Head of Altos Labs Cambridge Institute hails “exciting implications” for aging research after cellular reprogramming success with Yamanaka factors.

Can cells be reprogrammed to regain their youthful function, winding back the clock of aging? Research seems to show this is indeed possible, and scientists at Cambridge’s Babraham Institute have developed a method to ‘time jump’ human skin cells by 30 years – turning back the aging clock but without causing the cells to lose their specialised function.

Longevity.Technology: Researchers in the Babraham Institute’s Epigenetics research programme have been able to partly restore the function of older cells, as well as rejuvenating the molecular measures of biological age. The research is published today in the journal eLife and although still at an early stage of exploration, holds the potential to revolutionise regenerative medicine, as well as pointing the way towards future therapies for skin aging, Alzheimer’s and cataracts.

As we age, our cells’ ability to function declines and the genome accumulates marks of aging, but longevity research aims to repair or replace old and damaged cells, and induced stem cells could be the answer. The process is iterative, with each step erasing some of the marks that make cells specialised, and once the stem cells are ‘rewound’ to a pluripotent state, they have the potential to become any cell type, but as yet, scientists have not been able to reliably recreate the conditions to re-differentiate stem cells into all cell types.

Enter the Yamanaka factors

The new method, based on the Nobel Prize winning technique scientists use to make stem cells – the Yamanaka factors – overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This allowed researchers to find the sweet spot – the precise balance between reprogramming cells to make them biologically younger but still able to regain their specialised cell function.

In 2007, Shinya Yamanaka was 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, a discovery which netted him the 2012 Nobel Prize for Medicine. The full process of stem cell reprogramming takes around 50 days using four key molecules – Oct3/4, Sox2, Klf4, c-Myc – called the Yamanaka factors. The new method, called ‘maturation phase transient reprogramming’, exposes cells to Yamanaka factors for just 13 days. At this point, skin aging-related changes are removed and the cells have temporarily lost their identity. The 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 [1].

Clocking cellular changes 

To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of aging.

“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,” explained Dr Diljeet Gill, a postdoc in Professor Wolf Reik’s lab at the Institute. “We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved [2].”

Researchers looked at multiple measures of cellular age; the first is the epigenetic clock, where chemical tags present throughout the genome indicate age and the second is the transcriptome – all the gene readouts produced by the cell. Using these two measures, the research team determined that the reprogrammed cells matched the profile of cells that were 30 years younger compared with reference data sets.

Of course, the potential applications of this technique are dependent on the cells not only appearing younger, but actually 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. The rejuvenated fibroblasts produced more collagen proteins compared with control cells that did not undergo the reprogramming process [1].

Fibroblasts also move into areas that need repairing; 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 and 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 had an effect on other genes linked to age-related diseases and symptoms. The APBA2 gene, associated with Alzheimer’s disease, and the MAF gene with a role in the development of cataracts, both showed changes towards youthful levels of transcription.
“Our results represent a big step forward in our understanding of cell reprogramming,” said 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 ageing indicators in genes associated with diseases is particularly promising for the future of this work [2].”

Professor Wolf Reik, a group leader in the Epigenetics research programme who has recently moved to lead the Altos Labs Cambridge Institute, said: “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 [2].”

The mechanism behind the successful transient reprogramming is not yet fully understood, so there are more pieces of the puzzle to slot into place, but the paper authors posit that key areas of the genome involved in shaping cell identity might escape the reprogramming process.