Gene variant present in centenarians stops decline in heart function

A gene variant with a protective effect comparable to 'rewinding the heart's biological clock by more than ten years' has been described by an international team of researchers.

The researchers, based at the University of Bristol and the MultiMedica group in Italy, previously studied the cardiovascular health of a group of centenarians often called 'super-agers'. Despite being over 100 years old, this group have lower rates of heart disease than normal 80-year-olds. In 2018, the improved heart health among the super-agers was linked to a unique mutation in the BPIFB4 gene. Now the researchers have investigated this finding further, to uncover the mechanism behind the protective effect of this variant. 

'Having good genes inherited from parents can help to stay young and healthy. Genes are sequences of letters that encode proteins. By chance, some of these letters can mutate. Most of these mutations are insignificant; in a few cases, however, the mutation can make the gene function worse or better', explained Professor Paolo Madeddu, who led the team of researchers at the University of Bristol.

The study, published in Cardiovascular Research, describes the mutated form of the BPIFB4 gene, named the longevity-associated variant because it is common among super-agers.

The team began by studying a group of cardiac cells called pericytes, which play an important role in forming new blood vessels. Pericytes do not function properly in older patients with heart failure. Using a technique known as gene therapy, which is the process of introducing new genes to correct or prevent certain diseases, the longevity-associated variant of BPIFB4 was delivered to pericytes collected from patients with heart failure. The BPIFB4 gene rejuvenated the pericytes and led to them functioning properly again.

Building upon their findings, the researchers performed gene therapy experiments in mice. The longevity-associated variant of BPIFB4 blocked the normal decline in heart function seen in middle-aged mice. Moreover, when the BPIFB4 longevity-associated variant was delivered to elderly mice, the signs of heart decline were reversed, meaning that the hearts of elderly mice functioned as effectively as the hearts of middle-aged mice. When translated to human cardiac function, the improvements seen in elderly mice would correspond to a reversal of the heart's biological age by ten years, the researchers suggest.

The findings from this study represent an opportunity to treat, and even possibly prevent, heart failure. However, further research is needed before this is a possibility. The team plan to look at how this therapy could be improved by delivering the BPIFB4 protein directly into mice. Furthermore, they have received approval to begin trials in children with a genetic disorder that causes early ageing of the heart and blood vessels.

Professor James Leiper, associate medical director at the British Heart Foundation, highlighted the significance of the recent work, 'This is still early-stage research, but could one day provide a revolutionary way to treat people with heart failure and even stop the debilitating condition from developing in the first place.'