An Australian scientist appears to have cracked the code for controlling the processes of ageing. It may prove to be the biggest science story of 2023.
David Sinclair, a professor of genetics at Harvard Medical School, and a team of more than 60 researchers engineered mice to prematurely and quickly age.
As Science reported: “Within weeks, they lost hair and pigment; within months, they showed multiple signs of frailty and tissue ageing.”
Then they were made young again
Some of these lab-aged mice were then epigenetically engineered to be made young again.
Simply put, they were rebooted using a youthful template of themselves. Their muscles, eyes and kidneys appeared to reverse the ageing process.
The experiments were then re-enacted like a magic show: with mice repeatedly made old and young again.
In a statement from Harvard, Dr Sinclair said: “We hope these results are seen as a turning point in our ability to control ageing.
“This is the first study showing that we can have precise control of the biological age of a complex animal; that we can drive it forwards and backwards at will.”
Is it as simple as it sounds?
It takes some unpacking. Because, for one thing, the cause or main driver of ageing is a matter of complex debate – with much interest in the role of DNA, which contains our unique genetic code.
You may have heard DNA called “the blueprint of life” because it contains the instructions needed for us to grow, develop, survive and reproduce.
So, it makes sense that accumulated damage to DNA (in the form of genetic mutations) might be what causes our bodies to degrade in the way it functions, with the consequence our mind and hearts and muscles don’t work as well as they once did. In other words, we age.
And if damaged DNA isn’t the main cause, then surely, the argument goes, at least it’s an accelerant of ageing.
One theory has it that our ageing death is pre-programmed in our genetic code.
In other words, the DNA that predicts and determines your eye colour, and height and facial features will also determine and predict your gradual or not so gradual (in the case of early lethal cancer) decay and exit.
Proving this to be the case isn’t straightforward. And there’s an awkward question that lingers: does DNA damage cause ageing, or does ageing cause DNA damage?
Not the full story
The Harvard researchers point to evidence that “there’s more to the story”.
For instance, they say, some researchers have found “that some people and mice with high mutation rates don’t show signs of premature aging”.
And other studies found that “many types of aged cells have few or no mutations”.
So the question became: “What else works with or instead of DNA changes to cause ageing?”
Epigenetics gaining ground
A theory gaining traction is that epigenetics – the switch system that turns our genes on and off – is the main driver of ageing, and the key to reversing it.
Dr Sinclair and company believe that their study, 13 years in the making, shows “for the first time that degradation in the way DNA is organised and regulated … can drive ageing in an organism, independently of changes to the genetic code itself”.
Epigenetics is the study of how our behaviours and environment bring about changes that affect the way genes work.
Crucially, epigenetic changes are reversible, whereas DNA changes (genetic mutations) are not.
How the experiment worked
According to a statement from Harvard, the team’s main experiment involved “creating temporary, fast-healing cuts in the DNA of lab mice”.
These breaks mimicked “the low-grade, ongoing breaks in chromosomes that mammalian cells experience every day in response to things like breathing, exposure to sunlight and cosmic rays, and contact with certain chemicals”.
Which is how epigenetics works.
They then tested whether ageing might result from all these everyday injuries by speeding up the chromosomal breaks “to simulate life on fast-forward”.
The researchers were careful not to damage the genome and create genetic mutations.
Epigenetic malfunction
Some explanation here: the genome is the entire set of DNA instructions found in a cell. This is all the information needed for an individual to develop and function.
There’s also the epigenome which consists of chemical compounds that modify, or mark, the genome in a way that tells it what to do, where to do it, and when to do it. Think of it as the epigenetic toolkit.
In the experiment, initially, the epigenetic factors “paused their normal job of regulating genes”. Instead they moved to the induced DNA breaks to coordinate repairs.
“But as time passed, things changed,” the researchers found. These epigenetic factors became “distracted” and did not return home after repairing breaks.
Instead, the epigenome grew disorganised, began to lose its original information and thus malfunctioned. Here, it seemed was the process of ageing as a consequence of disorganisation.
As the authors explained: “As the mice lost their youthful epigenetic function, they began to look and act old … Cells lost their identities as, for example, muscle or skin cells. Tissue function faltered. Organs failed.”
The reverse
Next, the researchers gave the mice a gene therapy that reversed the epigenetic changes they had caused.
It was like “rebooting a malfunctioning computer,” said Dr Sinclair.
In 2007, Japanese biomedical researcher Dr. Shinya Yamanaka reprogrammed human adult skin cells to behave like embryonic or pluripotent stem cells, which are capable of developing into any cell in the body. The work earned Dr Yamanaka the Nobel Prize.
Central to this re-programming were four genes, which became known as ‘Yamanaka factors’.
The age-reversal therapy delivered three of these genes – Oct4, Sox2, and Klf4, together named OSK – into the prematurely aged mice. Their organs and tissues resumed a youthful state.
The therapy “set in motion an epigenetic program that led cells to restore the epigenetic information they had when they were young,” said Dr Sinclair.
“It’s a permanent reset.”
And this wasn’t the Harvard team’s first sensational reversal of fortune for lab mice.
Dr Sinclair – listed among Time Magazine‘s 100 Most Influential People of 2014 and the co-director of Harvard’s Paul F. Glenn Center for Biology of Ageing Research – used this same cocktail of genes to restore sight in blind mice in 2020.
The human factor?
However, these are very early days – and there’s a big leap in safely translating an experiment with mice into a treatment for people.
For one thing, to reprogram an entire human epigenome with genetic therapy carries risks, namely cancers.
But the potential for a new treatment of age-related diseases appears to be legitimate.
“We expect the findings will transform the way we view the process of ageing and the way we approach the treatment of diseases associated with ageing,” said co-first author Jae-Hyun Yang, research fellow in genetics in the Sinclair lab.
First, the results need to be replicated in larger mammals and in humans. Studies in non-human primates are already underway.
“We hope these results are seen as a turning point in our ability to control ageing,” said Dr Sinclair.
