14 June 2022

Genetic changes to blood stem cells contribute to the ageing process in human organs – and now UK scientists have provided new explanations of how this happens.

These somatic mutations occur in certain cells, either small groups of cells or single cells at a time, so studying them has been challenging.

But new technologies have allowed the study of somatic mutations in single cells, say Dr Elisa Laurenti of the University of Cambridge and colleagues.

In a report in Nature, they outline their experiments on somatic mutations that accumulate slowly in blood stem cells. They set out to discover how the gradual accumulation of damage to DNA develops into abrupt organ deterioration after 70 years of age.

They analysed blood stem cells from ten individuals of various ages. By sequencing the whole genome of 3,579 blood stem cells, they highlighted the somatic mutations contained in each cell. This showed how the relationships between blood cells change across the lifespan.

In adults aged 65 or under, the production of blood appears to come from between 20,000 to 200,000 cells, contributing in equal amounts. In contrast, after the age of 70, blood cells were produced by stem cells in unequal amounts, with a smaller number of stem cells doing most of the work.

These stem cells vary between people, becoming more active due to a rare subset of somatic mutations called ‘driver mutations’.

The scientists believe this explains the "dramatic and inevitable shift" towards certain blood cell populations after the age of 70, and explains the individual variation seen in disease risk.

First author Dr Emily Mitchell, a haematology registrar at Addenbrooke’s Hospital, said: “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.

"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.”

Source: Mitchell E, Spencer Chapman M, Williams N, Dawson KJ, Mende N, Calderbank EF, Jung H, Mitchell T, Coorens THH, Spencer DH, Machado H, Lee-Six H, Davies M, Hayler D, Fabre MA, Mahbubani K, Abascal F, Cagan A, Vassiliou GS, Baxter J, Martincorena I, Stratton MR, Kent DG, Chatterjee K, Parsy KS, Green AR, Nangalia J, Laurenti E, Campbell PJ. (2022) “Clonal dynamics of haematopoiesis across the human lifespan.” Nature, doi: 10.1038/s41586-022-04786-y

Link: https://www.nature.com/articles/s41586-022-04786-y

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