A new study finds that the accumulation of small DNA mutations is not sufficient to explain development of age-related disease. The researchers compared DNA taken from about a dozen people with inherited POLE or POLD1 exonuclease domain mutations with samples from non-affected people. Build-up of mutations in normal cells, they say, is unlikely to be the only factor in the development of age-related disease.
They write that, “Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging.”
The research was a collaboration between the Wellcome Sanger Institute, University of Birmingham, University of Edinburgh, and others. Their work was published this week in Nature Genetics,
A popular model of aging suggests accumulation of mutations in the DNA of healthy cells drive age-related changes. This model is based on the observation that mutations accumulate in normal cells throughout life, and theories 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 aging.
However, this new research shows that human cells and tissues can function apparently normally with many more mutations than are usually present, suggesting that aging may not be due to build-up of these types of mutations alone.
Phil Robinson, co-first author and a fellow at the Wellcome Sanger Institute, said: “Our research shows that a higher mutational burden does not appear to result in early onset signs and features that we typically associate with aging. While other types of mutations could potentially play a role, it suggests that there is a more complex process behind ageing than the accumulation of mutations alone.”
DNA replication is required for cell division and involves creating an entire error-free copy of the human genome from the existing strand. It is undertaken with very high accuracy in normal healthy cells by DNA polymerases. Mutations in these cause 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, sequenced the DNA of normal cells and tissues from patients who inherited mutated versions of the DNA polymerase genes, POLE and POLD1.
Both POLE and POLD1 have proofreading activities mediated by their exonuclease domains, which identify and remove mismatched bases. Somatic mutations in the POLE or POLD1 exonuclease domains can cause defective proofreading and, consequently, high burdens of somatic mutations with distinctive mutational signatures in tumors.
By comparing these tissue samples with those of unaffected individuals, the researchers found that tissues with faulty DNA polymerase had elevated mutation rates. These study participants did not, however, show features of early onset aging 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’. Other than an increased risk of certain cancers, the research shows that cells can accumulate many mutations and still not show features associated with aging.
Professor Sir Mike Stratton, senior author and director of the Wellcome Sanger Institute, said: “Understanding why our cells age and the mechanisms behind aging may help us find new ways to protect against age-related disease.”