‘Catastrophic’ blood change is thought to be the cause of sudden fragility in people over 70

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Research into aging tries to understand its mechanisms and the various factors that affect it, in the hope of slowing it down or even stopping it in a very utopian vision. But age-related body changes, in addition to illness, remain largely misunderstood. It’s hard to put all the pieces of this huge puzzle together. Recently, American researchers claim to have discovered how genetic mutations, accumulated over a lifetime, lead to changes in blood production, which are responsible for the sudden fragility in humans after 70 years. This new theory of aging is revolutionizing our vision and the prospects for new treatments for age-related pathologies as well as for certain blood cancers.

It is accepted, in the scientific community, that all cells in the human body through a life acquire genetic modifications called somatic mutations. Unlike germline mutations, these genetic mutations are not transmitted to offspring, and disappear with the individual at death. Taken individually, these mutations are said to be viable because they do not kill the cells that carry them.

But when their numbers get big, things get complicated. Thus, aging will most likely be caused by the accumulation of several cellular damages over time. All these somatic mutations would cause the cells to lose their functional reserve, which gradually impairs the body’s function. In particular, age-related changes in human hematopoiesis – all the processes that ensure continuous and regular replacement of blood cells – lead to decreased regenerative capacity, cytopenias, immune dysfunction and an increased risk of blood cancer. But the process that causes a sudden and brutal deterioration of the organs after 70 years is still far from understood and known.

This is why researchers from the Wellcome Sanger Institute and the Cambridge Stem Cell Institute examined the blood composition of a panel of individuals ranging from newborns to the elderly. The discovery of a radical change at the cellular level provides a new theory of aging, published in the journal Nature.

A “catastrophic” change in blood production

To better understand this aging process, the team studied the production of blood cells from the bone marrow by analyzing 10 individuals aged from 0 (a few months) to 81 years. They sequenced the entire genomes of 3579 blood stem cells and identified all the somatic mutations contained in each cell. The team used it to build ” family trees of each person’s blood stem cells, showing for the first time an objective view of the relationship between blood cells and how these conditions change throughout life.

First, the researchers found that hematopoietic stem cells (which are responsible for producing blood cells) accumulated an average of 17 mutations a year after birth.

Second, they found that hematopoiesis in adults under 65 was massively polyclonal, i.e. originated from a wide variety of stem cell types from the spinal cord. In fact, it involves between 20,000 and 200,000 types of hematopoietic stem cells that contribute uniformly to blood production. Which is no longer the case after 70 years. Although hematopoiesis is still polyclonal, it involves only 10 to 20 different types of stem cells. Not to mention that this small number contributes completely unequally to the production of blood cells.

Graphs showing (A) the increase in the number of driver mutations throughout life and (B) the loss of blood stem cell diversity with age. © E. Mitchell et al., 2022 (modified by Laurie Henry for Trust My Science)

Genetic dominance at the end of life

The authors estimate that these 10 to 20 types of stem cells gradually multiplied throughout life due to rare somatic mutations called ” motor mutations “. This is because these mutations accelerate stem cell growth, often producing lower quality blood cells. Then they end up replacing the thousands of types of stem cells that were present in the beginning.

Dr. Elisa Laurenti, of the Wellcome-MRC Cambridge Stem Cell Institute, co-author of the study, says that chronic inflammation, smoking, infection and chemotherapy can cause these stem cells to grow earlier, potentially carriers of carcinogenic mutations. She added in a statement: We anticipate that these factors also promote the decrease in blood stem cell diversity associated with aging. It is possible that certain factors also slow down this process. “.

As a result, the regular appearance of ” motor mutations causes disabled clones to grow, explains the dramatic and inevitable shift to reduced diversity in blood cell populations after age 70. The frequency of mutations varies from person to person, which explains the inequality in the risk of disease in the elderly.

Not to mention that the authors point out that this process is at work in many other tissues of the body. They conclude: We now have the exciting task of understanding how these newly discovered mutations affect blood function in the elderly so that we can learn to minimize the risk of disease and promote healthy aging. “.

Mutations responsible for the development of blood cancer

These findings also pave the way for further research into blood cancer. In fact, several members of the former team, affiliated with other collaborators, published in the journal Naturesame day, a study examining how these motor genetic mutations hijack the production of blood cells at different periods of life and their implications for the development of associated diseases.

As mentioned earlier, all human cells acquire genetic changes in their DNA throughout their lives. But a subset, the motor mutations », Is pointed out as responsible for the sudden fragility after 70 years, associated with the loss of diversity of blood stem cells. This process of clonal hematopoiesis, which becomes ubiquitous with age, is a risk factor for blood cancer and other age-related conditions.

To understand the link between clonal hematopoiesis and age-related diseases, researchers tracked nearly 700 blood cell clones from 385 people over the age of 55, part of the SardiNIA Longitudinal Study – Dr. study of the inhabitants of Sardinia to identify the genetic bases of age-related changes. Participants administered blood samples regularly for 16 years.

Infographic presenting the experimental progress of the study. © MA Fabre et al., 2022

Thus, during DNA sequencing of blood samples, the authors found that 92.4% of the clones grew at an exponential rate during the study period. As a result, the team used mathematical models to derive the growth pattern of these stem cells that carry ” drives mutations and their clones through a lifetime.

Dr. Moritz Gerstung, co-lead author of the study, explained in a press release: For the first time, we were able to use genomic analysis to understand the past, present, and future of mutant clones in our blood. These data show that the dynamics of blood clones are surprisingly predictable over a number of years, but change over a lifetime in ways we do not yet understand. “.

Furthermore, the researchers discovered that the behavior of the clones changed significantly with age depending on the identity of the mutated gene. They highlighted two main genes: DNMT3A and TET2. On the one hand, clones associated with mutations in DNMT3A grew rapidly in adolescents and then decreased in the elderly. While clones linked to mutations in TET2 grew uniformly throughout life. They then became more common than those associated with DNMT3A, after age 75.

Professor Georges Vassiliou, co-author of the two studies, concludes: ” Overall, our work reveals an amazing interplay between advanced age and DNA mutations in our blood cells, resulting in the expansion of cells with different mutations at different ages. These changes lead to the emergence of different types of blood cancer at different ages and with different risks of progression. “.

Therefore, these two complementary studies pave the way for new approaches and new treatments with the hope of stopping the development of blood cancer and allowing a healthier aging.

Source: Nature

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