New research exploring theories of ageing has found that small mutations accumulating in DNA are unlikely to be fully responsible for this process.
The research, a collaboration between the Wellcome Sanger Institute, University of Birmingham, University of Edinburgh and others, found that human cells and tissues can accumulate many more mutations than are normally present, without the body showing the features associated with ageing.
Image credit: Darryl Leja, NHGRI, Public Domain
The new study, published in Nature Genetics, compared DNA taken from individuals with inherited mutations in genes involved in DNA replication with DNA from individuals who have normal versions of these genes. The researchers aimed to understand the impact of defective DNA replication on cancer risk and features associated with ageing. The results 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 of the current models 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*. The model is based on the observation that mutations accumulate in normal cells throughout life, and theorises that the greater number of mutations in older people compared to younger people impairs the 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 be due to build-up of these types of mutations alone.
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 from the Wellcome Sanger Institute (including the Cancer Grand Challenges Mutographs team), University of Birmingham, and University of Edinburgh, applied recently developed 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.
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: Sanger Institute