BOSTON (WHN) – A gene associated with extreme longevity may offer a novel approach to treating Hutchinson-Gilford Progeria Syndrome (HGPS), a rare and fatal genetic disorder that causes children to age rapidly. Researchers from the University of Bristol and IRCCS MultiMedica have demonstrated that a gene found in centenarians can mitigate cardiovascular damage in preclinical models of Progeria.
The study, published in Signal Transduction and Targeted Therapy, is the first to explore the protective effects of a “longevity gene” against the accelerated heart aging characteristic of HGPS. This research introduces a potential therapeutic strategy focused on enhancing cellular resilience rather than directly targeting the disease-causing protein.
Progeria is caused by a mutation in the LMNA gene, leading to the production of a toxic protein called progerin. Progerin destabilizes the cell nucleus, the organelle that controls cellular activity. This disruption accelerates aging, particularly in the cardiovascular system, and is the primary cause of mortality in affected children, who typically die from heart complications in their teenage years.
Currently, the United States Food and Drug Administration (FDA) has approved lonafarnib, a drug that helps reduce progerin accumulation. Investigations are also underway to assess the combination of lonafarnib with an experimental drug, Progerinin, for potential synergistic effects.
The current investigation sought to determine if genes from individuals who live to exceptionally old age—supercentenarians—could confer protection against the cellular damage seen in Progeria. Dr. Yan Qiu of the Bristol Heart Institute and Professor Paolo Madeddu collaborated with Professor Annibale Puca’s team at IRCCS MultiMedica on this objective.
Their focus was on LAV-BPIFB4, a gene previously identified for its role in supporting healthy heart and blood vessel function during aging.
To test this hypothesis, the researchers utilized genetically engineered mice that exhibit Progeria-like cardiac abnormalities. Following a single administration of the LAV-BPIFB4 gene, these mice displayed notable improvements in heart function. Specifically, their diastolic function—the heart’s ability to relax and fill with blood—was enhanced. The gene treatment also resulted in a reduction of cardiac fibrosis, a type of scarring in heart tissue, and a decrease in the number of senescent, or “aged,” cells within the heart. Furthermore, the treatment appeared to stimulate the formation of new small blood vessels, potentially bolstering cardiac health and resilience.
Experiments were also conducted on human cells derived from patients with Progeria. Introducing the LAV-BPIFB4 gene into these cells led to a reduction in cellular aging and fibrosis. Importantly, this effect was observed without directly altering progerin levels. The findings suggest that the longevity gene may help cells better withstand the detrimental effects of progerin, essentially bolstering the cell’s intrinsic defense mechanisms rather than directly neutralizing the toxic protein.
Dr. Yan Qiu, an Honorary Research Fellow at the Bristol Heart Institute, commented on the findings, stating, “Our research has identified a protective effect of a ‘supercentenarian longevity gene’ against progeria heart dysfunction in both animal and cell models.”
“The results offer hope for a new type of therapy for Progeria,” Dr. Qiu continued, “one based on the natural biology of healthy aging rather than blocking the faulty protein. This approach, in time, could also help fight normal age-related heart disease.” He added that their work suggests “the genetics of supercentenarians could lead to new treatments for premature or accelerated cardiac aging.”
Professor Annibale Puca, Research Group Leader at IRCCS MultiMedica, highlighted the study’s novelty. “This is the first study to indicate that a longevity-associated gene can counteract the cardiovascular damage caused by progeria,” he stated.
Professor Puca noted that the results “pave the way for new treatment strategies for this rare disease, which urgently requires innovative cardiovascular drugs capable of improving both long-term survival and patient quality of life.” Looking ahead, he indicated that “the administration of the LAV-BPIFB4 gene through gene therapy could be replaced and/or complemented by new protein- or RNA-based delivery methods.”
His team is currently undertaking further research to investigate the potential of LAV-BPIFB4 in addressing cardiovascular and immune system deterioration across various pathological conditions, with the ultimate goal of developing a new biologic drug.