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Researchers at the Babraham Institute (USA) have developed a method to rejuvenate human skin cells by 30 years, turning back the clock on cell aging without losing their function.
The work of the researchers from the Epigenetics research program of the aforementioned Institute has been able to partially restore the function of the oldest cells, as well as rejuvenate the molecular measurements of biological age. The research is published today in the journal “eLife” and, although it is in an early stage of exploration, it could revolutionize regenerative medicine.
As we age, our cells’ ability to function declines and the genome accumulates age marks. Regenerative biology aims to repair or replace cells, including old ones.
One of the most important tools of the regenerative biology it is our ability to create induced stem cells. The process is the result of several steps, each of which erases some of the marks that cause cells to specialize. In theory, these stem cells have the potential to become any cell type, but scientists cannot yet reliably recreate the conditions to re-differentiate stem cells into all cell types.
The new method, based on the Nobel Prize-winning technique scientists use to make stem cells, overcomes the problem of completely erasing cell identity by stopping reprogramming partly in the process. This allowed the researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialized cellular function.
In 2007, Shinya Yamanaka He was the first scientist to convert normal cells, which have a specific function, into stem cells that have the special ability to become any type of cell. The entire stem cell reprogramming process takes about 50 days using four key molecules called Yamanaka factors.
The new method, called “transient reprogramming of the maturation phase,” exposes the 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 markers characteristic of skin cells (fibroblasts), and this was confirmed by looking at collagen production in the reprogrammed cells.
To show that the cells had rejuvenated, the researchers looked for changes in the hallmarks of aging.
As Diljeet Gill explains, “our understanding of aging at the molecular level has progressed over the past 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 extent of reprogramming that our new method achieved.”
The researchers looked at multiple measures of cell age: the epigenetic clock, where chemical tags present throughout the genome indicate age, and the transcriptome, all the gene readouts produced by the cell. Based on these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to the reference data sets.
Potential applications of this technique depend on cells not only appearing younger, but also functioning like young cells. Fibroblasts produce collagen, a molecule found in bones, skin, tendons, and ligaments, which helps structure tissues and heal wounds. The rejuvenated fibroblasts produced more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need repair.
The researchers tested the partially rejuvenated cells and found that their 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 are better at healing wounds.
In the future, this research may also open up other therapeutic possibilities; The researchers noted that their method also had an effect on other genes linked to age-related disease and symptoms. The APBA2 gene, associated with Alzheimer diseaseand the MAF gene with a role in cataract development, both showed changes toward juvenile levels of transcription.
The mechanism behind successful transient reprogramming is not yet fully understood and is the next piece of the puzzle to explore. There. the researchers speculate that key areas of the genome involved in shaping cell identity might escape the reprogramming process.
Diljeet concludes that “our results represent a major step forward in understanding cell reprogramming. We have proven that cells can be rejuvenated without losing their function and that rejuvenation seeks to restore some function to old cells. The fact that we also saw a reversal of markers of aging in disease-associated genes is particularly promising.”
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