Two new studies from Karolinska Institutet in Sweden have investigated how mutations that occur in muscles and blood vessels over time can affect ageing. The studies, which are published in Nature Aging, show that such mutations can reduce muscle strength and accelerate blood vessel ageing. The results can be of significance to the treatment of age-related diseases.

Somatic mutations are non-hereditary genetic changes in cells and occur during a lifetime as a result of environmental factors or through random errors when a cell copies its DNA before dividing. The mutations can give rise to cancer, but otherwise their effect has been disputed.

“We’ve discovered that mutations that accumulate in muscle cells and blood vessels can affect the tissue’s function and ability to regenerate – i.e. to replace damaged tissue with new healthy cells – an ability that also declines with age,” says principal investigator Maria Eriksson, professor at the Department of Medicine in Huddinge, Karolinska Institutet.

The same mutation as in progeria

In 2003, Professor Eriksson discovered the genetic cause of progeria, an inherited and extremely rare disease in children characterised by rapid ageing and cardiovascular complications. The child carries a mutation that leads to the formation of a pathogenic protein called progerin. Her research group has now been able to demonstrate the presence of the same mutation and protein in the blood vessels of some patients with chronic kidney disease.

“A somatic mutation has occurred in the patients’ vascular walls and we suspect that it’s related to the vascular damage that often accompanies kidney disease,” says the study’s first author Gwladys Revêchon, postdoc in Professor Eriksson’s group.

In complementary experiments in mice, the researchers discovered that cells that form progerin can propagate and cluster into groups of mutated cells that spread along the vascular walls, which can contribute to tissue damage and early vascular ageing.

The study combines basic and clinical research and was conducted in collaboration with Peter Stenvinkel, professor of nephrology at the Department of Clinical Science, Intervention and Technology at Karolinska Institutet and consultant at Karolinska University Hospital. He has established a large biobank of well-characterised material from patients, which has been crucial to the study.

“I’m very happy that we can now learn more about why people with kidney disease so easily become vascular compromised,” says Professor Stenvinkel.

Mutations affect muscle strength

In the second study, Professor Eriksson and her doctoral student Lara G. Merino and former postdoc Peter Vrtačnik used a mouse model to study how somatic mutations in muscles affect muscle strength. Such mutations accumulate during muscle regeneration, which is to say when muscles are rebuilt after having been damaged or strained.

An accumulation of somatic mutations in the muscles of mice led to impaired muscle regeneration, smaller muscle cells, lower muscle mass and reduced grip strength.

The results from both studies indicate that somatic mutations can reduce muscle strength and accelerate the ageing of the blood vessels.

“A better understanding of how somatic mutations affect the function of different tissues can help us develop new biomarkers and treatments for age-related diseases,” says Professor Eriksson. “Our findings also demonstrate the value of studying rare diseases since it can provide new approaches to more common conditions.”

The studies were primarily financed by grants from the Swedish Research Council, the Swedish Cancer Society, the European Research Council (ERC), the Center for Innovative Medicine (CIMED), the Loo and Hans Osterman Foundation for Medical Research and the Erik Rönnberg Award for Scientific Studies of Ageing and Age-related diseases. There are no reported conflicts of interest.