Turning back the clock on ageing skin
A team of researchers from the Epigenetics research program at the Babraham Institute in the UK have developed a method to ‘time jump’ human skin cells by thirty years, turning back the ageing clock for cells without losing their specialised function. The team have also partly restored the function of older cells as well as rejuvenated the molecular measures of biological age. The research, published in the journal eLife, could revolutionise regenerative medicine.
As we age, our cells’ ability to function declines and the genome accumulates marks of ageing. Regenerative biology aims to repair or replace cells, including old ones. One of its most important tools 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, stem cells have the potential to become any cell type, but scientists aren’t yet able to reliably recreate the conditions to turn stem cells into all cell types.
This new method overcomes the problem of entirely erasing cell identity by halting reprogramming part-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 that 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 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. The partly reprogrammed cells were then given time to grow under normal conditions. A genome analysis showed that these cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.
To show the cells had been rejuvenated, the researchers looked for changes in the hallmarks of ageing. 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 ageing 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 team looked at a number of measures of cellular age and found the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets. In other words, the cells not only appeared younger, but functioned like young cells too.
Fibroblasts produce collagen — a molecule found in bones, skin tendons and ligaments — which helps provide structure to tissues and to heal wounds. The rejuvenated fibroblasts produced more collagen proteins compared to control cells. 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. They found their treated fibroblasts moved into the gap faster than older cells, a promising sign that one day cells could be created that are better at healing wounds.
There are also other therapeutic possibilities for genes linked to age-related diseases and symptoms, specifically for Alzheimer’s and for cataracts.
“Our results represent a big step forward in our understanding of cell reprogramming,” Gill concludes. “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 ageing indicators in genes associated with diseases is particularly promising for the future of this work.”
Professor Wolf Reik, a group leader in the Epigenetics program, notes, “This work has very exciting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those to reduce the effects of ageing. This approach holds promise for valuable discoveries that could open up an amazing therapeutic horizon.”