Research from the Babraham Institute has developed a method to ‘time jump’
human skin cells by 30 years, turning back the ageing clock for cells
without losing their specialised function. Work by researchers in the
Institute’s Epigenetics research programme has 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
whilst at an early stage of exploration, it could revolutionise regenerative
medicine.
What is 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 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.
Turning back time
The new method, based on the Nobel Prize winning technique scientists use to
make stem cells, overcomes the problem of entirely erasing cell identity by
halting reprogramming part of the way through the process. This allowed
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 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. 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. 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.
Age isn’t just a number
To show that 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.”
Researchers looked at multiple 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 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.
The potential applications of this technique are dependent on the 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. 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. They found that
their 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 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.
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.
Diljeet concluded: “Our results represent a big step forward in our
understanding of cell reprogramming. 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, who lead the research, 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.”
Reference:
Diljeet Gill, Aled Parry, Fátima Santos, Hanneke Okkenhaug, Christopher D
Todd, Irene Hernando-Herraez, Thomas M Stubbs, Inês Milagre, Wolf Reik.
Multi-omic rejuvenation of human cells by maturation phase transient
reprogramming. eLife, 2022; 11
DOI: 10.7554/eLife.71624