‘Catastrophic’ blood changes thought to be responsible for sudden fatigue in people over 70

Research on aging is trying to understand its mechanisms and the various factors that influence it, in the hope of slowing it down, or even stopping it in a utopian perspective. But age-related bodily changes, other than disease, remain largely misunderstood. It’s hard to put together all the pieces in this huge puzzle. Recently, American researchers claim to have discovered how genetic mutations, accumulated throughout life, lead to changes in blood production, causing sudden weakness in people after 70 years. . This new theory of aging is changing our perspective and the prospects for new treatments for age-related pathologies, as well as certain blood cancers.

It is accepted, in the scientific community, that all cells in the human body acquire, throughout life, genetic modifications called somatic mutations. Unlike germline mutations, these genetic mutations are not passed on to offspring, disappearing with the individual at death. Taken individually, these mutations are said to survive because they cannot kill the cells that carry them.

However, if their numbers become large, things can get complicated. Thus, aging is likely due to the accumulation of multiple cell damages over time. All of these somatic mutations can cause cells to lose their functional reserve, which gradually impairs the functioning of the body. In particular, age-related changes in human hematopoiesis-all the processes that ensure continuous and regular replacement of blood cells-cause a decrease in the capacity of change, cytopenias , immune dysfunction and increased risk of blood cancer. But the process, causing sudden and brutal damage to 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 studied the blood composition of a panel of individuals 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 “harmful” change in blood production

To better understand this aging process, the team studied the production of blood cells from the bone marrow, analyzing 10 individuals aged from 0 (several months) to 81 years. They sequenced the entire genome of 3579 blood stem cells, identifying all the somatic mutations present in each cell. It was used by the team to build “ family heads of each person’s blood stem cells, showing, for the first time, an unbiased view of the relationships between blood cells and how those relationships can change throughout life.

First, the researchers found that the hematopoietic stem cell (responsible for the production of blood cells) accumulates an average of 17 mutations per year after birth.

Second, they found that hematopoiesis in adults under 65 was significantly polyclonal, i.e. from a variety of stem cell types from the spinal cord. In fact, it involves between 20,000 and 200,000 types of hematopoietic stem cells, which contribute equally to blood production. That will no longer happen after 70 years. True, hematopoiesis is still polyclonal, but only involves 10 to 20 different stem cell types. Not to mention that this small amount contributes to the complete inequality of the production of blood cells.

The graphs show (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 (edited by Laurie Henry for Trust My Science)

Genetic dominance at the end of life

The authors estimate that these 10 to 20 stem cell types gradually multiply throughout life, due to unique somatic mutations called “ motor mutations “. This is because these mutations accelerate stem cell growth, which often produces low -quality blood cells. Then they replace the thousands of stem cell types that existed 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, which can ‘ g lead to carcinogenic mutations. He added in a statement: We predicted that these factors also promote a reduction in the diversity of blood stem cells associated with aging. It is possible that some factors also slow down this process. “.

As a result, the regular appearance of ” motor mutations causes to grow clones with functional impairment, explains the unique and inevitable shift in the reduction of population variability of blood cells after the age of 70. The rate of mutation varies from one person to another, explaining the inequality in disease risk in the elderly.

Not to mention the authors point out that this process works in many other tissues in the body. They conclude: We now have the exciting task of understanding how this newly discovered mutation affects blood function in the elderly, so that we can learn how to reduce the risk of disease and promote healthy aging. “.

Mutations responsible for the development of blood cancers

These findings also pave the way for further research on blood cancers. In fact, several members of the previous team, along with other collaborators, were published in the journal NATUREon the same day, a study examined how this motor genetic mutation hijacks the production of blood cells at different stages of life and their implications for the development of associated diseases.

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

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

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

Thus, the authors found, during DNA sequencing of the blood sample, that 92.4% of the clones grew at an exponential rate during the study period. As a result, the team used mathematical models to determine the growth pattern of these stem cells that carry “ driver mutation and their clones, for life.

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 the mutant clone in our blood. These data suggest that the dynamics of blood clones are strangely predictable over a period of years, but change over a lifetime in ways we do not yet understand. “.

In addition, the researchers discovered that the behavior of the clones changed significantly with age depending on the birth of the mutated gene. They promote two main genes: DNMT3A and TET2. On the one hand, clones involved in the DNMT3A mutation grow rapidly in the young and then slow down in the elderly. While the clones involved in the TET2 mutation grew similarly throughout life. They became more common than those involved with DNMT3A, after age 75.

Professor Georges Vassiliou, co-lead author of both studies, concluded: “ Overall, our work reveals a strange interplay between age progression and DNA mutations in our blood cells, resulting in the expansion of cells with different mutations in different tissues. age. These changes lead to the emergence of different types of blood cancers at different ages and with different risks of progression. “.

Thus, these two complementary studies open the way to new methods and new treatments with the hope of stopping the progression of blood cancers, and allowing for healthier aging.

Source: Nature