Stopping the zombies: research to prevent heart failure in older people

Imagine if your heart kept working well, no matter how old you are. It might just be possible, thanks to BHF-funded research, as Sarah Brealey reports.

You might think it’s inevitable that your body doesn’t work quite as well as you get older. A few occasional aches and pains is one thing, but when it comes to your heart, a drop in function can really affect your life.

Heart failure means that your heart doesn’t pump blood as well as it should, and is much more likely the older you get. It can be caused by a heart attack but there’s not always an obvious reason.

But what if we found out it was caused by ‘zombie cells’ taking over your heart, and then multiplying to produce even more zombie cells? And what if we had drugs that could stop it?

Thanks to BHF funding, Dr Gavin Richardson and colleagues believe they have identified the process – and that yes, zombie cells are involved. Early tests have even found a drug that could help.

Researcher using state-of-the-art technology

Hearts that go downhill with age

The cells are not dead, but they don’t work properly, and they affect the cells around them explains Dr Richardson.

Dr Richardson, Research Fellow at Newcastle University, and a team of international collaborators have been studying senescent cells – in other words, cells that have decayed as they age. “These are called ‘zombie cells’ because they’re not dead, but they don’t work properly, and they affect the cells around them, so they don’t work as well either,” Dr Richardson explains. “So you can have just a few cells in your heart that drive a whole load of cell decay, and that affects how well your heart works.”

Dr Richardson believes that this process is what lies behind many of the problems of ageing. When it comes to your heart, ageing is a major problem.

Heart failure

It’s estimated that as many as 920,000 people in the UK are living with heart failure. The majority of those are over 65. “Heart failure can have a real effect on people’s quality of life – it can mean you can’t even walk up the stairs, or feel constantly tired or always out of breath,” says Dr Richardson. “If you are older, you are more likely to develop heart failure. And when you are older and have a heart attack, you are, unfortunately, less likely to recover well and more likely to die.” 

Dr Richardson and colleagues have found out more about what causes cells in the heart to become zombies. Although the process can happen in any part of the body, the answer seems to be unique to the way the heart works.

Previously, scientists thought that zombie cells were created when cells divide as they duplicate themselves. The genetic material in each cell has a protective cap, called a telomere, which protects our DNA during cell division. The telomeres get shorter each time a cell divides, until they become too short to offer any protection. But cell division doesn’t happen much in the heart, so this explanation doesn’t seem to work.

Now Dr Richardson and colleagues – including Dr João Passos of the Mayo Clinic in the US and Dr Jeanne Mialet-Perez at the University of Toulouse, France – have discovered that zombie cells are not caused by cells dividing or the telomeres getting shorter, but by damage to the telomeres, which is linked to ageing.

Finding the cure to reverse heart problems

Excitingly, they have found that a drug called navitoclax can kill these zombie cells and reverse some of the problems that occur in the heart during ageing. So far, it has been tested in mice, not humans, but has been found to remove the zombie cells, causing the heart to work better.

To check that these positive effects are caused by removing the zombie cells, rather than some other effect of the drug, the researchers also genetically modified some mice to remove the zombie cells, which had the same effect. “What is really exciting is that, when old mice that were given navitoclax have a heart attack, they survive and recover better,” says Dr Richardson. “In fact, they do almost as well as young mice.”

In future, when you start getting the signs of age-related diseases, you could take these drugs, suggests Dr Richardson.

The drug is already used as an experimental cancer drug, so could be safe to use. This could have wider benefits, too. Zombie cells are found in most organs as we age, as well as our arteries and veins. “In future, when you start getting the signs of age-related diseases, you could take these drugs,” suggests Dr Richardson.

But this won’t be the secret to eternal life. In mice, removing zombie cells doesn’t make them live much longer – but they do age more healthily. “We are not trying to make people live forever,” explains Dr Richardson, “but we are trying to give them a better quality of life." 

"Even if we can’t remove all the damage that has been caused by zombie cells,” he continues, “if we can improve the heart function, and that enables people to become more mobile and have a better standard of living, then that’s a big gain.”

The next steps in improving heart function

Before that, there is more work to do, starting with making sure the treatment is safe. “We do need to find out more about the long-term effects of removing these cells,” says Dr Richardson. “It may be that in the short term it helps people but in the long term it causes other problems. However, even if these drugs turn out not to work, our new understanding of how these cells form could help people in other ways.”

The next step will be to study these cells in the tissues of human hearts that have been donated to science. If that project is successful, they would look to move on to the first trials in humans in 2022 or 2023. “Hopefully one day we will see someone who has taken one of these drugs and their heart is working better, and they will have a better quality of life as a result,” says Dr Richardson. “That is what keeps us going.” 

Making a difference through research 

Dr Richardson came to this research because he is an expert in regeneration – the way cells reproduce themselves to make repairs where they are needed. He says: “I used to work on skin regeneration, but I left that area because I wanted to have a bigger impact on people. I thought I could have a real effect working on hearts.”

He’s been working on this project for the past five years, and studying the heart for nearly 10 years. “What I like about this research is you can really see how this will help people. It’s not often your job can make a difference to people’s lives.” 

He credits the BHF for allowing this research to happen. “I wouldn’t have got where I am without the BHF,” he says. The BHF funds members of his team as well as the project itself, and he is hoping that a future BHF grant will allow the research to go even further.

Dr Richardson standing in a research lab

 

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