Despite centuries of research and progress in medicine, there are still many mysteries that remain unresolved, chief among them being an understanding of what causes ageing and how can we slow it down or reverse it.
But a new study published in the scientific journal Nature may finally have found the answers to these questions.
Researchers from the University of Cologne in Germany have not only discovered that gene transcription – the process in which a cell makes an RNA copy of a strand of DNA – becomes faster with age but less precise and more error-prone; they also found that certain processes could help us reverse this decline.
“This is, so far, the only eureka moment in my life. I mean, this is a type of discovery that you don’t make every other day,” said Dr Andreas Beyer, the lead researcher, calling the findings “a major discovery”.
“There’s a storm on Twitter. Some colleagues are very excited,” he told Euronews Next.
Before Beyer and his team started their investigative project 10 years ago, the typical ageing study would “just look at differential gene expression,” says Beyer.
Previous studies, he explains, were asking questions like “When you age, which genes are getting turned on and which genes are getting turned off?” and “How does that change the regulation or the metabolism in the cell?'”
But nobody was asking how the transcription process itself changes as we age, a line of inquiry that could yield insights to ultimately help us reverse, or stop, decline.
Transcription, the key to healthy ageing
Transcription is fundamental to Beyer’s research as it is the process in which a cell makes an RNA copy of a piece of DNA.
This copy is important because it carries the genetic information needed to make new proteins in a cell. Proteins determine the health and function of the cells, and cells then structure all living things.
Throughout our lives, our cells regenerate, “but each cell is different, and what makes them different are the different genes that are activated in it,” explains Beyer. “This activation is called transcription”.
Because genes give cells their purpose, their transcription needs to be flawless.
“You need to create the right amount of transcripts for each gene and have an exact copy of the gene sequence, but also, you need to activate the exact genes that the cell needs to function as it should,” Beyer said.
There are many different types of cells in the human body: nerve cells, muscle cells, blood cells, skin cells, and so on. And because each cell fulfils a different function, a different set of genes are activated (transcribed) in each cell type.
The “machine” – as Beyer calls it – responsible for making the transcription copy of the gene sequences is called Pol II (RNA polymerase II).
And what his team discovered was that the process of transcription gets faster as we age, and this accelerated transcription causes Pol II to make more mistakes, leading to essentially “bad” copies that can lead to numerous diseases.
“If Pol II gets too fast, it makes more mistakes, and then the sequence is not identical anymore to the genome sequence. The consequences are similar to what you have when there are mutations in the genome itself,” Beyer said.
Stopping bad cell copies, the second great breakthrough
Previous research had already proven that low-calorie diets and inhibiting insulin signalling – blocking the signal between insulin and cells – could delay ageing and extend lifespan in many animals.
In their experiments, Beyer’s team sought to find out whether these had any impact to slow down the speed of Pol II and reduce the number of faulty copies.
The investigation – a joint collaboration of 26 people across six different labs – first worked with worms, mice and fruit flies genetically modified to inhibit insulin signalling as well as with mice on a low-calorie diet to determine the performance of cell transcription in old age. In both cases, Pol II reacted and travelled more slowly, making fewer mistakes.
Beyer and his team then tracked the survival of fruit flies and worms that carried the mutation that slowed Pol II down, and the animals lived 10 per cent to 20 per cent longer than their non-mutant counterparts.
When the researchers used gene editing to reverse the mutations in worms, the animals’ lifespans were shortened, establishing a causal connection.
To test their experiment in humans, they worked with blood samples from young and old individuals.
“And when we compared the young cells to the very old cells, in vitro, we got exactly the same results,” Argyris Papantonis, one of the principal investigators, told Euronews Next.
The cross-species results confirm it is “really a general phenomenon that applies to ageing, and not just specific to the single model of, for instance, flies,” said Beyer.
“Our study is saying that, for instance, having a healthy diet or, this caloric restriction intervention, would improve the quality of the transcription of the RNA production in the cell. And this would then have beneficial effects for the cells in the long run”.
The findings could help prevent cancer from manifesting, Papantonis notes, as “it’s a late-life disease because of errors. Constraining errors might be a way of constraining cancer emergence or late-life disease”.
They may also allow us to “better understanding ageing, better understanding what’s going on when we age,” and ultimately, “better understand interventions, which I think opens up new opportunities for delaying ageing or expanding healthy ageing,” said Beyer.