In vitro and in vivo studies have shown how an anti-aging gene identified in a population of centenarians can reverse the biological age of the heart by ten years. The discovery, led by scientists from the University of Bristol and the MultiMedica Group in Italy, could represent a breakthrough that offers a potential target for heart failure patients.
In their newly reported study, the team, co-led by Paolo Madeddu, MD, Professor of Experimental Cardiovascular Medicine at the Bristol Heart Institute, University of Bristol, has shown that the longevity-associated variant (LAV) of the BPIFB4 gene, which is particularly frequent in centenarians, may protect cells collected from heart failure patients who need a heart transplant. The team also found that a single administration of the LAV-BPIFB4 gene stopped the decline of heart function in middle-aged mice. What is even more remarkable is that when administered to elderly mice – whose hearts show the same changes as in elderly patients – the gene rewinds the heart’s biological clock by the human equivalent of more than a decade.
The researchers’ in vitro and in vivo findings are reported in Cardiovascular examinationin a paper titled “The longevity-associated BPIFB4 gene support card function and vascularization in aging cardiomyopathy”, in which they concluded: “The current study integrates multiple lines of evidence supporting the protective role of LAV-BPIFB4 against aging-related heart disease. … These findings are open to the use of LAV-BPIFB4 to reverse the decline in cardiac performance in older people.”
Older people develop progressive heart dysfunction, for which there is no specific treatment, the authors noted. “…in addition, the use of common cardiovascular medications represents a clinical challenge in this category of patients.” Madeddu further explained, “Cardiac and vascular function comes into play as we age. However, the speed at which these harmful changes occur varies from person to person.” So while smoking, alcohol and a sedentary lifestyle speed up the aging clock, eating right and exercising slow down the heart’s aging clock, Madeddu continued. “Plus, having good genes inherited from parents can help you stay young and healthy.”
Associated with exceptional longevity, carriers of healthy mutant genes, such as those living in the blue zones of the planet, often live to live 100 years or more and remain in good health. These individuals are also less prone to cardiovascular complications. “Genes are sequences of letters that code for proteins,” Madeddu continued. “Coincidentally, some of these letters can mutate. Most of these mutations are insignificant; in some cases, however, the mutation can make the gene function worse or better, such as for the mutated anti-aging gene that we studied here on human cells and older mice.”
Intrigued by cases of long-lived individuals (LLIs), the researchers investigated genetic mechanisms that enable these people to avoid cardiovascular complications until the very last years of their lives. They had previously reported that carriers of a longevity-associated variant of the bactericidal/permeability-enhancing fold-20-containing-family-B-member-4 gene (BPIFB4) express high levels of BPIFB4 in blood, circulating mononuclear cells and vascular cells and have a low atherosclerotic risk. Their work had also shown that the LAV-BPIFB4 gene variant conferred broad protection in rodent models of cardiovascular disease. “…We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene have a longer health span and fewer cardiovascular complications,” they explained. “In addition, supplementation of LAV-BPIFB4 via an adeno-associated viral vector improves cardiovascular performance in limb ischemia, atherosclerosis and diabetes models.”
The team’s latest study aimed to investigate whether the LAV-BPIFB4 gene may also slow spontaneous aging of the heart. The team performed in vitro studies on tissue from elderly patients with ischemic heart failure (IHF) and healthy controls. Researchers at the MultiMedica Group in Milan, led by Annibale Puca, MD, administered the gene to heart cells from elderly patients with severe heart problems, then compared their function to cells from healthy individuals. Monica Cattaneo, PhD, a researcher from the MultiMedica Group, and first author of the reported work, explained: “The cells of older patients, particularly those that support the construction of new blood vessels, called ‘pericytes’, have been shown to perform less By adding the longevity gene/protein to the test tube, we saw a process of heart rejuvenation: the heart cells of older heart failure patients function properly again and appear to build new blood vessels more efficiently.”
As the researchers further noted, the results showed “a remarkable benefit of LAV-BPIFB4 supplementation on senescent vascular cells … LAV-BPIFB4 supplementation reduced the expression of senescence markers and improved angiogenic functions of PCs from aged, failing human hearts.”
The researchers also reported on their gene delivery experiments in live rodents, which showed that “gene therapy with LAVBPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in elderly mice by improving microvasculature density and pericyte coverage. The in vivo studies further demonstrated “a preventive and therapeutic effect of LAV-BPIFB4 gene therapy in animal models of cardiac aging…Translated to the human condition, the restoration of contractility indices seen in aged mice would correspond to the rewinding of the biological clock of the heart by more than ten years.”
Centenarians pass on their healthy genes to their offspring, but the new study shows for the first time that a healthy gene found in centenarians can be passed on to unrelated people to protect their hearts. In the future, other mutations may be found with similar or even superior curative potential to the one investigated in this study. Madeddu and Puca believe this study could spark a new wave of treatments inspired by the genetics of centenarians.
Madeddu added: “Our findings confirm that the healthy mutant gene can reverse the decline in heart performance in older people. We are now interested in determining whether giving the protein instead of the gene could also work. Gene therapy is being widely used. used to treat diseases caused by bad genes. However, a protein-based treatment is safer and more viable than gene therapy. We received funding from the Medical Research Council to test healthy gene therapy in Progeria. This genetic disease, also known as as Hutchinson-Gilford syndrome, causes premature aging damage to the hearts and blood vessels of children. We have also been funded by the British Heart Foundation and Diabetes UK to test the protein in elderly and diabetic mice respectively.”
Acknowledging the need for further research, the authors concluded: “More research is needed to determine the duration of the in vivo therapeutic effect and the need for repeated administrations. It remains to be determined whether the benefit observed in mice can be translated into therapeutic outcomes in advanced stages of heart failure.”
Puca, who is head of the lab of the IRCCS MultiMedica and a professor at the University of Salerno, further pointed out, “Gene therapy with the healthy gene has already been shown to prevent the onset of atherosclerosis, vascular aging, and diabetic disease in mouse models of disease. complications, and to rejuvenate the immune system.”We have a new confirmation and enhancement of the therapeutic potential of the gene/protein. We hope to soon test its effectiveness in clinical trials in patients with heart failure.” The team stated in their paper: “Additional efficacy/safety studies for regulatory approval of the gene/protein for longevity will determine whether this new technology can introduce a change in the prevention and treatment of age-related diseases, restoring health in instead of repairing the damage caused by aging.”
Professor James Leiper, PhD, Associate Medical Director at the British Heart Foundation, who part-funded the research, said: “We all want to know the secrets of aging and how to slow down age-related diseases. Our heart function declines with age, but this research has extraordinarily revealed that a variant of a gene commonly found in longevity humans can halt and even reverse heart aging in mice This is still early stage research but it could one day could be a revolutionary way to treat people with heart failure and even prevent the debilitating condition from developing in the first place.”