Blood production changes due to accumulating mutations

Aging is likely caused by the gradual accumulation of molecular damage or genetic mutations in our body’s cells that occur throughout life. However, how this affects the rapid deterioration in organ function after the age of 70 was not clear until now.

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

The new study, published in Naturepoints to a change in the diversity of the stem cells that produce blood cells as a reason for the predominance of reduced cell regeneration capacity, cytopenia (one or more blood cell types are lower than they should be), immune disorders and blood risk of cancer increases dramatically after 70.

“We have shown for the first time how steadily accumulating mutations throughout life lead to a catastrophic and inevitable change in blood cell populations after age 70,” says joint senior author Dr. Peter Campbell, Head of the Cancer, Aging and Somatic Mutations Program at the Wellcome Sanger Institute, UK.

“The exciting thing about this model is that it can also apply to other organ systems.”

Blood cells are made in a process called hematopoiesis

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

Flow chart of hematopoiesis showing the cells into which multipotent hematopoietic stem cells can differentiate. Credit: JulieJenksButteCollege/Creative Commons

Wanting to better understand how this process changes with age, the researchers sequenced the entire genomes of 3,579 hematopoietic stem cells from a total of 10 people – ranging in age from newborns to 81 years.

Using this information, they were able to create something like a family tree (a phylogenetic tree) for each stem cell, showing how relationships between blood cells change over the course of human life.

They found that in adults under the age of 65, blood cells were made from between 20,000 and 200,000 different stem cells – each contributing about the same amount of production.

But after 70 years, they observed a dramatic decline in the diversity of the stem cells responsible for hematopoiesis 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 outstripped others and progressively multiplied in numbers (clones) throughout that person’s life, and this expansion (called clonal hematopoiesis) was caused by a rare subset of mutations known as driver mutations that had occurred decades earlier .

“Our results show that the diversity of blood stem cells is lost in old age due to positive selection of faster-growing clones with driver mutations. These clones “outperform” the slower-growing ones,” explains lead researcher Dr. Emily Mitchell, Resident in Hematology at Addenbrooke’s Hospital in the UK and PhD student at the Wellcome Sanger Institute in the US.

“In many cases, this increased fitness at the stem cell level likely comes at a price – their ability to produce functional mature blood cells is impaired, explaining the observed age-related loss of function in the blood system.”

Which clones became the dominant stem cells varied from person to person, which explains why differences in disease risk and other characteristics are seen in older adults.

“Factors such as chronic inflammation, smoking, infection and chemotherapy lead to earlier growth of clones with cancer-causing mutations. We predict that these factors also drive the age-related decline in blood stem cell diversity,” says co-author Dr. Elisa Laurenti, Assistant Professor at Wellcome-MRC Cambridge Stem Cell Institute, UK.

“There may also be factors slowing down this process,” 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 minimize the risk of disease and promote healthy aging.”



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