Research from the Babraham Institute has developed a method to “time jump” human skin cells 30 years old, turning back the cells’ aging clock without losing their specialized function. The work of researchers from the Institute’s Epigenetics research program has partially restored the function of older cells, as well as rejuvenating molecular measures of biological age. The research is published today in the journal eLife and although at an early stage of exploration, it could revolutionize regenerative medicine.
What is Regenerative Medicine?
As we age, the ability of our cells to function decreases and the genome accumulates the marks of aging. Regenerative biology aims to repair or replace cells, including old ones. One of the most important tools in regenerative biology is our ability to create “induced” stem cells. The process is the result of several steps, each erasing some of the marks that make cells specialize. In theory, these stem cells have the potential to become any cell type, but scientists are not yet able to reliably recreate the conditions to re-differentiate stem cells into all cell types.
Go back in time
The new method, based on the Nobel Prize-winning technique used by scientists to make stem cells, overcomes the problem of completely erasing cell identity by halting reprogramming in the process. This allowed the researchers to find the precise balance between reprogramming cells, making them biologically younger, while being able to regain their specialized cellular function.
In 2007, Shinya Yamanaka was the first scientist to transform normal cells, which have a specific function, into stem cells which have the special ability to grow into 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 maturation phase reprogramming,” exposes cells to Yamanaka factors for just 13 days. At this point, the age-related changes are removed and the cells have temporarily lost their identity. The partially reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that the cells had found markers characteristic of skin cells (fibroblasts), which was confirmed by observing the production of collagen in the reprogrammed cells.
Age is not just a number
To show that the cells had been rejuvenated, the researchers looked for changes in the characteristics of aging. As Dr. Diljeet Gill, a post-doctoral fellow in Wolf Reik’s lab at the Institute who conducted the work as a PhD student, explains: “Our understanding of aging at the molecular level has advanced over the past decade, giving birth 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 our new method achieved.
The researchers looked at several measures of cellular age. The first is the epigenetic clock, where chemical tags present throughout the genome indicate age. The second is the transcriptome, all gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger than the reference data sets.
The potential applications of this technique depend not only on the cells looking 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 protein than control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need to be repaired. 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 through space faster than older cells. It’s a promising sign that one day this research could eventually be used to create cells that can heal wounds better.
In the future, this research could also open up other therapeutic possibilities; 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 disease, and the CRG gene playing a role in the development of cataracts, both showed changes towards young transcription levels.
The mechanism behind successful transient reprogramming is not yet fully understood and is the next piece of the puzzle to explore. The researchers believe that key areas of the genome involved in the formation of cellular identity could escape the reprogramming process.
Diljeet concluded: “Our results represent a major step forward in our understanding of cellular reprogramming. We have proven that cells can be rejuvenated without losing their function and that rejuvenation seeks to restore certain functions of old cells. The fact that we also saw an inverse effect of aging indicators in disease-associated genes is particularly promising for the future of this work.
Professor Wolf Reik, Group Leader of the Epigenetics Research Program who recently took over as head of the Altos Labs institute in Cambridge, said: “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target these to reduce the effects of aging. This approach brings valuable discoveries that could open up an astonishing therapeutic horizon.