Blood, epigenetics and aging
Hematopoietic stem cells give rise to all blood cells, including erythrocytes, platelets and various cells of the immune system. At an advanced age, both in 80-year-old people and in 2-year-old mice, the hematopoiesis system begins to malfunction. This manifests itself in the form of weakened immunity due to a decrease in the number of T- and B-lymphocytes and the development of anemia due to a decrease in the content of red blood cells in the blood. Moreover, in old age, the risk of oncological diseases of the hematopoiesis system increases.
Researchers at Harvard University Medical School decided to check whether there is a universal defect in the epigenome of hematopoietic cells transmitted by them to progenitor cells and differentiated blood cells and causing the problems listed above.
An epigenome is a system of molecules that activate or block certain genes of various cells of the body at different stages of its development through physical and chemical interactions with DNA. They ensure the transition of an organism from one stage of development to another (for example, from childhood to puberty), and also determine the differences between cells of one organism among themselves (for example, erythrocytes from platelets).
According to one of the leaders of the study, Associate Professor Derrick Rossi, it turned out that, in general, the epigenome of hematopoietic stem cells is highly stable. However, as it ages, certain changes occur in it that have a pronounced effect on the functions of cells, changing their ability to differentiate into certain types of blood cells.
The authors came to such conclusions as a result of studying samples of hematopoietic cells of young and old mice using a high-performance method of deep epigenome sequencing developed by Harvard University specialists. They also analyzed the ability of these cells to restore hematopoiesis by introducing them to animals whose hematopoietic system was previously destroyed by radioactive irradiation. Some of the samples were subjected to additional stress factors, such as the need for extremely active division due to the small number of transplanted cells.
Identification of epigenetic changes allowed scientists to identify the genes involved in age-related changes in hematopoietic cells. It turned out that these genes are mainly responsible for the development of differentiated blood cells and are not expressed in hematopoietic cells. Moreover, the data obtained indicate that the revealed changes in the epigenome are manifested by a decrease in the ability of stem cells to give rise to cells of the immune system and an increase in their tendency to differentiate into cells involved in the development of malignant diseases affecting the bone marrow mainly in old age.
A special epigenetic regulator known as polycomb-repressive complex-2 (PRC2) is involved in this process, modifying DNA–packing proteins – histones - in such a way that a kind of switch is formed, which is in the "off" state in hematopoietic stem cells, but is activated in intermediate cells that form blood cells of certain types.
It turned out that with age, this mobile epigenetic modification is replaced by methyl residues that irreversibly interact with DNA, completely blocking this molecular switch.
However, unlike genetic mutations, even the most stable epigenetic changes can be corrected. For example, in myelodysplastic syndrome, one of the classic age–related diseases of old age, some patients respond to therapy with hypomethylating agents that remove methyl groups from DNA, which restores the normal functioning of hematopoietic cells.
According to the authors, understanding the fundamental biological mechanisms that control the vital activity of hematopoietic stem cells in the aging process will allow scientists to understand in more detail not only the basics of the aging process, but also the mechanisms of the development of diseases of the hematopoietic system, and such knowledge is invaluable in developing new approaches to their treatment.
Article by Isabel Beerman et al. Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging is published in the journal Cell Stem Cell.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Harvard Medical School: Ills of Aging Blood.
20.02.2013