Research carried out by the Babraham Institute in the United Kingdom has developed a method that promises to delay the aging of cells without losing their function . The time jump could be up to 30 years and could revolutionize regenerative medicine.
The new method, carried out by scientists from the Institute’s epigenetics research programme, is based on the Nobel Prize-winning technique for making stem cells. In addition, it has managed to overcome the problem of completely erasing the cell identity by stopping the reprogramming part of the process. Researchers have found the perfect balance between reprogramming cells, making them biologically younger, and being able to regain their specialized cellular function.
In 2007, Shinya Yamanaka was the first scientist to convert normal cells into stem cells. The latter have the special ability to become any type of cell. The entire stem cell reprogramming process takes about 50 days and uses four key molecules called Yamanaka factors. The new method, called “maturation-phase transient reprogramming,” exposes cells to Yamanaka factors for just 13 days. At that time, the age-related changes are removed and the cells temporarily lose their identity. The partially reprogrammed cells were given time to grow under normal conditions, to see if their specific skin cell function returned. Genome analysis showed that the cells had recovered the characteristic markers of skin cells as they were capable of making collagen.
To show that the cells had rejuvenated, the researchers looked for changes in the characteristics of aging. As Dr Diljeet Gill of the Babraham Institute explains: “Our understanding of aging at the molecular level has progressed in the last decade, leading to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the degree of reprogramming that our new method achieved.”
The researchers looked at multiple measures of cell age. The first is the epigenetic clock , where chemical tags present throughout the genome indicate age. The second is the transcriptome , which is all the gene readouts produced by the cell. Based on these two measures, the reprogrammed cells matched the profile of cells 30 years younger compared to the reference data sets.
Potential applications of this technique depend on cells not only appearing younger, but also functioning as such. Fibroblasts (skin cells) produce collagen, a molecule found in bones, tendons, and ligaments that helps give tissue structure and heal wounds. The rejuvenated fibroblasts produced more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also travel to areas that need to be repaired. The researchers tested the partially rejuvenated cells by creating an artificial slice in a layer of cells in a dish. They found that the treated fibroblasts moved into the gap faster than the older cells . This is a promising sign that this research could one day be used to create cells that heal wounds better.
In the future, this research could also open up other therapeutic possibilities, as the researchers observed that their method also had an effect on other genes linked to age-related diseases and symptoms. The APBA2 gene, associated with Alzheimer’s, and the MAF gene, which is involved in the development of cataracts, showed changes towards juvenile transcription levels.
The mechanism underlying the transient reprogramming is still not fully understood, and is the next piece of the puzzle to explore. The researchers speculate that key areas of the genome involved in the formation of cell identity escape the reprogramming process.
“Our results represent a major step forward in our understanding of cell reprogramming. We have shown that cells can rejuvenate themselves without losing their function and that rejuvenation seeks to restore some function to old cells. The fact that we have also observed a reversal of markers of aging in disease-associated genes is especially promising for the future of this work,” said Diljeet Gill.
Professor Wolf Reik, Group Leader of the Epigenetics Research Programme, who has recently moved to head Cambridge’s High Institute Labs, said: “This work has very exciting implications. Over time, we may be able to identify the genes that age without reprogramming and specifically targeting them to reduce the effects of aging. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon .”
Diljeet et al. 2022. Multi-omic rejuvenation of human cells by maturation phase transient reprogramming. eLife. DOI: 10.7554/eLife.71624