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Effects of ageing are ‘not due to DNA mutations alone’, Wellcome Sanger Institute and collaborators find





What is it that causes the changes we see in our bodies as we age?

It has been thought that an accumulation of mutations in the DNA of healthy cells as we grow older was responsible for the visible features we associate with ageing, along with diseases of old age.

That theory suggests the greater number of mutations found in older people’s genetic code impairs the functions of genes and disturbs cells functions

But new research, published in Nature Genetics, suggests that is unlikely to be the full story.

Scientists from the Wellcome Sanger Institute - including the Cancer Grand Challenges Mutographs team - along with researchers at the University of Birmingham and University of Edinburgh, applied cutting-edge techniques to sequence the DNA of normal cells and tissues from patients who have inherited mutated versions of the DNA polymerase genes, POLE and POLD1.

They compared tissue samples with unaffected individuals and found that normal tissues from those who had a faulty DNA polymerase had elevated mutation rates.

However, these individuals did not have features of early onset ageing or age-related diseases, despite having accumulated numbers of mutations that would, in terms of their ‘mutational age’, have made them hundreds of years old.

Other than an increased risk of certain cancers, the work demonstrates that cells can accumulate many mutations and not show features associated with ageing.

Dr Phil Robinson, co-first author and Wellcome Clinical PhD fellow at the Wellcome Sanger Institute, said: “By focusing on people who have a known increased risk of cancer, we discovered that most or potentially all of the cells in these individuals carry an increased burden of mutations. We were amazed to see that normal and seemingly healthy cells could tolerate so many mutations.

“This research has given us an insight into the potential reasons for their increased risk of cancer and also offers an immensely valuable window into the process of ageing.”

Professor Sir Mike Stratton, senior author and director of the Wellcome Sanger Institute, said: “Understanding why our cells age and the mechanisms behind ageing may help us find new ways to protect against age-related disease. This research indicates that accumulation of mutations during the course of a lifetime is unlikely, on its own, to account for the constellation of features that we term ageing. Further studies are therefore required to understand what changes occurring in cells during life cause the behaviours associated with ageing.”

Dr David Scott, director of Cancer Grand Challenges at Cancer Research UK, added: “The Cancer Grand Challenges Mutographs team is making incredible progress in helping us better understand the roles mutations play in tumour development. But as this study shows, the scope of the team’s work goes beyond cancer and is helping us to understand more about mutations in normal tissue and even the processes of ageing.”

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