A new target to slow down ageing and reduce blood cancer risk

A few weeks ago, we wrote about the relationship between cancer and ageing. 

In that article, we explained that although potentially cancer-causing mutations in our DNA are usually fixed by our bodies, they can slip through the net and begin to build up, which means we accumulate mutations in our cells as we age.  

If a cell accumulates enough mutations, it may begin to divide and multiply uncontrollably, thus turning into cancer. 

But the accumulation of mutations with age alone does not fully explain why we get more cancer as we get older. 

Ageing in normal cells and tissues makes it easier for cancer cells to take root. But how this happens can differ between different tissues. For example, in blood stem cells, ageing reduces their ability to replenish themselves, and mutated cells begin to dominate ‘normal’ cells, increasing the likelihood of a blood cancer like leukaemia developing. 

If we had a way of slowing down ageing, we could both keep cells healthier for longer and reduce their cancer risk. The problem is that we don’t fully understand the biological processes that cause this potentially dangerous dysfunction in aged blood stem cells as we age.  

But that could be about to change. 

Damage and ageing

New research from the Weatherall Institute of Molecular Medicine at the University of Oxford, and the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge has shown that a molecule called formaldehyde causes DNA damage to blood stem cells, which can accelerate their ageing and increase the likelihood of blood cancers. 

Most importantly, this research now identifies a common link between DNA damage in blood cancer and ageing.  

Previous research, led by our chief scientist Professor KJ Patel, had identified aldehydes, the group of molecules to which formaldehyde belongs, as a source of DNA damage that causes mutations in blood stem cells and increases blood cancers.  

Now, this latest research shows that the DNA damage arising from formaldehyde can also age the blood stem cells. 

Therefore, if we can find ways to limit formaldehyde production in our bodies, we may be able to slow, or even fully stop, this DNA damage occurring. Doing that could slow the ageing process of these cells and could be a step toward preventing certain blood cancers. 

Lowering the defences

Formaldehyde is commonly used as a chemical preservative, safely kept in containers like the specimen jars at the Natural History Museum. So how do we get exposed to formaldehyde?  

“It turns out our own body’s metabolism produces far more formaldehyde than most of us can ever be exposed to from the environment,” says Dr Meng Wang, who co-led the new study. 

“So, in this work, we wanted to ask whether the formaldehyde generated by our metabolism can cause significant damage to DNA, and more importantly, lead to detrimental effects.’”  

Our bodies have natural defence mechanisms against the harmful effects of formaldehyde. One in the form of enzymes, proteins that can break formaldehyde down into non-toxic products, and another in DNA repair pathways that undo the DNA damage inflicted by formaldehyde. 

So, to determine the potential effects of formaldehyde accumulation throughout our lifetime, Wang and his colleagues switched off these defence mechanisms in the blood stem cells of mice. And in doing so, it was like they pressed fast forward. 

They found that allowing formaldehyde to accumulate in the blood stem cells of these mice caused the cells to age much faster than usual. The blood stem cells of an 8-week-old mouse looked like those of a 2-year-old mouse and were functioning like old cells too. 

It seemed to confirm a long-held theory that DNA damage is a key driver of ageing. 

The guardian of the genome

“There’s this debate in ageing,” Wang explains.  

“One side says that ageing is a result of slow, gradual, accumulated damage. Like riding the same bicycle over the years. Slowly bits of rust and everything makes it not work as well as it used to.   

“And then there’s the other camp that says actually ageing is a programmed response triggered by various stressors that turns a young cell into an older one. And what we found is actually, at least in blood stem cells, it is very much a triggered response, dependent on a protein called p53.”   

p53 is a type of protein called a transcription factor. It plays a vital role in controlling when the code of our DNA is read by our cells to make proteins. It’s also in charge of activating a cell’s response to DNA damage.  

As such, it’s been nicknamed the the ‘guardian of the genome’. 

In the mice without the natural defences against formaldehyde damage, much more p53 was present that would be usually, a sign that it’s trying to undo as much DNA damage as it can.  

But this research shows that this p53 activation has another effect. It speeds up the ageing process.  

“When we then removed p53, we rejuvenate these mice,” Wang says.  

“We reversed the onset of accelerated ageing. And what that shows is that ageing isn’t just the result of cumulative damage, it’s very much the way our body responds to the damage.” 

A new target

So, now we know that formaldehyde is damaging DNA, and that our body’s response of activating p53 is accelerating the ageing process. What’s next? 

“There’s little doubt that we make a lot of this stuff,” Wang says. “But knowing that this specific chemical is causing the damage is actually really exciting because it means there is something that we can potentially target. 

“So, let’s find out where formaldehyde is made in the cell, and whether we can modulate it.” 

If we can lower the amount of formaldehyde in our cells, or block the processes that make it entirely, we might be able to prevent this accelerated ageing. 

Beyond blood cancers

This study looked at ageing in mice, but do we have some clues about the role of formaldehyde in human ageing. 

People with a disease called Falconi’s anaemia (FA) naturally lack the DNA repair defence against the DNA damage formaldehyde causes. They display the signs of accelerated blood ageing observed in this study.  

And importantly, most people with FA develop not only blood cancers, but also liver, skin and oesophageal cancers. 

That suggests that formaldehyde-induced DNA damage and ageing could play a role in a variety of cancer types. 

“Formaldehyde, we think, is produced in all cells,” says Wang. “So, it is a very generalizable cause of DNA damage.”  

“Now, we still don’t know why we see certain cancers more frequently than others, why DNA damage, in certain cells turns into cancer and doesn’t in others. But that is a separate question to tackle. It’s a big question in cancer generally.” 

But while the answers to the big questions may still be a way off, a new target for cancer prevention could be closer on the horizon.  

 Jacob