Accumulation of somatic mutations drives vascular damage in people with progeria

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder that causes remarkable premature aging. Most patients die during their teenage years from cardiovascular disease, but the precise mechanisms underlying vascular damage remain unclear.

In the new study, researchers analyzed cells from the aorta of mice carrying the same genetic mutation found in people with progeria. Using single-cell RNA sequencing, which enables gene activity to be studied in individual cells, they tracked how the vascular wall changes over time. In total, nearly 9,000 cells from mice of different ages were analyzed.

This approach allows us to follow, step by step, how different cell types are affected throughout the course of the disease."

Maria Eriksson, Professor, Department of Medicine, Huddinge, Karolinska Institutet

The researchers focused particularly on vascular smooth muscle cells, which provide blood vessels with strength and elasticity and are essential for normal vascular function. They observed that these cells gradually declined in number.

"Smooth muscle cells are progressively lost both in HGPS and during normal aging. As these cells die, the vessel wall becomes weaker and more susceptible to disease," says Lara Garcia Merino, doctoral student at the same department and first author of the study.

The study also showed that smooth muscle cells accumulated higher numbers of so-called somatic mutations, meaning genetic alterations that arise during an individual's lifetime. The mutation burden was associated with increased cellular stress and activation of genes involved in DNA damage responses.

"This is the first evidence that the accumulation of somatic mutations is a hallmark of vascular disease in HGPS," says Maria Eriksson.

The findings link DNA damage to cellular stress, loss of cellular identity and cell death, thereby revealing a previously unrecognized mechanism driving irreversible vascular injury.

The researchers also found evidence that changes in cell behavior may be influenced by signalling between different cell types within the vessel wall, suggesting that the process is not driven solely by alterations within individual cells.

"We see that cells undergo multiple changes over time, from stress to identity changes and ultimately cell death. Our results suggest that several different mechanisms interact in the development of vascular damage in progeria," says Lara Garcia Merino.

The researchers believe that the findings may contribute to a better understanding of how vascular damage develops in progeria and underline the importance of initiating treatment early, before irreversible DNA damage has accumulated.

"New gene-editing approaches can correct the disease-causing mutation in HGPS, but correcting the mutation alone is unlikely to reverse damage in cells that have already accumulated a large number of somatic mutations. Early intervention is therefore essential," says Maria Eriksson.

The study also provides new insights into the biological processes underlying normal vascular aging. Several important similarities exist between HGPS and the cardiovascular disease that affects the general population. HGPS is therefore widely used as a model for understanding normal aging and vascular disease.

The researchers emphasize that further studies are needed to confirm the findings in humans.

The study was conducted in collaboration with researchers from, among others, the Indian Institute of Technology in India and the University of Bergen in Norway. The research was funded by the Swedish Research Council, the European Research Council (ERC), the Swedish Cancer Society and the Center for Innovative Medicine, among others.