It has been the dream of women – and men – for centuries. Now scientists say they have found a way to reverse the ageing process in human skin.
Researchers in Cambridge reveal they’ve reprogrammed skin cells from people aged 38 and 53 to make them ‘younger’ by 30 years.
The method rewinds the ageing clock further than previous reprogramming methods without damaging the cells.
Researchers say they are even able partly to restore functions that have been lost in older cells.
While the research is still in its early stages, the findings could eventually revolutionise regenerative medicine, especially if it can be replicated in other cell types and other tissues in the body, the researchers claim.
In experiments, ageing cells had regained markers characteristic of skin cells that produce collagen, a molecule found in bones, skin tendons and ligaments, helping provide structure to tissues and heal wounds. Here, red shows collagen production by skin cells called fibroblasts
Cells temporarily change shape during transient reprogramming. This image shows an individual cell with fibroblast surface marker in green
In experiments, ageing cells became more like skin cells called fibroblasts that produce collagen, a protein that holds the body together and keeps it strong.
The number of fibroblasts in human skin decreases progressively with age. These cells also become shrivelled as we get older.
The new findings could lead to a targeted approach for treating ageing, which could ‘revolutionise’ regenerative medicine, according to the researchers.
The new research was conducted at the Babraham Institute, a life sciences research institute in Cambridge, and published in the journal eLife.
‘Our results represent a big step forward in our understanding of cell reprogramming,’ said Dr Diljeet Gill at the Babraham Institute.
‘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.’
As people age, their cells’ ability to function declines and the genome – their DNA blueprint – accumulates signs 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.
However, this process essentially wipes the cells of their function and gives them the potential to become any cell type.
The work originally stems from the work at the Roslin Institute in Edinburgh back in the 1990s to take a mammary cell taken from a six-year-old sheep into an embryo.
This project famously led to the creation of Dolly the sheep, the first mammal cloned from an adult somatic cell.
Dolly’s creation showed that genes in the nucleus of a mature cell are still able to revert back to an embryonic totipotent state – meaning the cell can divide to produce all of the difference cells in an animal.
Dolly the sheep (pictured) was born at the Roslin Institute in Edinburgh in July 1996. She was created from a mammary cell taken from a six-year-old sheep
EPIGENETICS AND THE YAMANAKA FACTORS
As organisms age, every cell in their bodies carries a molecular clock that records the passage of time.
Cells isolated from older people or animals have different patterns of chemicals along their DNA – called epigenetic markers – compared to younger people.
Scientists know that adding a mixture of four reprogramming molecules to cells (the Yamanaka transcription factors; Oct4, Sox2, Klf4 and cMyc) can reset these epigenetic marks to their original patterns.
This paved the way for a Nobel Prize winning scientist Dr Shinya Yamanaka, who, in 2007, 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.
This method, called IPS, takes around 50 days using four key molecules called the Yamanaka transcription factors – Oct4, Sox2, Klf4 and cMyc.
Babraham Institute’s new method, called ‘maturation phase transient reprogramming’, exposes cells to Yamanaka factors for just 13 days, instead of 50.
At this point, the cells had not turned into embryonic stem cells, but become ‘rejuvenated’ as if 30 years younger.
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.
To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of ageing.
The research involves what is known as Yamanaka transcription factors, named after Nobel Prize-winning Japanese scientist, Dr Shinya Yamanaka (pictured)
Researchers looked at multiple measures of cellular age. The first is the epigenetic clock, where chemical tags present throughout the genome indicate age.
STEM CELLS: EMBRYONIC AND ADULT
Stem cells are special human cells that have the ability to develop into many different cell types, from muscle cells to brain cells.
In some cases, they also have the ability to repair damaged tissues.
Stem cells are divided into two main forms – embryonic stem cells and adult stem cells.
Embryonic stem cells can become all cell types of the body because they are pluripotent – they can give rise to many different cell types.
Adult stem cells are found in most adult tissues, such as bone marrow or fat but have a more limited ability to give rise to various cells of the body.
Meanwhile, induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to be more like embryonic stem cells.
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 team say.
The technique can’t immediately be translated to a clinical setting because IPS increases risk of cancers.
At the moment the next steps of the research are to understand the precise mechanism that has allowed this partial reprogramming, but eventually it could be used for cellular therapies in situations where the age of the cells makes a difference, such as in skin healing for burns.
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, Babraham Institute researchers found.
Fibroblasts also move into areas that need repairing, so 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 – a promising sign that one day could be used to create cells that are better at healing wounds.
Researchers also want to see if the new method will work on other tissues such as muscle, liver and blood cells.
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 new findings could lead to a targeted approach for treating ageing, which could ‘revolutionise’ regenerative medicine (file photo)
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.
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.’
Professor Reik told the BBC that the concept of an elixir of youth or an anti-ageing pill are not completely far-fetched.
‘The technique has been applied to genetically modified mice and there are some signs of rejuvenation,’ he said.
‘One study showed signs of a rejuvenated pancreas, which is interesting for its potential to tackle diabetes.’
GENES, GENOMES AND DNA: A PRIMER
Gene: a short section of DNA
Chromosome: a package of genes and other bits of DNA and proteins
Genome: an organism’s complete set of DNA
DNA: Deoxyribonucleic acid – a long molecule that contains unique genetic code
Your genome is the instructions for making and maintaining you. It is written in a chemical code called DNA. All living things – plants, bacteria, viruses and animals – have a genome.
Your genome is all 3.2 billion letters of your DNA. It contains around 20,000 genes.
Genes are the instructions for making the proteins our bodies are built of – from the keratin in hair and fingernails to the antibody proteins that fight infection.
Source: Genomics England/Your Genome/Cancer Research