Research at the Babraham Institute has developed a method to “time-jump” human skin cells 30 years, turning back the aging clock for cells without losing their specialized function. The work of researchers in the Institute’s Epigenetics research program has partially restored the function of older cells and rejuvenated the molecular measures of biological age. The research is published today in the journal eLife and although it’s in the early stages of research, it could revolutionize regenerative medicine.
What is Regenerative Medicine?
With increasing age, the functionality of our cells decreases and the genome accumulates signs of age. Regenerative biology aims to repair or replace cells, including old ones. One of the most important tools in regenerative biology is our ability to generate “induced” stem cells. The process is the result of multiple steps, each of which erases some of the markings that make cells specialized. In theory, these stem cells have the potential to become any cell type, but scientists are not yet able to reliably recreate the conditions for stem cells to redifferentiate into all cell types.
Turn back time
The new method, based on the Nobel Prize-winning technique scientists use to create stem cells, overcomes the problem of completely erasing the cell’s identity by halting reprogramming part way through the process. This allowed researchers to strike the precise balance between reprogramming cells, making them biologically younger, while regaining their specialized cellular function.
In 2007, Shinya Yamanaka was the first scientist to convert normal cells, which have a specific function, into stem cells, which have the special ability to develop into any cell type. The full process of reprogramming stem cells takes about 50 days, using four key molecules called Yamanaka factors. The new method, called “maturation phase transient reprogramming,” exposes cells to Yamanaka factors for only 13 days. At this point, age-related changes have cleared and the cells have temporarily lost 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 regained markers characteristic of skin cells (fibroblasts), which was confirmed by observing collagen production in the reprogrammed cells.
Age is not just a number
To show that the cells had rejuvenated, the researchers looked for changes in the characteristics of aging. like dr Diljeet Gill, a postdoc in Wolf Reik’s lab at the institute who led the work as a PhD student, explained: “Our understanding of aging at the molecular level has evolved over the past decade, yielding techniques that researchers can use to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming of our new method.”
The researchers examined several measures of cell age. The first is the epigenetic clock, where chemical markers present throughout the genome indicate age. The second is the transcriptome, all of the gene displays that are produced by the cell. With these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets.
The possible applications of this technique depend on the cells not only appearing younger, but also functioning like young cells. Fibroblasts produce collagen, a molecule found in bones, skin tendons, and ligaments that 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 by creating an artificial cut in a layer of cells in a dish. They found that their treated fibroblasts moved into the gap faster than 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 could also open up other therapeutic possibilities; The researchers observed that their method also affected other genes linked to age-related diseases and symptoms. That APBA2 Gene associated with Alzheimer’s disease and the MAF Genes implicated in cataract development, both showed changes towards juvenile transcription levels.
The mechanism behind the successful temporary reprogramming is not yet fully understood and is the next piece of the puzzle to explore. The researchers speculate that key areas of the genome involved in cell identity formation may escape the reprogramming process.
Diljeet concluded: “Our results represent a major step forward in our understanding of cell reprogramming. We have demonstrated that cells can be rejuvenated without losing their function and that rejuvenation aims to restore some function to old cells. The fact that we also saw a reversal of indicators of aging in disease-associated genes is particularly promising for the future of this work.”
Professor Wolf Reik, a group leader in the Epigenetics research program who has recently moved to lead Altos Labs Cambridge Institute, said: “This work has very exciting implications. Ultimately, we may be able to identify genes that rejuvenate without reprogramming, specifically targeting to reduce the effects of aging. This approach promises valuable discoveries that could open amazing therapeutic horizons.”