Researchers have found that human cells and tissues cells tolerate many more mutations than previously thought, without impacting their function or showing the features associated with ageing.
To understand the impact of defective DNA replication on cancer risk and features associated with ageing, researchers compared DNA taken from individuals with inherited mutations in genes involved in DNA replication with DNA from individuals with normal versions of these genes. The results, published in Nature Genetics, suggest that build-up of mutations in normal cells is unlikely to be the only factor in the development of age-related disease, adding to the ongoing debate about the causes of ageing.
One model of ageing suggests that accumulation of mutations in the DNA of healthy cells results in the changes that we see as the body grows older. This model is based on the observation that mutations accumulate in normal cells throughout life, theorising that the older people having more mutations compared to younger people results in impaired function of genes and disturbs cell function, ultimately leading to diseases of old age and the visible features typically associated with ageing.
However, this new research shows that human cells and tissues can function apparently normally with many more mutations than are usually present, suggesting that ageing may not solely be due to buildup of such mutations.
DNA replication is required to duplicate the DNA in a cell ready for cell division. It involves creating an entire error-free copy of the human genome from the existing strand, and is undertaken with very high accuracy in normal healthy cells by proteins called DNA polymerases. When the DNA polymerases have a mutation, causing them to be faulty, it leads to more DNA errors, or small mutations, accumulating with each and every cell replication.
In this study, researchers applied new 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.
By comparing tissue samples with unaffected individuals, they found that normal tissues from those who had a faulty DNA polymerase had elevated mutation rates. These study participants did not, however, 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’. Therefore, other than an increased risk of certain cancers, the research shows that cells can accumulate many mutations and not show features associated with ageing, challenging the current model.
Further research is therefore needed to understand the biological processes underlying ageing.
Source: Wellcome Trust Sanger Institute
