“Catastrophic” blood change that is believed to be responsible for sudden weakness in people over 70

“Catastrophic” blood change that is believed to be responsible for sudden weakness in people over 70

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Aging research is trying to understand its mechanisms and the various factors that affect it, in the hope that it will slow it down or even stop it in a very utopian vision. But age-related physical 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, responsible for the sudden fragility of people after 70 years. This new theory of aging is changing our vision and prospects for new treatments for age-related pathologies as well as some types of blood cancer.

The scientific community recognizes that all cells in the human body undergo lifelong genetic modifications called somatic mutations. Unlike germline mutations, these genetic mutations are not passed on to offspring and disappear with the individual after death. Individually, these mutations are considered viable because they do not kill the cells that carry them.

However, as their number increases, things get complicated. Thus, aging would most likely be due to the accumulation of several cellular lesions over time. All these somatic mutations would cause the cells to lose their functional reserve and gradually degrade the functioning of the body. In particular, age-related changes in human hematopoiesis – all processes that ensure continuous and regular blood cell turnover – lead to reduced regenerative capacity, cytopenias, immune dysfunction and an increased risk of blood cancer. But the process that caused the sudden and brutal damage to organs after 70 years is still far from misunderstood and well-known.

That’s why researchers at the Wellcome Sanger Institute and the Cambridge Stem Cell Institute have studied the blood composition of a group of individuals from newborns to seniors. The discovery of 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 and analyzed 10 individuals aged 0 (several 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 pedigrees from each person’s blood stem cells, which for the first time shows an unbiased view of the relationships between blood cells and how those relationships change over the course of a lifetime.

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

Second, they found that hematopoiesis in adults under the age of 65 was massively polyclonal, that is, it came from a wide variety of bone marrow stem cell types. In fact, it includes 20,000 to 200,000 types of hematopoietic stem cells that contribute evenly to blood production. Which is no longer the case after 70 years. It is true that hematopoiesis is still polyclonal, but it involves only 10 to 20 different types of stem cells. Not to mention that this small number contributes completely unevenly to the production of blood cells.

blood stem cell diversity
Graphs showing (A) an increase in lifetime driving mutations and (B) a loss of blood stem cell diversity with age. © E. Mitchell et al., 2022 (adapted 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 have multiplied over the course of their lives due to rare somatic mutations called motor mutations These mutations accelerate the growth of stem cells and often produce lower quality blood cells. Then they end up replacing the thousands of stem cell types present at the outset.

Dr. Elisa Laurenti, Wellcome-MRC Cambridge Stem Cell Institute, co-author of the study, says thatChronic inflammation, smokinginfections and chemotherapy could cause earlier growth of these stem cells, potentially carrying carcinogenic mutations. It supplies you communicated : ” We hypothesize that these factors also support the decline in blood stem cell diversity associated with aging. It is possible that certain factors also slow down this process. “.

The result is a regular ” motor mutations causes the growth of functionally impaired clones, explains the dramatic and inevitable shift to reduced diversity in blood cell populations after the age of 70. The rate 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 works in many other tissues of the body. They concluded: We now have the exciting task of understanding how these newly discovered mutations affect blood function in older people, so that we can learn how 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 blood cancer research. Several members of the previous team, connected with other collaborators, actually published in the magazine Natureon the same day a study examining how these motor genetic mutations abduct blood cell production at different stages of life and their implications for the development of associated diseases.

As mentioned earlier, all human cells acquire genetic changes in their DNA during their lifetime. But a subset, motor mutations », Points out that he is responsible for the sudden fragility after 70 years, associated with the loss of blood stem cell diversity. 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, the researchers looked at nearly 700 blood cell clones from 385 people over the age of 55 as part of a longitudinal study. Sardinia – a project to study the people of Sardinia to determine the genetic basis of age-related changes. Participants took blood regularly for 16 years.

age blood mutation experience infographic
Infographics representing the experimental course 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 bearing ” driver mutation and their clones for life.

Dr. Moritz Gerstung, co-author of the study, explains in communicated : ” 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 the years, but over the course of life they change in ways we do not yet understand. “.

In addition, the researchers found that the behavior of the clones changed significantly with age, depending on the identity of the mutated gene. They highlighted two major genes: DNMT3A and TET2. On the one hand, clones associated with mutations in DNMT3A grew rapidly in young people and then slowed in old people. While clones associated with mutations in TET2 grew steadily throughout life. Then, after the age of 75, they became more common than those associated with DNMT3A.

Professor Georges Vassiliou, co-author of both studies, concludes: Together, our work reveals the amazing interplay between advancing age and DNA mutations in our blood cells, leading to the expansion of cells with different mutations at different ages. These changes lead to different types of blood cancer at different ages and with different risks of progression. “.

These two complementary studies therefore pave the way for new approaches and treatments in the hope of halting the development of blood cancer and enabling healthier aging.

source: Nature

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