At the same time, there is new data on the pathogenesis of atherosclerosis, the analysis of which may be reflected in the approach to the treatment of this group of patients. Atherosclerosis appears to be an age-associated disease. Premature biological aging (which usually differs from that chronological aging) contributes to the pathogenesis of atherosclerosis. This is confirmed by the results of clinical studies, indicating that in stable atherosclerotic plaques, there is a small number of old cells. In contrast, in complicated atherosclerotic plaques, there is a deposition of old cells. Telomere shortening serves as a biological trigger mechanism that explains cellular aging.

Oxidative Stress – Atherosclerosis and Telomere Length

Oxidative stress is a common pathophysiological mechanism responsible for the development of age-related diseases and aging. At a high local level of reactive oxygen species (ROS), their biological effects consist of a direct oxidative effect on all cell components (including proteins, lipids, and DNA), which leads to the initiation of chain chemical reactions. Such as lipid peroxidation, which occurs mainly within the bilayer of membranes, nuclei, and mitochondria. Telomeres and risk factors for atherosclerosis:

• Smoking. There is a direct correlation between smoking and oxidative stress. This may explain the results of numerous studies that indicate a shorter telomere length in tobacco users.
• Arterial hypertension. The results of numerous studies indicate that there is a relationship between telomere length and blood pressure. In contrast, the shortening of telomeres, causing changes in phenotypic expression in vascular cells, can contribute to hypertension.
• Obesity. There is no doubt that obesity is closely associated with the risk of developing diseases associated with the cardiovascular system. An overweight patient usually has risk factors such as hypertension, metabolic syndrome, and dyslipidemia. Adipose tissue is a source of ROS, pro-inflammatory cytokines, and various bioactive molecules that affect function and structural integrity.
• Diabetes. Obesity is only the beginning of a cascade of physiological events that lead to various age-associated diseases, including diabetes mellitus (DM). It is now known that hyperglycemia, even at the stage of pre-diabetes (impaired glucose tolerance), increases oxidative stress and, ultimately, leads to cellular aging.
• Insulin Resistance. The presence of insulin resistance harms endothelial function. This relationship is explained by the effect of insulin on mitogenesis. Under hypoxia conditions, excess insulin promotes the secretion of various growth factors and cytokines, leading to pathological vascular remodeling of blood vessels (hypertrophy of smooth muscle cells, endothelial dysfunction, thickening of the intima-media).

Ways to Protect Against Cellular Aging

Drug and non-drug therapy of clinical manifestations of atherosclerosis can indirectly affect the processes of cellular aging. Among non-drug methods, an active lifestyle, a high level of physical activity, a healthy diet, and a reduction in the salt intake should be noted.

The Cherkas LF study showed that a sedentary lifestyle (in addition to smoking, a high body mass index, and a low socioeconomic status) impacts telomere length and can accelerate the aging process. The study included 2401 twins from England.

(2152 women and 249 men aged 18 to 81). It turned out that the length of telomeres in more active participants was 200 nucleotides more than less active (7.1 and 6.9 kilobases, respectively).

Similar results were obtained in a study by J. Krauss, who analyzed the length of telomeres in 944 patients with a stable course of coronary heart disease. Telomere length in individuals with a low level of physical activity was less than in individuals with a high-level physical activity (53493781 b.p. and 5566±3829 p.o., respectively).

The issue of rational nutrition is also important, in particular, a sufficient diet of omega-3 polyunsaturated acids. A sufficient dietary intake of omega-3s is associated with low levels of F2-isoprostane (a standard indicator of systemic oxidative stress) and higher levels of antioxidant enzymes (catalase and superoxide dismutase), which reduce oxidative stress.

Particularly noteworthy are drugs that are prescribed for the treatment of diseases of the cardiovascular system. Acetylsalicylic acid is known to have antithrombotic and anti-inflammatory effects. In addition, ASA reduces the synthesis of dimethylarginine, an endogenous inhibitor of NO synthase, thereby reducing oxidative stress and the rate of aging of endothelial cells. Some scientists hypothesize that the effect of drugs of this group on telomeres can explain the increased survival rates of cardiac patients on long-term statin therapy. Spyridopoulos proved that statins could increase the migratory ability of endothelial progenitor cells through the effect of the TRF2 protein, which is part of the telomere T-loop shelterin complex.

Conclusion

Treatments aimed at delaying cellular aging by influencing telomeres and telomerase. The development and progression of atherosclerosis, in most cases, occurs over decades and does not always have clinical manifestations in the early stages. Analysis of individual risk factors for atherosclerosis is not always highly effective. Numerous studies indicate that telomere length reflects the total degree of DNA damage throughout a person’s life by factors responsible for the development of atherosclerosis and its complications. The rate of telomere shortening increases even before the onset of a clinical disease, which may be of diagnostic and prognostic value – measuring the length of telomeres in the first years of life may indicate a genetic predisposition to CVD.

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What is the essence of the Nobel results of Blackburn, Shostak and Greider, and how do they correlate with Olovnikov’s hypothesis? Telomeres are the ends of linear chromosomes. The role of telomeres in ensuring the “correctness” and stability of chromosome inheritance became apparent as early as the 1930s (by correctness and stability we mean that each of the daughter cells receives the entire set of maternal chromosomes and this process can occur an infinite number of times). It was also understood that telomeres of different chromosomes were interchangeable. At the beginning of the 1980s, the mechanism of the stabilizing function of chromosomes was unknown. The main focus of Liz Blackburn’s scientific work before her Nobel results was to study the linear DNA of the infusoria Tetrahymena. This single-celled organism has a gigantic size compared to normal cells, and therefore the genes in the genome itself are not sufficient to meet the needs of the huge volume of cytoplasm. The problem is solved by amplification (increasing the number of copies) of some important genes. In this case, each amplified gene is located on a separate linear DNA molecule. These linear molecules are “properly” distributed into daughter cells, i.e. they behave as mini-chromosomes. The ends of such mini-chromosomes can be considered as telomeres.

The study of the mechanisms of inheritance of mini-chromosomes in infusoria (a fundamental problem extremely far removed from the needs of the economy, medicine, etc.) was complicated by methodological difficulties of working with infusoria, in particular by the impossibility of using powerful genetic approaches. Jack Szostak studied plasmids – small self-replicating DNA molecules – in yeast, one of the favorite objects of molecular biology and genetics. He showed that while ring plasmids are stably inherited during yeast cell division, linear plasmids, in contrast, are rapidly lost. Although yeast chromosomes are linear, they are not lost and are inherited stably. What is the reason for the different behavior of linear plasmids and chromosomes? In a paper published in 1982, Shostak and Blackburn showed that if the end sites (telomeres) of linear amplified infusoria DNA molecules are placed on the ends of linear yeast plasmids, such hybrid plasmids are stably inherited. After the publication of this work, Shostak did not actually deal with the telomere problem. However, the experimental system he created made it possible to easily detect the function of telomeres (in terms of their ability to ensure stable inheritance of linear plasmids) in yeast. Since molecular biologists have at their disposal a huge arsenal of effective methods for studying yeast, further progress was a matter of technique. Very soon it became clear that the presence of a terminal short DNA sequence was necessary and sufficient to stabilize the inheritance of linear plasmids. This sequence must be repeated several times and is called a telomere repeat. It is very important that it would have been impossible to obtain such data in Tetrahymena, the organism that started it all, neither then nor now.

The fact that the same section of DNA functions both in infusoria and in yeast, organisms that are evolutionarily very far apart, meant that researchers were dealing with a fundamental mechanism that ensures stable inheritance of linear DNA molecules in many or even all living organisms. There could be a great number of such mechanisms (e.g. “looping” of linear DNA molecules at the moment of cell division, when the probability of loss of linear DNA is the highest). The task was to determine which mechanism is actually implemented.

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In the mid-1980s Carol Greider came to work in Blackburn’s laboratory and it was she who discovered that telomere repeats were attached to synthetic telomere-like “seed” in infusoria cell extracts. Apparently, the extract contained some protein that promoted telomere buildup. Thus, Olovnikov’s conjecture was brilliantly confirmed and the telomerase enzyme was discovered. In addition, Greider and Blackburn determined that telomerase consists of a protein molecule that actually carries out telomere synthesis and an RNA molecule that serves as a matrix for their synthesis.

WITHOUT TELOMERASE THE CELL AGES, BUT WITH TELOMERASE IT IS REBORN.

Later, Shostak’s lab discovered that certain mutations in certain yeast genes lead to a rapid shortening of telomeres after each cell division cycle, causing chromosomes to become unstable and cells to go into senescence (senescence). We now know that these genes encode telomerase. The data obtained confirmed another hypothesis of A.M. Olovnikov that the loss of telomere repeat length in each round of chromosome replication depends on the number of cell divisions.

Thus, telomerase solves the “end replication” problem: it synthesizes repeats and maintains telomere length. In the absence of telomerase, with each cell division telomeres become shorter and shorter, and at some point the telomere complex is destroyed, signaling programmed cell death. That is, the length of telomeres determines how many divisions the cell can complete before its natural death.

In fact, different cells may have different lifespans. In embryonic stem cell lines, telomerase is very active, so telomere length is kept constant. This is why embryonic cells are “forever young” and capable of unlimited reproduction. In normal stem cells, telomerase activity is lower, so telomere shortening is only partially compensated. In somatic cells, telomerase does not work at all, so telomeres shorten with each cell cycle. Telomere shortening leads to the Heiflick limit – the transition of cells to the sessence state. This is followed by mass cell death. The surviving cells are reborn as cancer cells (as a rule, telomerase is involved in this process). Cancer cells are capable of unlimited division and maintenance of telomere length.

The presence of telomerase activity in those somatic cells where it is not normally present can be a marker of malignancy and an indicator of an unfavorable prognosis. For example, if telomerase activity appears at the very beginning of lymphogranulematosis, we can talk about oncology. In cervical cancer, telomerase is already active at the first stage.

Mutations in the genes encoding components of telomerase or other proteins involved in telomere length maintenance cause hereditary hypoplastic anemia (hematopoiesis associated with bone marrow depletion) and congenital X-linked dyskeratosis (a severe hereditary disease accompanied by mental retardation, deafness, irregular development of tear ducts, nail dystrophy, various skin defects, tumor development, immune disorders, etc.).

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How does telomerase work? The enzyme binds to a special RNA molecule that contains a sequence complementary to the telomere repeat. It adds nucleotides to the end “tail” of the telomere DNA strand, using this complementary RNA as a matrix. When the tail becomes long enough, the complementary strand is synthesized using the normal DNA replication mechanism (that is, using the RNA primer and DNA polymerase), thus producing double-stranded DNA.
The primer is rarely exactly at the end of the chromosome and cannot be replaced with DNA, so the “tail” will still remain. Nevertheless, the telomere length will still increase.

Telomerase is generally not active in most somatic cells (body cells), but it is active in sex cells (sperm- and egg-producing cells) and some adult stem cells. Such cells must divide very many times, and in the case of germ cells, they give rise to new organisms in which the telomere “clock” must be “reset”.

Interestingly, many cancer cells have shortened telomeres and telomerase is active in them. If telomerase is inhibited by drugs used for anti-tumor therapy, their progressive division and thus the growth of the cancerous tumor can potentially be stopped.

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