Genetic mutations accumulated over a lifetime can change how blood is formed after the age of 70, according to a study published in the journal Nature. The authors suggest a new theory of ageing based on these results.
All cells inevitably accumulate genetic changes throughout life. These are known as somatic mutations. The current theory is that ageing is a consequence of multiple damage to cells over time, and the build-up of somatic mutations causes cells to lose function. However, researchers don’t know how such a gradual accumulation of damage translates into an abrupt deterioration after the age of 70 years.
To investigate this process, a team of researchers from the Wellcome Sanger Institute and the Cambridge Stem Cell Institute in the UK joined forces to study the production of blood cells in 10 participants, from newborns to elderly patients. The team sequenced the whole genomes of over 3500 blood stem cells and identified the somatic mutations in each cell. Using this data, they managed to reconstruct the family tree for each person’s stem cells and showed the relationships among blood cells and how they change over time.
It turned out these family trees change significantly after the age of 70 years. Blood is produced in adults under 65 years of age from 20,000 to 200,000 stem cells, each contributing roughly the same amount. In contrast, in participants over 70, production was very uneven. A small number of stem cells — in some cases, as few as 10 to 20 — contributed as much as half of all blood cells produced in elderly patients. These highly active stem cells increase in numbers across a person’s life caused by a rare type of mutations called driver mutations.
Based on these results, the team proposed a new model for ageing: changes in blood production come from mutations that originate in these more active stem cells that end up dominating the bone marrow in older adults. This explains the dramatic reduction in diversity in blood cell populations after the age of 70.
“Our findings show that the diversity of blood stem cells is lost in older age due to positive selection of faster growing clones with driver mutations. These clones ‘outcompete’ the slower growing ones. In many cases, this increased fitness at the stem cell level likely comes at a cost – their ability to produce functional mature blood cells is impaired, so explaining the observed age-related loss of function in the blood system,” said Dr. Emily Mitchell, Haematology Registrar at Addenbrooke’s Hospital, Ph.D. Student at the Wellcome Sanger Institute and lead researcher on the study.
The researchers also found that risk factors such as smoking, infection, or undergoing chemotherapy can bring these changes earlier. “We predict that these factors also bring forward the decline in blood stem cell diversity associated with ageing. It is possible that there are factors that might slow this process down, too. We now have the exciting task of figuring out how these newly discovered mutations affect blood function in the elderly, so we can learn how to minimise disease risk and promote healthy ageing,” said Dr. Elisa Laurenti, Assistant Professor and Wellcome Royal Society Sir Henry Dale Fellow at the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge.
“We’ve shown, for the first time, how steadily accumulating mutations throughout life lead to a catastrophic and inevitable change in blood cell populations after the age of 70. What is super exciting about this model is that it may well apply to other organ systems too. We see these selfish clones with driver mutations expanding with age in many other tissues of the body – we know this can increase cancer risk, but it could also be contributing to other functional changes associated with ageing,” concluded Dr. Peter Campbell, Head of the Cancer, Ageing and Somatic Mutation Programme at the Wellcome Sanger Institute.
Mitchell, E., Spencer Chapman, M., Williams, N. et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature (2022). https://doi.org/10.1038/s41586-022-04786-y