8th April 2022
Age of skin cells reversed by 30 years
Researchers at the UK's Babraham Institute have rejuvenated a 53-year-old woman's skin cells, so they are the equivalent of a 23-year-old's.
Recent years have seen a string of breakthroughs in the longevity field, raising hopes that aging could one day be conquered. Most of these advances have occurred in mice, worms, and fruit flies.
Now, scientists at the Babraham Institute near Cambridge, UK, have announced a new technique to "time jump" human skin cells by 30 years, turning back the aging clock for cells without losing their specialised function. Whilst at an early stage of development, the team behind it claim their breakthrough could revolutionise regenerative medicine. The research is published today in the journal eLife.
As we age, our cells' ability to function declines and the genome accumulates damage. The emerging field of regenerative medicine 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 a result of several steps, each erasing some of the marks that make cells specialised. In theory, these stem cells have the potential to become any cell type, but scientists aren't yet able to reliably recreate the conditions to re-differentiate stem cells into all cell types.
The new method announced today – based on the Nobel Prize-winning technique scientists use to make stem cells – overcomes the problem of entirely erasing a cell's identity, by halting reprogramming part of the way through the process. This allows researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialised cell function.
In 2007, Shinya Yamanaka became the first scientist to turn 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 stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called "maturation phase transient reprogramming", exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed, and the cells have temporarily lost their identity. In the study, partly reprogrammed cells were given time to grow under normal conditions to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells, as seen in the image above.
To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of aging. As explained by Dr Diljeet Gill, a postdoc in Wolf Reik's lab at the Institute who conducted the work as a PhD student: "Our understanding of aging on a molecular level has progressed over the last decade, giving rise 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 multiple measures of cellular age. First, they used the epigenetic clock, where chemical tags throughout the genome indicate age. Secondly, they looked at the transcriptome, all the gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger, compared to reference data sets. In other words, cells from a woman of 53 now appeared like those of a woman aged 23.
The potential applications of this technique are dependent on cells not only appearing younger, but functioning like young cells too. Fibroblasts produce collagen – a molecule found in bones, skin tendons, and ligaments, helping provide structure to tissues and heal wounds. In this study, 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 repairing. Researchers tested the partially rejuvenated cells by creating an artificial cut in a layer of cells in a dish, seen in the video below. The treated fibroblasts moved into the gap faster than older cells. This is a promising sign that one day this research could eventually 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 observed that their method also influenced other genes linked to age-related diseases and symptoms. The APBA2 gene – associated with Alzheimer's, and the MAF gene with a role in the development of cataracts – both showed changes towards youthful levels of transcription.
The mechanism behind the successful transient 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 shaping cell identity might escape the reprogramming process.
"Our results represent a big step forward in our understanding of cell reprogramming," said Dr Gill. "We have proved that cells can be rejuvenated without losing their function and that rejuvenation looks to restore some function to old cells. The fact that we also saw a reverse of aging indicators in genes associated with diseases is particularly promising for the future of this work."
"This work has very exciting implications," concluded Professor Wolf Reik, who led the research. "Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those to reduce the effects of aging. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon."
Fibroblast cells migration as part of a wound healing test. Credit: Fátima Santos, analysis by Hanneke Okkenhaug
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