The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy

Professor Paolo Madeddu and his team are working to delay the ageing of the heart. He tells Dr Leanne Grech how this research could allow older people to live a healthier life for longer.

The BPIFB4 gene has been associated with exceptional longevity

Each day, your heart beats around 100,000 times, pumping about eight pints of blood around your body. By the time you are 20, the heart’s function can begin to decline as part of normal ageing. As you get older, activities like running or playing tennis become more difficult. However, some 100-year-olds, like those living in Okinawa, a cluster of islands in southern Japan, appear to have unlocked the secret to a long and healthy life, with some of them seemingly having a heart younger than their age. “It’s a combination of a good lifestyle and good genes,” explains Professor Paolo Madeddu at the University of Bristol. “And we have discovered that one of these good genes can stop ageing.”

The gene that can stop ageing Professor Madeddu and his team have discovered that a naturally occurring variant of the BPIFB4 gene, which is more common in people who live to 100 or more, could help keep the heart young. A gene variant is a permanent change in the DNA sequence that makes up a gene. The team have already learned that mice treated with this variant have healthier hearts. In fact, transferring this gene variant to old mice seemed to help relax blood vessels in mice with high blood pressure and increase the amount of blood delivered to the muscles. In humans, ageing can affect many parts of the body, including weakening the heart and circulatory system. For example, heart failure, a serious and sometimes disabling condition for which there is no cure other than a heart transplant. Symptoms include breathlessness and feeling abnormally tired. Heart failure can occur at any age, but it is more common in older people, and in people who have had a heart attack and who have cardiomyopathy or high blood pressure.

Scientists are now beginning to understand how some natural variations in our genes might protect against heart diseases linked to ageing, such as heart failure. In this study, Professor Madeddu and his team in Bristol have been funded by the BHF with more than £172k to further investigate the role of the BPIFB4 gene variant. The BPIFB4 gene has been associated with exceptional longevity, helping protect against atherosclerosis (build-up of fatty material inside your arteries) and high blood pressure. The team now want to know if this gene variant can be given as a tablet and if it can reduce chronic inflammation (a damaging set of processes often seen in ageing hearts). Most genes contain the information needed to make functional molecules called proteins. Giving the corresponding protein as a pill instead of the gene variant could be an easier way to get the same result. Professor Madeddu and his team will test this idea in mice. If it succeeds, they hope to go on to a clinical trial in humans. “The study will provide proof of concept that our solution is valid. More studies are needed to show it is also safe – the fact that it is a human protein and not a [new] drug is encouraging. However, producing large quantities of protein is extremely expensive, and we will need investors or an industrial partner in the future. The BHF could help us to find the right partner,” explains Professor Madeddu.

I hope that the results of my work can make a difference in the lives of a lot of patients.

Helping older hearts Professor Madeddu is a cardiologist by background, and has been fascinated by the heart since he was a medical student. “Research requires a lot of determination and effort. I hope that the results of my work can make a difference in the lives of a lot of patients.” In 2021, around 12.5 million people in the UK were 65 or older. Life expectancy had been rising for decades, but the increases have slowed since 2010, and life expectancy for both men and women has fallen since the Covid-19 pandemic. Research like that of Professor Madeddu aims to help older adults stay healthy and independent for longer, which is among the UK Government priorities. “There is no current treatment to stop the heart’s ageing, and drugs used for heart disease can cause side effects in seniors,” explains Professor Madeddu. “We hope that giving older people a protein that is present in healthy centenarians, like those in Okinawa, helps their hearts work better for longer. Our approach proposes to increase health rather than simply combat disease. If we can find an effective treatment to delay ageing of the heart, we may be able to prevent serious disease in older people.”

Read the case report

Monica Cattaneo , Antonio P Beltrami , Anita C Thomas , Gaia Spinetti , Valeria Alvino , Elisa Avolio , Claudia Veneziano , Irene Giulia Rolle , Sandro Sponga , Elena Sangalli , Anna Maciag , Fabrizio Dal Piaz , Carmine Vecchione 4,5 , Aishah Alenezi , Stephen Paisey , Annibale A Puca , Paolo Madeddu The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy.  Cardiovasc Res. 2023 Jan 13;cvad008. PMID: 36635236 DOI: 10.1093/cvr/cvad008.

Stem cell plasters to stop children needing repeated heart surgeries

Researchers at the University of Bristol, funded by the British Heart Foundation (BHF), have developed ‘stem cell plasters’ to revolutionise the way surgeons treat children living with congenital heart disease, so they don’t need as many open-heart operations.

Heart defects are the most common type of anomaly that develop before a baby is born, with around 13 babies diagnosed with a congenital heart condition every day in the UK.  These include defects to the baby’s heart valves, the major blood vessels in and around the heart, and the development of holes in the heart.

Currently, for many of these children, surgeons can perform open-heart surgery to temporarily repair the problem, but the materials used for the patches or replacement heart valves are not completely biological and cannot grow with the baby. This means they can be rejected by the patient’s immune system which causes the surgical materials to gradually break down and fail in a few months or years.

A child might therefore have to go through the same heart operation multiple times throughout its childhood, which keeps them in hospital for weeks at a time, hugely impacts their quality of life and causes a lot of stress for the family.

Now, BHF Professor Massimo Caputo has developed the first type of stem cell patch to repair abnormalities to the valve in the large blood vessel that controls blood flow from the heart to the lungs, and to mend holes between the two main pumping chambers of the heart.

The stem cell plasters are designed to be sewn into the area of the child’s heart that needs repairing during surgery. The stem cells could then boost the repair of heart tissue without being rejected by the child’s body.

These patches have the potential to adapt and grow with the child’s heart as they get older, removing the need for repetitive heart surgeries and the many days at hospital recovering after each one.

There are around 200 repeat operations for people living with congenital heart disease every year in the UK. The technology could save the NHS an estimated £30,000 for every operation no longer needed, saving millions of pounds each year.

The BHF has awarded Professor Caputo nearly £750,000 with the aim to get these patches ready for testing in patients so clinical trials can start in the next two years, enabling more children and babies to benefit from the life-altering technology. The materials have already proven to work safely in animals.

The team is also in the early stages of developing other stem cell technologies using 3D bioprinting and gene therapy to one day be able to mend more complex congenital heart defects.

Massimo Caputo, BHF Professor of Congenital Heart Surgery at the Bristol Heart Institute, University of Bristol, said: “For years families have come to us asking why their child needs to have heart surgery time and time again. Although each operation can be lifesaving, the experience can put an unbelievable amount of stress on the child and their parents. We believe that our stem cell patches will be the answer to solve these problems.

“Our ultimate vision in the next decade is to create a paradigm shift in the way doctors treat congenital heart disease, by developing personalised stem cell and genetically-engineered treatments for the most complex of heart defects.”

Dr Sonya Babu-Narayan, Associate Medical Director at the British Heart Foundation, added: “If successful, this new stem cell therapy that acts like a healing plaster could revolutionise the results of heart surgery for children and adults living with congenital heart disease.

“It could offer a solution that means their heart is mended once and forever in a single operation, preventing people from facing a future of repeated surgeries and giving them the gift of a happier and healthier life.”

The work was partly funded by the National Institute of Health and Care (NIHR) Bristol Biomedical Research Centre (NIHR Bristol BRC), a partnership between University Hospitals Bristol and Weston NHS Foundation Trust (UBHW) and the University of Bristol.