Genetic mutations slowly accumulated over a lifetime change blood production after 70 years of age

Ageing is likely caused by the gradual accumulation of molecular damage, or genetic mutations, in the cells of our bodies that occurs over a lifetime. But how this translates into the rapid deterioration in organ function that’s seen after the age of 70 has so far not been clear.

Now, scientists have discovered that the accumulation of genetic mutations in blood stem cells are likely responsible for the abrupt change in how blood is produced in the body after 70 years of age.

The new study, published in Nature, points to a change in the diversity of stem cells that produce blood cells as the reason why the prevalence of reduced cell regeneration capacity, cytopenia (one or more blood cell types is lower than it should be), immune disfunction, and risk of blood cancer dramatically rises after 70.

“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,” says joint-senior author Dr Peter Campbell, head of the Cancer, Ageing and Somatic Mutation Program at the Wellcome Sanger Institute, UK.

“What is super exciting about this model is that it may well apply in other organ systems too.”

Blood cells are made in a process called haematopoiesis

All of the cells in our blood – including red cells, white cells and platelets – develop in a process called haematopoiesis from haematopoietic stem cells in our bone marrow. These stem cells are what’s known as multipotent progenitor cells, which simply means that they can develop into more than one cell type.

Flow chart of haematopoiesis (blood production) showing the cells that multipotent haematopoietic stem cells can differentiate into.
Flow chart of haematopoiesis showing the cells that multipotent haematopoietic stem cells can differentiate into. Credit: JulieJenksButteCollege/Creative Commons

Researchers were interested in better understanding how this process changes as we age, so they sequenced the entire genomes of 3,579 haematopoietic stem cells from a total of 10 people – ranging in age from newborn to 81 years.

Using this information, they were able to construct something similar to a family tree (a phylogenetic tree) for each stem cell, showing how the relationships between blood cells changes over the human lifespan.

They found that in adults under 65, blood cells were produced from between 20,000 and 200,000 different stem cells – each contributing roughly equal amounts to production.

But after 70 years of age they observed a dramatic decrease in the diversity of stem cells responsible for haematopoiesis in the bone marrow. In fact, only 12-18 independent expanded sets of stem cell clones accounted for 30-60% of cell production.

These highly active stem cells had outcompeted others and progressively expanded in numbers (clones) across that person’s life, and this expansion (called clonal haematopoiesis) was caused by a rare subset of mutations known as driver mutations that had occurred decades earlier.

“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,” explains lead researcher Dr Emily Mitchell, a haematology registrar at Addenbrooke’s Hospital,UK, and PhD student at the Wellcome Sanger Institute, US.

“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.”

Which clones became the dominant stem cells varied between individuals, which explains why variation is seen in disease risk and other characteristics in older adults.

“Factors such as chronic inflammation, smoking, infection and chemotherapy cause earlier growth of clones with cancer-driving mutations. We predict that these factors also bring forward the decline in blood stem cell diversity associated with ageing,” says joint-senior author Dr Elisa Laurenti, assistant professor at the Wellcome-MRC Cambridge Stem Cell Institute, UK.

“It is possible that there are factors that might slow this process down, too,” she adds. “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.”

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