In vitro and in vivo studies have shown how an anti-aging gene identified in a population of centenarians can rewind the heart’s biological age by ten years. The discovery, led by scientists at the University of Bristol and the MultiMedica Group in Italy, could represent a breakthrough that offers a potential target for patients with heart failure.

In their newly reported research, the team, co-led by Paolo Madeddu, MD, Professor of Experimental Cardiovascular Medicine at the Bristol Heart Institute, University of Bristol, demonstrated that the longevity-associated variant (LAV) of the BPIFB4 gene, which is particularly frequent in centenarians, can protect cells collected from patients with heart failure requiring cardiac transplantation. The team also found that a single administration of the LAV-BPIFB4 gene, halted the decay of heart function in middle-aged mice. Even more remarkably, when given to elderly mice – whose hearts exhibit the same alterations observed in elderly patients – the gene rewound the heart’s biological clock age by the human equivalent of more than ten years.

The researchers’ in vitro and in vivo findings are reported in Cardiovascular Research, in a paper titled “The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy,” in which they concluded, “The present study integrates multiple, mutually supporting lines of evidence for the protective role of LAV-BPIFB4 against age-related heart disease … These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.”

Older people develop progressive cardiac dysfunction, for which there is no specific treatment, the authors noted. “… moreover, the use of common cardiovascular medications represents a clinical challenge in this category of patients.” Madeddu further explained, “The heart and blood vessel function is put at stake as we age. However, the rate at which these harmful changes occur is different among people.” So while smoking, alcohol, and sedentary life make the aging clock faster, eating well and exercising delay the heart’s aging clock, Madeddu continued. “In addition, having good genes inherited from parents can help to stay young and healthy.”

Associated with exceptional longevity, carriers of healthy mutant genes, like those living in blue zones of the planet, often live to 100 years or more and remain in good health. These individuals are also less prone to cardiovascular complications. “Genes are sequences of letters that encode proteins,” Madeddu continued. “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, like for the mutant anti-aging gene we have studied here on human cells and older mice.”

Intrigued by cases of long-living individuals (LLIs), the researches have been investigating genetic mechanisms that allow 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-increasing fold-20 containing-family-B-member-4 gene (BPIFB4) express high levels of BPIFB4 in blood, circulating mononuclear cells, and vascular cells, and have low atherosclerotic risk. Their work had also indicted that the LAV-BPIFB4 gene variant offered broad protection in rodent models of cardiovascular disease. “… We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications,” they stated. “Moreover, 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 was designed to investigate whether the LAV-BPIFB4 gene could also delay the heart’s spontaneous aging. The team carried out in vitro studies on tissue from elderly patients with ischemic heart failure (IHF) and healthy controls. Researchers from the MultiMedica Group in Milan led by Annibale Puca, MD, administered the gene to heart cells from elderly patients with severe heart problems, and then compared their function with those of cells from healthy individuals. Monica Cattaneo, PhD, a researcher of the MultiMedica Group, and first author of the reported work, explained, “The cells of the elderly patients, in particular those that support the construction of new blood vessels, called ‘pericytes’, were found to be less performing and more aged. By adding the longevity gene/protein to the test tube, we observed a process of cardiac rejuvenation: the cardiac cells of elderly heart failure patients have resumed functioning properly, proving to be more efficient in building new blood vessels.”

As the investigators further commented, the results demonstrated “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 LAV-BPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage.” The in vivo studies further demonstrated “a preventative and therapeutic action of LAV-BPIFB4 gene therapy in animal models of cardiac aging … Translated to the human condition, the recovery of contractility indexes seen in older mice would correspond to rewinding the heart’s biological clock by more than ten years.”

Centenarians pass their healthy genes to their offspring, but the new study demonstrates for the first time that a healthy gene found in centenarians could be transferred to unrelated people to protect their hearts. Other mutations might be found in the future with similar or even superior curative potential than the one investigated by this research. Madeddu and Puca believe this study may fuel a new wave of treatments inspired by the genetics of centenarians.

Madeddu added: “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 aging 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.”

The authors acknowledged the need for further research, concluding, “More investigation is needed to determine the duration of the in vivo therapeutic effect and the necessity of repeated administrations. It remains to be ascertained whether the benefit observed in mice can be translated into therapeutic results at advanced stages of heart failure.”

Puca, who is head of the laboratory at the IRCCS MultiMedica and Professor at the University of Salerno, further pointed out, “Gene therapy with the healthy gene in mouse models of disease has already been shown to prevent the onset of atherosclerosis, vascular aging, and diabetic complications, and to rejuvenate the immune system. “We have a new confirmation and enlargement of the therapeutic potential of the gene/protein. We hope to test its effectiveness soon in clinical trials on patients with heart failure.” The team stated in their paper, “Additional efficacy/safety studies toward regulatory approval of the longevity gene/protein will determine if this new technology can introduce a change in the prevention and treatment of age-related disease, restoring health rather than amending the damage inflicted by aging.”

Professor James Leiper, PhD, Associate Medical Director at the British Heart Foundation, which part funded the research, said, “We all want to know the secrets of aging and how we might slow down age-related disease. Our heart function declines with age but this research has extraordinarily revealed that a variant of a gene that is commonly found in long-lived people can halt and even reverse aging of the heart in mice. 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.”

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