Researchers announced on July 31 that the accumulation of somatic mutations may drive vascular damage in people with Hutchinson-Gilford progeria syndrome (HGPS), a genetic disorder characterized by premature aging. Most individuals with HGPS die during their teenage years from cardiovascular disease, but the mechanisms behind this vascular damage have remained unclear.
In the study, scientists analyzed nearly 9,000 cells from the aorta of mice carrying the same genetic mutation found in people with progeria. Using single-cell RNA sequencing to track gene activity over time, they observed a gradual decline in vascular smooth muscle cells—cells that provide blood vessels with strength and elasticity.
"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," said Lara Garcia Merino, doctoral student and first author of the study.
The research revealed that smooth muscle cells accumulated higher numbers of somatic mutations—genetic alterations arising during an individual's lifetime—which were linked to increased cellular stress and activation of DNA damage response genes. "This is the first evidence that the accumulation of somatic mutations is a hallmark of vascular disease in HGPS," said Maria Eriksson.
The findings suggest DNA damage leads to cellular stress, loss of identity, and cell death within blood vessels. The researchers also noted evidence for signaling between different cell types influencing these changes. "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," said Garcia Merino.
The team concluded that early intervention is crucial for treating HGPS before irreversible DNA damage occurs. "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," said Eriksson.
Further studies are needed to confirm these findings in humans.
