Higher rates of mutation alone are not sufficient to cause ageing
A study has found that human cells and tissues can accumulate many more mutations than are normally present, without the body showing the features associated with ageing: October 2021
A genome is the complete set of genetic information that our bodies require to operate. In living organisms, the genome is stored in chromosomes containing long molecules of Deoxyribonucleic acid (DNA). Replication of chromosomes is required at each cell division.
As we age, our cells accumulate changes in DNA sequence known as mutations. Mutations can result from DNA copying mistakes made during cell division, exposure to ionizing radiation, exposure to chemicals called mutagens, infection by viruses and some other factors.
It has been theorised that the greater number of mutations in older people compared to younger people impairs the function of our cells ultimately leading to diseases of old age and the visible features typically associated with ageing.
However, a new study, titled “Increased somatic mutation burdens in normal human cells due to defective DNA polymerases” and published in the journal Nature Genetics, demonstrated that human cells and tissues can function apparently normally with many more mutations than are usually present, indicating that ageing may not be due to build-up of these types of mutations alone.
Researchers from Wellcome Sanger Institute, University of Cambridge, University of Birmingham, University of Hong Kong, Erasmus University and University of Edinburgh, used recently developed cutting-edge techniques to sequence and analyse the DNA of normal cells and cells from patients who have inherited mutated versions of the DNA polymerase genes, POLE and POLD1. Mutations in POLE and POLD1 genes, whose protein products are involved in DNA replication during cell division, cause markedly elevated mutation burdens in tissues of affected individuals.
By comparing tissue samples with unaffected individuals, they found that normal tissues from those who had a faulty DNA polymerase had elevated mutation rates, but 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”. 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. This challenges some of the past believes and underscores need to better understand the biological processes underlying ageing.
The work was supervised by Professors Ian Tomlinson (Cancer Research UK Edinburgh Centre) and Michael R. Stratton (Wellcome Sanger Institute).
This study goes some way to explaining why many cancer-causing genes increase the risk of a few cancer types, rather than all cancers. We also show that the problems and features of aging are not simply caused by accumulated damage to DNA. Overall, this work feeds into a bigger aim which is to understand why some cancers are common and others are very rare, helping us to find ways to prevent cancer.
Article in Nature Genetics: https://www.nature.com/articles/s41588-021-00930-y
Prof Ian Tomlinson Group website: https://www.ed.ac.uk/cancer-centre/research/tomlinson-group
An Introduction to the Human Genome – interesting youtube video: https://www.youtube.com/watch?v=jEJp7B6u_dY