Blood production changes due to accumulated mutations

It is possible that aging is caused by the gradual accumulation of molecular damage or genetic mutations in the cells of our bodies that occur over a lifetime. But how this translates to the rapid decline in organ function seen after the age of 70 is not yet clear.

Now, scientists have discovered that the accumulation of genetic mutations in blood stem cells is likely responsible for the sudden change in how this occurs. the blood It is produced in the body after the age of seventy.

The New studypublished in temper naturerefers to the change in the diversity of stem cells that produce blood cells as the cause of the proliferation of reduced regeneration capacity of cells, Leukopenia (One or more types of blood cells are less than they should be), impaired immunity, and the risk of developing leukemia rise 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 the age of 70,” says co-lead author Dr. Peter Campbell, chair of the Cancer, Aging and Somatic Mutation Program at Wellcome Sanger Institute, UK United.

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

Blood cells are formed in a process called hematopoiesis

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

Hematopoietic (blood production) flow chart showing cells in which pluripotent hematopoietic stem cells can differentiate.
Hematopoietic flow chart showing the cells into which pluripotent hematopoietic stem cells can differentiate. Credit: JulieJenksButteCollege/Creative Commons

The researchers were interested in better understanding how this process changes as we age, so they sequenced the complete 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 build something similar to a family tree (phylogenetic tree) for each stem cell, showing how relationships between blood cells change over a human’s lifespan.

They found that in adults younger than 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 noticed a significant decrease in the diversity of stem cells responsible for hematopoiesis in the bone marrow. In fact, 12-18 independent extended populations of stem cell clones accounted for 30-60% of cell production.

These highly active stem cells have outgrown others and gradually expand in numbers (clones) throughout that person’s life, and this expansion (called clonal blood formation) is caused by a rare subset of mutations known as driver mutations that occurred decades ago.

“Our findings show that blood stem cell diversity is lost in old age due to positive selection of faster-growing clones with driver mutations. Explains lead researcher Dr Emily Mitchell, registrar of hematology at Addenbrooke Hospital, UK, and a doctoral student at the Wellcome Sanger Institute, United States, that these clones “outperform” the slower-growing ones.

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

The types of clones that become stem cells become dominant varies between individuals, which explains why variance in disease risk and other characteristics appears in older adults.

Factors such as chronic inflammation, smoking, infection, and chemotherapy cause premature growth of clones with cancer-causing mutations. We expect these factors to also lead to a decrease in blood stem cell diversity associated with aging, says co-lead author Dr Elisa Llorente, Associate Professor at the Wellcome-MRC Cambridge Stem Cell Institute, UK.

“It is possible that there are factors that could slow this process down as well,” she adds. “We now have an exciting task to discover how these newly discovered mutations affect blood function in older adults, so that we can learn how to reduce disease risk and promote healthy aging.”