A new study from Germany has potentially found the answers to time-old questions: what drives ageing and what can be done to reverse it?
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 it can be slowed down or reversed.
But the answers to these questions may finally have been found in a new study conducted by a team of scientists in Germany, published in the scientific journal Nature.
It has been discovered by researchers from the University of Cologne in Germany 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. Furthermore, it has been found that certain processes could help reverse this decline.
“This is, so far, the only eureka moment in my life. I mean, this is a type of discovery that is not made every other day,” said Dr Andreas Beyer, the lead researcher, referring to the findings as “a major discovery”.
Before the investigative project was started by Beyer and his team 10 years ago, the typical ageing study would “just look at differential gene expression,” according to Beyer.
Previous studies, he explains, were asking questions like
“When we 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?'”
However, nobody was asking how the transcription process itself changes as we age, a line of inquiry that could yield insights to ultimately help reverse, or stop, decline.
Transcription, the key to healthy ageing.
Transcription plays a crucial role in Beyer’s research as it involves the process of an RNA copy of a piece of DNA being made by a cell.
This copy holds significant genetic information required for producing new proteins within a cell. The health and function of cells, which ultimately structure all living things, are determined by proteins.
Throughout our lives, cells regenerate, but each cell possesses its distinct characteristics due to the activation of different genes within them, as explained by Beyer. This activation is referred to as transcription.
Since genes provide cells with their purpose, it is essential for transcription to be flawless.
“The production of the right amount of transcripts for each gene, along with an exact replication of the gene sequence and the activation of the precise genes necessary for proper cell function, are all necessary,” stated Beyer.
Various cell types exist within the human body, such as nerve cells, muscle cells, blood cells, and skin cells. Each cell type activates (transcribes) a distinct set of genes to fulfill its specific function.
The responsible “machine,” as Beyer calls it, for transcribing the gene sequences is known as Pol II (RNA polymerase II).
The team’s discovery revealed that the transcription process speeds up as we age. This accelerated transcription leads to more errors made by Pol II, resulting in essentially “flawed” copies that can contribute to various diseases.
“If Pol II becomes too fast, it makes more mistakes, causing the sequence to deviate from the genome sequence. The consequences resemble those seen when there are mutations in the genome itself,” explained Beyer.
Halting the production of flawed cell copies
It had been previously demonstrated through research that low-calorie diets and the inhibition of insulin signaling, which involves blocking the communication between insulin and cells, could effectively delay the aging process and extend lifespan in various animals.
In their experiments, the impact of these interventions on slowing down the speed of Pol II and reducing the occurrence of faulty copies was investigated by Beyer’s team.
A collaborative effort involving 26 individuals from six different laboratories, the study initially focused on worms, mice, and genetically modified fruit flies with inhibited insulin signaling, as well as mice subjected to a low-calorie diet. The objective was to assess the performance of cell transcription during old age. In both scenarios, Pol II demonstrated a slower rate of reaction and movement, resulting in fewer errors.
Following this, Beyer and his team monitored the survival of fruit flies and worms that possessed the mutation responsible for slowing down Pol II. Remarkably, these mutated animals exhibited lifespans that were 10 to 20 percent longer compared to their non-mutant counterparts.
To establish a causal connection, the researchers utilized gene editing techniques to reverse the mutations in the worms, which subsequently led to a shortened lifespan for the animals.
To test their experiment in humans, blood samples from young and old individuals were utilized.
“And when the comparison was made between the young cells and the very old cells, in vitro, the exact same results were obtained,”
hared Argyris Papantonis, one of the principal investigators, with Euronews Next.
The results across different species confirm that it is “truly a general phenomenon that applies to aging, rather than being specific to a single model, such as flies,” stated Beyer.
“Our study suggests that adopting a healthy diet or implementing interventions like caloric restriction would enhance the quality of RNA production transcription in cells. Consequently, this would have long-term beneficial effects on the cells,” he added.
According to Papantonis, these findings could aid in preventing the development of cancer, which is often a late-life disease caused by errors. By mitigating errors, the emergence of cancer or late-life diseases could potentially be constrained.
Furthermore, these discoveries can contribute to a
“better understanding of aging, comprehending the processes that occur during aging, and ultimately, gaining better insights into interventions.”
Beyer emphasized that this opens up new possibilities for delaying aging or extending the period of healthy aging.
Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing1,2,3,4. 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.