This is the first study, published in Signal Transduction and Targeted Therapy, to show that a gene from long-lived people can slow down heart ageing in a progeria model. Also known as Hutchinson-Gilford Progeria Syndrome (HGPS), Progeria is a rare, fatal genetic condition of “rapid-ageing” in children.
HGPS is caused by a mutation in the LMNA gene, which leads to the production of a toxic protein called progerin. Most affected individuals die in their teens due to heart problems, although a few, like Sammy Basso, the oldest known person with progeria, have lived longer. Sadly, late last year (24 October) at the age of 28 Sammy passed away.
Progerin damages cells by disrupting the structure of their nucleus — the ‘control centre’ of the cell — leading to early signs of ageing, especially in the heart and blood vessels.
Currently, the only United States Food and Drug Administration (FDA)-approved treatment is a drug called lonafarnib, which helps reduce the build-up of progerin. A newer clinical trial is now testing lonafarnib in combination with another drug called Progerinin to see if the combination works better.
In this study, researchers from Bristol Heart Institute, Dr Yan Qiu and Professor Paolo Madeddu, in collaboration with Professor Annibale Puca’s team at IRCCS MultiMedica in Italy, sought to explore whether genes from supercentenarians could help protect children with Progeria from the damageing effects of progerin.
The team focused on a ‘longevity gene’ found in centenarians, called LAV-BPIFB4. Previous research has showed that this gene helps keep the heart and blood vessels healthy during ageing.
Using animal mice models genetically engineered to have Progeria, the research team were able to show early heart problems like those seen in children with the disease. The team found a single injection of the longevity gene helped improve heart function, specifically how the heart relaxes and fills with blood - called diastolic function.
It reduced heart tissue damage - called fibrosis - and decreased the number of ‘aged’ cells in the heart. The gene also boosted the growth of new small blood vessels, which could help keep heart tissue healthy.
The team then tested the effect of the longevity gene in human cells from Progeria patients. Their findings showed adding the longevity gene to these cells reduced signs of ageing and fibrosis, without changing progerin levels directly. This suggests the gene helps protect cells from the effects of progerin, rather than removing it. Importantly, the treatment doesn’t try to eliminate progerin but instead helps the body cope with its toxic effects.
Dr Yan Qiu, Honorary Research Fellow in the Bristol Heart Institute at the University of Bristol, said: “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 to a new type of therapy for Progeria; one based on the natural biology of healthy ageing rather than blocking the faulty protein. This approach, in time, could also help fight normal age-related heart disease.
“Our research brings new hope in the fight against Progeria and suggests the genetics of supercentenarians could lead to new treatments for premature or accelerated cardiac ageing, which might help us all live longer, healthier lives.”
Professor Annibale Puca, Research Group Leader at IRCCS MultiMedica and Dean of the Faculty of Medicine at the University of Salerno, added: "This is the first study to indicate that a longevity-associated gene can counteract the cardiovascular damage caused by progeria.
"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, the administration of the LAV-BPIFB4 gene through gene therapy could be replaced and/or complemented by new protein- or RNA-based delivery methods.
“We are currently conducting numerous studies to investigate the potential of LAV-BPIFB4 in counteracting the deterioration of the cardiovascular and immune systems in various pathological conditions, with the goal of translating these experimental findings into a new biologic drug."
Paper
‘A longevity-associated variant of the human BPIFB4 gene prevents diastolic dysfunction in progeria mice’ by Yan Qiu, Monica Cattaneo, Anna Maciag, Annibale A Puca, Paolo Madeddu in Signal Transduction and Targeted Therapy [open access]