Ageing seems to affect cellular processes in the same way across five very different kinds of life — humans, fruit flies, rats, mice and worms — according to a study published in Nature on 12 April. The findings could help to explain what drives ageing and offer suggestions for how to reverse it.

“It opens up a really fundamental new area of understanding how and why we age,” says Lindsay Wu, a biochemist at UNSW Sydney in Australia.

As animals age, a variety of molecular processes inside cells become less reliable — gene mutations become more frequent, and the ends of chromosomes snap off, making them shorter. Many studies have explored ageing’s effects on gene expression, but few have investigated how it affects transcription — the process whereby genetic information is copied from a blueprint DNA strand to RNA molecules — says Andreas Beyer, a computational biologist at the University of Cologne in Germany.

Careless copying

To find out, Beyer and his colleagues analysed genome-wide transcription changes in five organisms: nematode worms, fruit flies, mice, rats and humans, at different adult ages. The researchers measured how ageing changed the speed at which the enzyme that drives transcription, RNA polymerase II (Pol II), moved along the DNA strand as it made the RNA copy. They found that, on average, Pol II became faster with age, but less precise and more error-prone across all five groups. “We saw more mismatches between the reads and reference genome,” says Beyer.

Previous research had shown that restricting diet and inhibiting insulin signalling can delay ageing and extend lifespan in many animals, so the researchers then investigated whether these measures had any effect on the speed of Pol II. In worms, mice and fruit flies that carried mutations in insulin signalling genes, Pol II moved at a slower pace. The enzyme also travelled more slowly in mice on a low-calorie diet.

But the ultimate question was whether changes in Pol II speed affected lifespan. Beyer and his team tracked the survival of fruit flies and worms that carried a mutation that slowed Pol II down. These animals lived 10% to 20% longer than their non-mutant counterparts. When the researchers used gene editing to reverse the mutations in worms, the animals’ lifespans shortened. “That really established a causal connection,” says Beyer.

Picking up the pace

The researchers wondered whether Pol II’s acceleration could be explained by structural changes in how DNA is packed inside cells. To minimize the space that they take up, the vast threads of genetic information are tightly wound around proteins called histones into bundles called nucleosomes. By analysing human lung cells and umbilical vein cells, the researchers found that ageing cells contained fewer nucleosomes, smoothing the path for Pol II to travel faster. When the team boosted the expression of histones in the cells, Pol II moved at a slower pace. In fruit flies, the elevated histone levels seemed to increase their lifespans.

The study is a “really exciting piece of work” that demonstrates how ageing mechanisms are consistent across distantly related species, says Colin Selman, who studies ageing in mammals at the University of Glasgow, UK. It also opens the door to exploring how Pol II could be a target for drugs that slow down the ageing process. Changes to Pol II’s transcription process have been implicated in many diseases, including various types of cancer, and a range of drugs have been developed that target Pol II and the molecules that facilitate it. “There may be opportunities to effectively repurpose some of these drugs to investigate their effects on ageing,” says Selman.

Citation: Debès, C. et al.Nature, Ageing-associated changes in transcriptional elongation influence longevity. (2023) https://doi.org/10.1038/s41586-023-05922-y (open-access)

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