells could divide.

Overall, these findings suggest that the speed of transcription could be an important part of what makes us age, and could provide targets for delaying the onset of age-related diseases, as well as slowing general age-related decline.

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    Ageing-associated changes in transcriptional elongation influence longevity

    Title image by ANIRUDH Unsplash

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