Gene editing probably isn’t the first method that comes to mind for keeping your brain young. However, recent research suggests that the DNA-modification technology known as CRISPR has the potential to rejuvenate our stem cells and reverse ageing. Stem cells are unspecialised cells that are capable of dividing and renewing into specific, differentiated cells.
While the technology is a long way from being used in humans, fresh breakthroughs could prove huge in fundamental biology. Specifically, scientists may have found a way to boost the ability of old stem cells in your brain to produce young new cells, rejuvenating the organ.
“We think [this] could be part of a resilience mechanism for an older brain,” says the study’s principal investigator, Prof Anne Brunet of Stanford Medicine in the US.
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But in humans, she says, “this is extremely speculative.”
So far, the researchers in Brunet’s lab have successfully boosted the brain function of mice into old age. They used CRISPR, a tool that works like molecular scissors to precisely cut sections of DNA, to disrupt the neural stem cells in the mice. This reactivated the cells, prompting them to generate new neurons.
While human stem cells don’t work exactly the same way, the discovery could still guide research towards creating treatments for age-related diseases, like dementia.
How do genes affect ageing?
As you age, your stem cells deteriorate. Usually able to activate and produce new ones, they instead stay dormant (or, to scientists, ‘quiescent’). The same is true with mice.
In 2016, the Stanford scientists first started investigating the ageing process in mice and ways to boost their stem cells. They focused on a part of the mouse brain known as the subventricular zone, due to its high density of neural stem cells.
They extracted cells from the brains of old mice and infected this cluster of cells (or ‘cell culture’) with viruses. Rather than causing any damage, these viruses acted as vessels to guide the CRISPR technology to the 23,000 genes in the mice genome.
The aim? To find ‘knockouts’: genes that when disabled could improve, or even restore, the ability of old neural stem cells to reactivate. This process is called functional screening.
“What’s exciting is when you do the functional screen, you’re testing all the genes in the genome. It’s neat because it ranks the important genes. And we found 300 of them,” says Brunet.
What was more fascinating was that these 300 genes specifically boosted old stem cells when activated, rather than young ones.
“We were pretty excited about this!" she says. “But we also thought, well, this is in a culture outside the brain. So, of course, we wanted to know what happens in the brain itself.”
The team then did the same screening in living mice, injecting the virus into the brains of old mice and allowing the CRISPR to knock out certain genes. This time, they tested 50 genes, including 30 of those 300 age-specific genes.
Five weeks later, they extracted samples from the mice brains to see whether they had an enriched bank of these knockouts in the neurons (or whether they had a depleted bank). They discovered that 20 of those 50 genes successfully boosted the old mice’s neurons.
Sugar's role ageing
One of the genes is particularly interesting to scientists and could be targeted more closely in further studies – it's hoped that disabling it could stave off cognitive decline. It's (catchily) called Slc2a4, and makes one of the proteins that transports glucose (the simple sugar vital to energy in living organisms) around your body.
But is shutting off this transport a good idea? Won't it break the link between your key energy source and vital organs? According to Brunet, no – at least not in old neural stem cells. She argues that it could actually help them.
In fact, when the researchers restricted glucose to the old neural stem cells, rather than having a negative effect, the cells were better able to generate new, younger cells.
They discovered that as the mice aged, their brain’s stem cells contained more glucose than those of younger mice. So, Brunet thinks, this glucose (which is usually so helpful) could be causing trouble in older brains – explaining why removing it is actually a good thing.
The interesting part, according to Brunet? When they removed glucose from the cell culture, something strange happened: the neural stem cells went through the same rejuvenation as when the glucose transporter gene was disabled by CRISPR.
Next, when they run the same experiment on live mice, they hope to find out if giving them less sugar could have the same effect.
CRISPR in human brains
Could any of this apply to a human brain? As you'd probably guess, the organ between your ears is vastly complicated, comprising of 12.6 million km (7 million miles) of brain in terms of volume (that’s almost 40 times greater than the distance between Earth and the Moon). A mouse brain, by comparison, is only 5,000 km (3,107 miles) in volume – the distance between Boston and Lisbon.
Nevertheless, the neural stem cells the researchers were studying in the mice can be found in your human brain. Their exact function isn’t clear but, Brunet says, there are indications that they are important for injury repair – and reactivating these neural stem cells could help to make our brains more resilient.
But don’t get too excited. Brunet says there’s still a long way to go before we know for sure.
“There are so many steps between the fundamental discoveries and their potential application,” says Brunet. She adds that one of the biggest hurdles is the question of whether new cells, produced by rejuvenated stem cells, could fit in without “wreaking havoc” on the tightly packed and spatially precise circuit we’ve developed since childhood.
So, will we see CRISPR therapeutics in humans in the future? “There is hope, but it’s not going to be easy.”
About our expert
Prof Anne Brunet is the Michele and Timothy Barakett professor of genetics at Stanford University in the US. Her lab is working to identify the fundamental pathways involved in delaying ageing, and her research has been published in Nature Aging, Nature Cell Biology and Cell.
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