According to a study that was published on the 12th April in Nature, ageing affects cellular processes in a similar way in five different types of life – humans, fruit fly, rats, mice, and worms. These findings may help explain why ageing occurs and provide suggestions on how to reverse the process.
Lindsay Wu, an Australian biochemist from UNSW Sydney, says: “It’s a new way to understand how and why people age.”
Animals age and their molecular processes become less reliable. Gene mutations increase, while the ends of chromosomes are snapped off. There have been many studies on the effects of ageing on gene expression. However, few have looked at how it impacts transcription, the process by which genetic information is copied to RNA molecules from a DNA blueprint strand. Andreas Beyer, computational biologist, University of Cologne, Germany, says that this has not yet been studied.
Copying without permission is a serious offense
Beyer and colleagues studied genome-wide transcriptional changes in five organisms at different adult age levels: fruit flies (nematode), mice, rats, and humans. Researchers measured the changes in the rate at which RNA polymerase II, the enzyme responsible for transcription, moved along the DNA strand to make the RNA copies. The researchers found that Pol II, in general, became faster as it aged, but also less precise and more prone to errors across all five groups. Beyer says that “we saw more mismatches” between reads and the reference genome.
Researchers investigated whether restricting diet or inhibiting insulin signalling could have any impact on the speed of Pol II. Previous studies had shown that these measures can delay ageing in animals and increase lifespan. Pol II was slower in worms and fruit flies with mutations of insulin signalling genes. The enzyme moved more slowly in mice that were on a diet low in calories.
The ultimate question was if changes in Pol II’s speed affected lifespan. Beyer and his group tracked the survival rate of fruit flies, worms and other organisms with a mutation slowing Pol II. The animals that carried the mutation lived 10-20% longer than their counterparts without it. The lifespan of the animals was reduced when the researchers reversed the mutations using gene editing. Beyer says that “that really established a causal link”.
Picking up pace
Researchers wondered if the structural changes to how DNA is packed in cells could explain Pol II’s rapid acceleration. The genetic information is tightly wrapped around histone proteins into nucleosomes to minimize their space. The researchers discovered that older cells had fewer nucleosomes. This made it easier for Pol II travel. The team found that Pol II travelled slower when they increased the expression of histones within the cells. The elevated histone levels in fruit flies seemed to extend their lives.
Colin Selman who studies the ageing of mammals at University of Glasgow in UK, describes this study as a “really interesting piece of work”. It shows how ageing mechanisms can be consistent between distantly related species. The study opens up the possibility of using Pol II as a drug target to slow down ageing. Pol II transcriptional changes have been linked to a variety of diseases, such as cancer. A range of drugs targeting Pol II, and molecules that promote it, have been developed. Selman says that there may be ways to repurpose these drugs in order to study their effects on aging.
