Human cells are making a vital mistake and this is why we are aging

In a collaborative effort between 26 scientists across six laboratories, the team investigated changes in the transcription process among a wide range of tissues from fruit flies, mice, rats, and humans. 

The process of gene transcription is critical as the RNA copy created, called messenger RNA (mRNA), carries the genetic information needed to make proteins in a cell. mRNA carries the information from the DNA in the nucleus of the cell to the cytoplasm, where proteins are made.

They inferred that the average speed of the transcription increases with age in all the species. 

The ‘machine’ responsible for making the transcriptions, called Pol II, makes more mistakes as we age, leading to error-prone copies of our genes, which can lead to diseases like cancer.

“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,” said Dr. Andreas Beyer, the lead researcher of the study.

The team then further investigated if they could somehow slow down the speed of Pol II and reduce the number of imperfect copies of genes. They genetically modified mice, fruit flies, and worms. The team intervened in the insulin signaling in their bodies and put them on a low-calorie diet to determine transcription in old age. In both cases, the PoI II’s performance slowed and made fewer mistakes.

In a statement, the team said they tracked the survival of fruit flies and worms that carried the mutation that slowed Pol II down. Their analysis revealed that the animals lived 10 percent to 20 percent longer than their non-mutant counterparts.

Beyer added that their study provided clues on how to contribute to healthy aging in the future. “The fact that interventions, such as a reduced calorie intake, also have a positive effect on a healthy aging process on the molecular level via improving the quality of gene transcription is something which we have now been able to prove quite clearly with our study.”

Study abstract:

Physiological homeostasis becomes compromised during ageing, as a result of impairment of cellular processes, including transcription and RNA splicing. 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 worms and flies 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.