A breakthrough offers a potential target for treating heart failure patients.
An anti-aging gene found in centenarians has been shown to reverse the heart’s biological age by 10 years. This groundbreaking discovery, published in the journal Cardiovascular Research and led by scientists from the University of Bristol and MultiMedica Group in Italy, offers a potential target for heart failure patients.
Individuals who carry healthy mutant genes, commonly found in populations known for exceptional longevity such as the “blue zones,” often live to 100 years or more and remain in good health. These carriers are also less susceptible to cardiovascular complications. Scientists funded by the British Heart Foundation believe the gene helps keep their hearts youthful by guarding against diseases related to aging, such as heart failure.
In this new study, researchers demonstrate that one of these healthy mutant genes, previously proved particularly frequent in centenarians, can protect cells collected from patients with heart failure requiring cardiac transplantation.
The Bristol team, led by Professor Paolo Madeddu, has found that a single administration of the mutant anti-aging 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.
Professor Madeddu, Professor of Experimental Cardiovascular Medicine from Bristol Heart Institute at the University of Bristol and one of the study’s authors, 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. Smoking, alcohol, and sedentary life make the aging clock faster. Whereas eating well and exercising delay the heart’s aging clock.
“In addition, 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, like for the mutant anti-aging gene we have studied here on human cells and older mice.”
The three-year study was also performed in test tube human cardiac cells in Italy. Researchers from the MultiMedica Group in Milan led by Professor Annibale Puca, administered the gene in heart cells from elderly patients with severe heart problems, including transplantation, and then compared their function with those of healthy individuals.
Monica Cattaneo, a researcher of the MultiMedica Group in Milan, Italy, and first author of the work said: “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.”
Centenarians pass their healthy genes to their offspring. The 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. Professor Madeddu and Professor Annibale Puca of the MultiMedica Group in Milan believe this study may fuel a new wave of treatments inspired by the genetics of centenarians.
Professor 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.”
Annibale Puca, Head of the laboratory at the IRCCS MultiMedica and Professor at the University of Salerno, added: “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.”
Professor James Leiper, Associate Medical Director at the British Heart Foundation, which 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 the 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.”
Reference: “The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy” by Monica Cattaneo, Antonio P Beltrami, Anita C Thomas, Gaia Spinetti, Valeria Vincenza Alvino, Elisa Avolio, Claudia Veneziano, Irene Giulia Rolle, Sandro Sponga, Elena Sangalli, Anna Maciag, Fabrizio Dal Piaz, Carmine Vecchione, Aishah Alenezi, Stephen Paisey, Annibale A Puca and Paolo Madeddu, 13 January 2023, Cardiovascular Research.
The study was funded by the British Heart Foundation and the Italian Ministry of Health.