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Anti-Ageing Gene LAV-BPIFB4: A Breakthrough for Heart Health?

In a recent study published in the journal Cardiovascular Research, researchers investigated whether the longevity-associated variant of the bactericidal/permeability-increasing fold21 containing-family-B-member-4 gene (LAV-BPIFB4) could be used to reverse heart damage due to ageing.

Researchers have previously explored the genetic mechanisms that allow long-living individuals to avoid cardiovascular complications until the very last years of their lives. They found that carriers of LAV-BPIFB4 express high levels of BPIFB4 in the blood, circulating mononuclear cells, vascular cells and have low atherosclerotic risk despite their age. In this study, researchers funded by the British Heart Foundation and the Italian Ministry of Health investigated how LAV-BPIFB4 works to delay the ageing of the heart.

The secret to a long life

As we all know, age comes with many problems, cardiovascular dysfunction being a common issue. This includes a decrease in the ability of the heart’s ventricles to relax and contract, as well as thickening and stiffening of the coronary arteries. Structural and functional changes in cardiomyocytes, endothelial cells and fibroblasts are all associated with microvascular rarefaction – the loss of small blood vessels such as arterioles and capillaries. More recent evidence has suggested that pericyte coverage is reduced – pericytes are cells along the walls of capillaries – which leads to a weakening in cellular cross-talk between neighbouring cells. The mechanistic effects of ageing on human cardiac cells are still unknown, and there is no specific treatment to stop the progression of cardiac dysfunction in the elderly.

Many studies sparked by the intriguing case of long-living individuals – those who often live to 100 years or more in exceptional health – have looked to investigate the secret to their long healthy lives. These individuals are less prone to cardiovascular complications, and previous studies have shown that long-living individuals are often carriers of the LAV-BPIFB4 gene. The researchers of this study set out to investigate how the LAV-BPIFB4 gene works to help these individuals have good heart health for so long, and whether LAV-BPIFB4 can be a potential therapeutic target to halt the progression of cardiac dysfunction in elderly patients.

How does LAV-BPIFB4 work?

This study used many different methods to investigate the protective role of LAV-BPIFB4 including immunohistochemistry on human heart samples from patients with end-stage ischemic heart failure and gene therapy experiments with LAV-BPIFB4 in mice. They found that reduced BPIFB4 expression was found in elderly failing human hearts and was associated with microvascular rarefaction and reduced pericyte coverage. LAV-BPIFB4 supplementation improved angiogenic functions and reduced senescence markers of aged failing human heart pericytes. NCL was found to provide a sub-cellular platform for LAV-BPIFB4 to regulate the transcription of angiogenesis and mediate pro-angiogenic processes. LAV-BPIFB4 gene therapy increased systolic and diastolic function, basal perfusion, and coronary flow response, improved vascularization and pericyte coverage, and reduced cellular senescence and collagen accumulation in the ageing murine heart.

A treatment to stop heart ageing?

This study demonstrates the impact of genetics on heart function and vascularization, but more research is needed to determine the effectiveness and safety of the LAV-BPIFB4 gene/protein as a therapy. It remains uncertain if the results from mice can be replicated in humans with advanced heart failure. Further studies will determine if this can be a potential therapy to prevent and treat age-related disease by restoring health, rather than just mitigating the spontaneous cardiac damage caused by ageing.

Professor Madeddu, an author of the study, said “Our findings confirm the healthy mutant gene can reverse the decline of heart performance in older people. We are now interested in determining if giving the protein instead of the gene can also work. Gene therapy is widely used to treat diseases caused by bad genes. However, a treatment based on a protein is safer and more viable than gene therapy. We have received funding from the Medical Research Council to test healthy gene therapy in Progeria. This genetic disease, also known as Hutchinson-Gilford syndrome, causes early ageing damage to children’s hearts and blood vessels. We have also been funded by the British Heart Foundation and Diabetes UK to test the protein in older and diabetic mice, respectively.”

More on these topics

Ageing / Cardiovascular disease / Heart