Small mutations accumulating in DNA are unlikely to be fully responsible for ageing, according to a new study.
The research, published in Nature Genetics last night, compared DNA from individuals with inherited mutations in genes involved in DNA replication with DNA from individuals who have normal versions of these genes.
The aim of the research, carried out by scientists at the Wellcome Sanger Institute, University of Birmingham, University of Edinburgh and others, was to understand the impact of defective DNA replication on cancer risk and features associated with ageing.
They found that human cells and tissues can accumulate many more mutations, without the body showing the features associated with ageing, leading them to conclude that build-up of mutations in normal cells is unlikely to be the only factor in the development of age-related disease.
A study published last year suggested that accumulation of mutations in the DNA of healthy cells results in the changes we see as the body grows older.
The model is based on the observation that mutations accumulate in normal cells throughout life. It had been thought that the increasing number of mutations in older people impairs the function of genes and disturbs cell function.
However, this new research shows that human cells and tissues can function normally with many more mutations than are usually present, the researchers say.
Researchers from the Wellcome Sanger Institute, including the Cancer Grand Challenges Mutographs team, University of Birmingham, and University of Edinburgh, sequenced the DNA of normal cells and tissues from patients who have inherited mutated versions of the DNA polymerase genes, POLE and POLD1.
When they compared tissue samples with unaffected individuals, they found that normal tissue from those with the faulty DNA polymerase had elevated mutation rates.
However, these participants did not show features of early onset ageing or age-related diseases despite having accumulated numbers of mutations that would have made them hundreds of years old in terms of their “mutational age”.
Co-first author Dr Phil Robinson, 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.”
Co-first author Dr Claire Palles, Birmingham fellow at the Institute of Cancer and Genomic Sciences at the University of Birmingham, added: “Knowing the impact of different polymerase mutations on the genetic material in cells is crucial if we are to fully understand the risk of patients with these mutations developing certain cancers and age-related disease.
“By showing that healthy cells can contain as many mutations as some cancer cells do, it emphasises that there are more factors that go into making a cell cancerous than mutational burden.”
Senior Professor Sir Mike Stratton, 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.”
Robinson, T. Coorens, C. Palles, et al. (2021) Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nature Genetics 30 September 2021. DOI: 10.1038/s41588-021-00930-y
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