Telomeres and diseases (5)

Telomeres in regenerative medicine

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Telomeres and their restoration are important objects of study in regenerative medicine. When cloning Dolly sheep from adult breast cells, its chromosomes were not identical to the chromosomes of the cells of the original sheep. Dolly's short telomeres may have contributed to the development of various diseases in her, especially progressive lung disease [30]. Theoretically, this disadvantage can be overcome by using embryonic stem cells that express telomerase and are able to maintain a constant telomere length despite numerous divisions.

A little later, scientists managed to achieve reprogramming of mature adult skin cells into a pluripotent state by introducing only a few "embryonic" genes into them. In the process of returning cells to a pluripotent state, their telomeres were significantly lengthened [31]. At the first stages of reprogramming and, possibly, at the early stages of embryogenesis, cells can effectively lengthen ("rejuvenate") their telomeres. Given that telomeres limit the limit of proliferative capabilities of cells, the mechanisms of their elongation are a very promising tool for regenerative medicine.

Telomerase is expressed only by some types of cells, especially those characterized by high proliferative potential. But even in these cells, telomerase expression is tightly regulated. There are only a few copies of the complex in the cell nucleus that function during strictly defined periods of the cell cycle. The mechanisms that modulate the expression of the telomerase gene and cause an increase in enzyme activity and telomere elongation are the object of active study. The MYC proto-oncogene, which regulates the expression of many other genes and cell pluripotency, activates telomerase expression [32]. Sex hormones also activate telomerase expression in reproductive and somatic organs such as bone marrow. The promoter region of the telomerase gene contains regulatory sequences modulated by estrogen. Positive regulation of telomerase expression occurs in cells exposed to estrogens or androgens eventually converted to estrogens [32]. Retrospectively, the reaction to androgens of patients with aplastic anemia, especially children with hereditary bone marrow insufficiency, may be due to this mechanism. However, it is currently unknown whether high levels of sex hormones in the blood or exposure to exogenous sex hormones cause telomere elongation.

ConclusionThe functioning of telomeres and their restoration are the basic molecular processes occurring in eukaryotic cells – with chromosomes from linear DNA chains.

It is obvious that accelerated telomere shortening caused by genetic defects of telomerase and genes encoding shelterin proteins underlies the development of a number of human diseases that were previously considered clinically unrelated: aplastic anemia, pulmonary fibrosis and liver cirrhosis. Telomeropathies, especially their mild and chronic forms, can be relatively common and almost certainly often go unnoticed by attending physicians. The possibility of restoring telomeres in tissues under the influence of regenerative stress, as well as the role of telomere shortening in the relationship between chronic inflammatory processes and many oncological diseases, is a subject of special interest. Drugs and hormones potentially capable of modulating telomerase expression and maintaining or increasing telomere length would be very useful in the treatment of telomeropathies and conditions in which telomere shortening has known clinical consequences. However, we still do not have an explanation for the geno- and phenotypic anomalies observed in telomeropathies – high variability in the degree of telomerase gene penetrance, organ specificity and clinical course. Both the genomic architecture modulating telomerase expression and the influence of the body environment on the process of telomere shortening are still practically unclear, and the data concerning the causal relationship between telomere shortening and human aging and the possibility of preventing the development of age-related diseases or reversing the aging process by lengthening telomeres remain contradictory.

The list of references is given in a separate file.

Portal "Eternal youth" http://vechnayamolodost.ru25.05.2012