Currently, new global medical, social and demographic trends have emerged associated with a significant increase in the average life expectancy of a modern person. In these conditions, modern medicine is also faced with new tasks, which are to ensure not so much a further increase in life expectancy, but to ensure the duration of the highest quality life (quality survival) through early prevention of age-associated diseases. All modern anti-aging medicine relies on the achievements of fundamental science, which has made it possible to date to formulate numerous theories of cellular aging. One of the youngest theories of biological aging is the telomerase theory, based on the revolutionary discoveries of fundamental science in recent decades. The article examines the mechanisms of cellular aging associated with the activity of chromosome telomeres and their key regulatory enzyme, telomerase. Brief modern data on the first synthetic substance with telomerase activity - cycloastrogenol are presented and data on the composition and mechanisms of action of a new combined substance with telomerase activity - a complex of cycloastrogenol and regulatory peptides of the pineal gland and thymus (thymus), which appeared under the trade label "Telomerol" in 2017 in the Russian pharmaceutical market. The clinical experience of using Telomerol in domestic medicine is still very modest, but it is beginning to accumulate, which served as the basis for a preliminary analysis and discussion of the first clinical Russian experience of using Telomerol in the framework of this article.
From a biological point of view, aging is a process of gradual disruption and loss of important functions of the body or its parts, in particular, the ability to reproduce and regenerate. Aging of a person is the aging of his internal organs, aging of organs, in turn, is the aging of their cells, and aging of cells is the aging of their information-hereditary system in the form of a DNA molecule, which is contained in the nuclei of human cells.
At its core, the death of a person from aging is a deterioration to a critical level of all biochemical mechanisms of the vital activity of a billion cells due to the structural degradation of DNA molecules.
Human aging is a more multifaceted, complex and genetically determined process. It cannot be prevented, but slowing down is completely real. A person becomes old and very old only if he allows himself: one can be old even at 30–40 years old, and at 90–100 years old - only old. Why and how do we age? Mankind has been looking for answers to these questions since its inception. To date, many theories of aging have been proposed, various pathological processes that develop over time in the body are identified, and methods for their inhibition are being actively developed.
The most popular modern THEORY OF AGING boil down to the following:
- The theory of programmed death(aging is encoded in genes, and death is a kind of programmed suicide).
- Telomerase theory... At the end of each chromosome, there are several thousand copies of specific DNA sequences, each containing 6 base pairs and forming together a so-called telomere. With each division of a somatic cell, chromosomes lose about 200 base pairs. Therefore, the lifespan of an organism is limited by the length of the telomere.
- Mutation theory explains aging by the accumulation of spontaneous cell mutations during life, which leads to their death.
- Theory of the accumulation of harmful metabolic products(lipofuscin, free radicals) - the death of the body occurs due to toxic damage to cells by these substances.
- Autoimmune theory- with age, autoimmune antibodies to the cells of the body accumulate, which leads to their death.
- Theory of physiological changes in endocrine organs (dishormonal theory) - with age, the endocrine system undergoes irreversible loss of the structure and function of cells associated with a deficiency of hormones, among which a deficiency of sex hormones plays a key role.
The variety of existing theories of biological aging allows us to make an unambiguous conclusion that all the known mechanisms of cellular and systemic aging are closely related to each other and, obviously, there is still no single key aging mechanism. Nevertheless, at present, the universal mechanisms of cellular aging are well known (age-related hormonal imbalance, oxidative stress, mitochondrial dysfunction, shortening of the telomere length of chromosomes, instability of the cell's genetic material, acceleration of cellular apoptosis against the background of modern negative epigenetic influences - these are, obviously, the main links age biology, a kind of "death cycle", within which the synergistic interaction and mutual aggravation of these factors leads to aging and subsequent death of the cell and the organism at any of these stages (Fig. 1.)
Rice. one. Key factors in biological aging
Telomerase theory of aging. To date, the genetic theory of telomeres (telomerase theory of aging) has the greatest resonance in the scientific community. In 1961, the American gerontologist L. Hayflick, through simple experiments, determined that skin fibroblasts can divide outside the body about 50 times. Hayflick tried to freeze fibroblasts after 20 divisions, and then thawed it a year later. And they shared an average of 30 more times, that is, to their limit. This maximum number of divisions for a given cell has been called the Hayflick limit. Of course, different cells have their own "Hayflick limits" and a finite number of divisions. Some cells in our body, such as stem cells, germ cells, and cancer cells can divide an unlimited number of times. However, for a long time it remained unclear why DNA in chromosomes is stable, and fragments without terminal sequences are subject to rearrangements. Research by Paul Hermann Müller (1946 Nobel Prize in Physiology or Medicine) and Barbara McClintock (1983 Nobel Prize in Physiology or Medicine) in the early 1940s showed that the end regions protect chromosomes from rearrangements and breaks. Müller called these special areas telomeres - from two Greek words: telos - end and meros - site. But what these areas are and what function they perform in the cell, scientists did not yet know at that time.
In 1975, Elizabeth Blackburn in the laboratory of Joseph Gal at Yale University, studying the extrachromosomal DNA molecules of ciliates, found that the end regions of these molecules contain tandem repeating sequences consisting of six nucleotides: at each end of such repeats were from 20 to 70. In further experiments Blackburn and Shostak added DNA molecules to yeast with attached repeats from ciliates and found that the DNA molecules became more stable. In 1982, in a joint publication, they suggested that these repeating nucleotide sequences are telomeres. Their guess was confirmed. Now it is already known for sure that telomeres consist of repeating nucleotide regions and a set of special proteins that organize these regions in space in a special way. Telomeric repeats are very conservative sequences, for example, repeats of all vertebrates consist of six nucleotides - TTAGGG, repeats of all insects from five - TTAGG, repeats of most plants from seven - TTTAGGG.
Due to the presence of stable repeats in telomeres, the cellular repair system does not confuse the telomere region with an accidental break. In this way, the stability of chromosomes is ensured: the end of one chromosome cannot join with a break in the other. Telomeres are repeating sequences of TTAGGG nucleotides located at the ends of chromosomes that do not carry genetic information. Each cell in our body contains 92 telomeres, which play an important role in the process of cell division - they ensure the stability of the genome, protect chromosomes during replication from degradation and fusion, ensure the structural integrity of the endings of chromosomes and protect cells from mutation, aging and death.
Human telomeric DNA is about 15,000 base pairs (base pairs, BP) in length. With each cell division, telomeres become 200-300 BP shorter. Upon reaching the boundary of 3,000 - 5,000 BP, the telomere length becomes critically short - the cells can no longer divide. They either age or die. With age, the telomere length of human somatic cells decreases (Fig. 2.).
Fig. 2. Age-related dynamics of human telomere length
Telomere repeats do more than just stabilize chromosomes, they have another important function. As you know, the reproduction of genetic material from generation to generation occurs due to the duplication of DNA molecules using a special enzyme (DNA polymerase). This process is called replication. The problem of "terminal replication" was independently formulated in the 1970s by Alexei Matveyevich Olovnikov and Nobel laureate James Watson. It lies in the fact that DNA polymerase is unable to completely copy the end portions of linear DNA molecules, it only builds up the already existing polynucleotide strand. Where does the initial section come from? A special enzyme synthesizes a small "seed" RNA. Its size (<20 нуклеотидов) невелик по сравнению с размером всей цепи ДНК. Впоследствии РНК-«затравка» удаляется специальным ферментом, а образовавшаяся при этом брешь заделывается ДНК-полимеразой. Удаление крайних РНК-«затравок» приводит к тому, что «дочерние» молекулы ДНК оказываются короче «материнских». То есть теоретически при каждом цикле деления клеток должна происходить потеря генетической информации. Но так происходит далеко не во всех клеточных популяциях. Чтобы клетки не растеряли при делении часть генетического материала, теломерные повторы обладают способностью восстанавливать свою длину. В этом и заключается суть процесса «концевой репликации». Но учёные не сразу поняли, каким образом наращиваются концевые последовательности. Было предложено несколько различных моделей. Русский учёный А.М. Оловников предположил существование специального фермента (теломеразы), наращивающего теломерные повторы и тем самым поддерживающего длину теломер постоянной. В середине 1980-х годов в лабораторию Блэкбёрн пришла работать Кэрол Грейдер, и именно она обнаружила, что в клеточных экстрактах инфузории происходит присоединение теломерных повторов к синтетической теломероподобной «затравке». Очевидно, в экстракте содержался какой-то белок, способствовавший наращиванию теломер. Так блестяще подтвердилась догадка Оловникова и был открыт фермент теломераза. Кроме того, Грейдер и Блэкбёрн определили, что в состав теломеразы входят белковая молекула, которая, собственно, осуществляет синтез теломер, и молекула РНК, служащая матрицей для их синтеза. Теломераза решает проблему «концевой репликации»: синтезирует повторы и поддерживает длину теломер. В отсутствие теломеразы с каждым клеточным делением теломеры становятся короче и короче, и в какой-то момент теломерный комплекс разрушается, что служит сигналом к программируемой гибели клетки. То есть длина теломер определяет, какое количество делений клетка может совершить до своей естественной гибели (Рис. 3.).
Rice. 3. Mechanism of action of telomerase
In fact, different cells can have different lifespan. In embryonic stem cell lines, telomerase is very active, so telomere length is kept constant. That is why embryonic cells are “forever young” and capable of unlimited reproduction. In ordinary stem cells, telomerase activity is lower; therefore, 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 reaching the Hayflick limit - to the transition of cells into a state of senescence. This is followed by massive cell death. The surviving cells are reborn into cancerous 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 usually not manifested can be a marker of a malignant tumor and an indicator of a poor prognosis. So, if telomerase activity appears at the very beginning of lymphogranulomatosis, then we can talk about oncology. In cervical cancer, telomerase is already active at the first stage. Mutations in genes encoding components of telomerase or other proteins involved in maintaining telomere length are the cause of hereditary hypoplastic anemia (hematopoiesis disorders associated with bone marrow depletion) and congenital X-linked dyskeratosis (a severe hereditary disease accompanied by mental retardation, deafness, abnormal the development of lacrimal canals, nail dystrophy, various skin defects, the development of tumors, impaired immunity, etc.) (Fig. 4.).
Fig. 4. Telomerase regulation of the cell life cycle
At the same time, the rate of shortening of the telomere length of chromosomes is considered by many researchers as one of the most accurate markers of the rate of cellular aging, which is manifested by the entire spectrum of age-associated diseases and pathological conditions (Fig. 5.).
Rice. 5. Age-associated diseases and pathological conditions associated with accelerated shortening of telomeres
Telomerase activators are a new direction in epigenetic therapy of the 21st century. Lifestyle and lifestyle are the key that opens the door to changing genes in the new millennium. Intensive studies of the telomerase activity of various natural substances, carried out over the past 5 years, made it possible, by empirical screening, to obtain, artificially synthesize and bring to the pharmaceutical market the first telomerase activator based on cycloastrogenol - an extract of the membranous astragalus root (Astragalus membranaceus) with a purity of 98%, obtained by a multistage purification method and subsequent concentration of one of the 2000 components found in the roots of the plant. Membranous Astragalus has a long history of use in Chinese and Tibetan medicine. In Russia, it also grows in Western Siberia and the Far East.
Despite the fact that the evidence base for the efficacy and safety of this cycloastrogenol is still at the stage of its formation, since it was synthesized relatively recently, the available results of clinical and experimental studies indicate that it has a proven dose-dependent effect of telomerase activation by increasing the expression of the hTERT gene - one of the key molecular regulators of the activity of this enzyme, which was accompanied by an increase in telomere length in neonatal keratinocytes and human fibroblasts.
According to available data, cycloastrogenol (TA-65) increases the average telomere length, reduces the proportion of critically short telomeres and DNA damage in mouse fibroblasts, but does not increase telomerase activity and does not lengthen telomeres in fibroblasts of hTERT knockout mice. In mice receiving TA-65, the condition of the skin and bones improved, glucose tolerance increased, but the incidence of malignant diseases did not increase. In people who took TA-65 (10-50 mg daily for 3-6 months) and were observed for a year, the immune system improved: the number of aging cytotoxic (CD8 + / CD28–) T-lymphocytes and natural killer cells decreased significantly the number of cells with short telomeres decreased, although the average telomere length did not change.
Thus, cycloastrogenol slows down the rate of telomere shortening by activating the key hTERT gene for the expression of this enzyme in the cell (hTERT gene). Recent studies have shown that telomerase activity really depends on the amount of the enzyme in the cell, which is largely determined by the expression level of at least two genes, primarily the genes of the core telomerase subunits (hTERT and hTR), which are represented in the human genome by only one copy. At the same time, various manifestations of telomerase activity depend, first of all, on the expression of the hTERT gene, on which cycloastrogenol has an activating effect.
Later, various cellular transcription factors were identified that regulate the expression of the hTERT gene. Thus, the tumor suppressor WT1 (interacts with the hTERT gene promoter), the CTCF factor (interacts with exons 1 and 2 of the hTERT gene), DNA methylation in the region of the hTERT core promoter, and some other factors can dramatically inhibit telomerase activity. On the contrary, Akt kinase (phosphorylation increases telomerase activity), TCAB1 protein (transfers the RNA component of telomerase to the nucleus), TPP1 protein (presumably involved in telomerase delivery to telomeres and increases telomerase processivity) and ER (estrogen receptor) have an activating effect on telomerase. α and β.
Recently, it was found that some plant substances also have the ability to stimulate telomerase activity (auxin containing indoleacetic acid), genistein (isoflavone phytoestrogen isolated from soy, meadow clover and other plants, dose-dependently regulates telomerase activity), as well as rosveratrol, which rich in red grapes and a number of other plants (it belongs to phenols-phytoalexins and affects the post-translational modification and localization of telomerase, inhibits the enzyme in tumor cells and increases its activity in the precursors of epithelial and endothelial cells).
Regulatory peptides (for example, complexes of peptides of the pineal gland (epithalon), thymus and a number of others) also have an activating effect on telomerase.
Telomerol - a new word in anti-aging medicine XXI<века. At the beginning of 2017, a unique drug Telomerol appeared on the Russian market, developed on the basis of fundamental research in the field of cell biology and the latest developments in world pharmacology. It includes the already well-known cycloastrogenol molecule, as well as the peptide complexes Epivial and Timovial. Thus, Telomerol consists of unique components that have a double synergistic effect on telomerase activity (cycloastrogenol and peptide complexes increase the expression of the telomerase hTERT gene, while the latter enhance the stimulating effect of the former).
Peptides are a family of substances whose molecules are built from two or more amino acid residues linked in a chain by peptide (amide) bonds. These peptide complexes are short proteins that our body must receive from the outside (with food intake) for the full work and functioning of all systems. The mechanism of action of peptides is as follows: short peptides penetrate the cell through the cytoplasmic and nuclear membranes, participate in the activation of individual genes, in particular, activate the telomerase molecule. Peptides increase the content of euchromatin in the cell nucleus, more genes become available for transcription, transcription is intense and protein synthesis increases. The interaction of peptides with nucleotide blocks leads to the reactivation of the telomerase promoter in somatic cells, which initiates the intracellular synthesis of telomerase, lengthens telomeres, thereby affecting the duration and quality of life. Short peptides are not immunogenic and are tissue specific .
The peptide complex Epivial contains peptides ASP-GLU-GLU, LYS-ASP-GLU, ALA-ASP-GLU-LEU as active components in therapeutically effective amounts.
The pineal gland is a special gland in our body that affects the aging rate of the entire body. The pineal gland regulates the activity of all endocrine glands that produce hormones. Melatonin - the main hormone of the pineal gland - has antioxidant, adaptogenic and hypnotic effects, regulates the sleep-wake cycle, positively affects brain function, adapts the body to rapid jet lag, reduces stress responses and performs a number of other important physiological functions.
Epivial peptide complex is produced from 6 amino acids: L-alanine, L-glutamic acid, glycine, L-aspartic acid, L-lysine, L-leucine.
Alanine is an amino acid that is used as a "building material" for carnosine, which is known to increase endurance and prevent rapid aging. The main stores of carnosine are concentrated in skeletal muscles, partly in the cells of the brain and heart. By its structure, carnosine is a dipeptide - two amino acids (alanine and histidine) linked together. It is present in various concentrations in almost all cells of the body.
One of the key functions of carnosine is to maintain the acid-base balance in the body. But besides this, it has neuroprotective, anti-aging, antioxidant properties, is a powerful chelator (prevents the excessive accumulation of metal ions that can damage cells). Also, carnosine can increase the sensitivity of muscles to calcium and make them resistant to heavy physical exertion. In addition, this amino acid is able to relieve irritability and nervousness, relieve headaches.
The uniqueness of glutamic and aspartic acids is that they play an integrating role in nitrogen metabolism, since all nonessential amino acids must first be converted into glutamic and aspartic acids. The leading role in the process of nitrogen redistribution belongs to glutamic acid. Glutamic acid makes up 25% of the total amount of all (nonessential and irreplaceable) amino acids in the body. Although glutamic acid is considered a classic nonessential amino acid, in recent years it has been found that glutamic acid is essential for certain tissues of the human body and cannot be replaced by anything else (no other amino acid). The body has a kind of "fund" of glutamic acid. Glutamic acid is consumed primarily where it is needed most.
Aspartic acid does not have such a large specific gravity in the body as glutamic acid. In addition to the redistribution of nitrogen in the body, along with glutamic acid, aspartic acid takes part in the neutralization of ammonia.
First, aspartic acid is capable of attaching a toxic ammonia molecule to itself, turning into non-toxic asparagine. And, secondly, aspartic acid promotes the conversion of ammonia into non-toxic urea, which is then excreted from the body.
Lysine is an irreplaceable, that is, not synthesized by the body on its own, an amino acid that is part of almost every protein in the human body. This means that it must constantly enter the human body with food, since he himself cannot synthesize it. Lysine is a part of almost all proteins, which is necessary for the human body for normal growth, the production of hormones, antibodies, enzymes, as well as for tissue repair. This amino acid has antiviral effects, especially against viruses that cause herpes and acute respiratory infections.
Leucine is an essential branched chain aliphatic amino acid. It is part of all natural proteins. It is used to treat various diseases and has a significant effect on the general condition of the body. Leucine protects our cells and muscles, protects them from decay and aging. Promotes the regeneration of muscle and bone tissue after damage, participates in the maintenance of nitrogen balance and lowers blood sugar. Leucine strengthens and restores the immune system, participates in hematopoiesis and is necessary for the synthesis of hemoglobin, normal liver function and stimulation of the production of growth hormones. It should be noted that this essential amino acid has a positive effect on the central nervous system, as it has a stimulating effect. Leucine prevents excess serotonin and its effects. And also leucine is able to burn fat, which is important for overweight people.
And finally, glycine, which does not need to be introduced, as it is widely and well known. Glycine is the simplest aliphatic amino acid, the only one that does not have optical isomers. Glycine, improves mental and physical performance. Thus, the Epivial peptide complex is a unique and essential source of peptides for every human body. The peptide complex occupies a special place in the prevention of diseases and in the activation of the body's natural immunity. Peptide complex Timovial is a synthetic mirror analogue of natural peptide extract of thymus. It is obtained by solid-phase synthesis of the Lys-Glu dipeptide from two amino acids - D-glutamic acid and D-lysine. The thymus is a powerful immune organ that forms immune cells, providing a stable relationship between immunity and a long life span. In the experiment, it was found that the Lys-Glu dipeptide has immunomodulatory activity.
Telomerol is the first Russian clinical experience of using telomeres in managing the aging rate.
Today in Russia it is possible to make a blood test and measure the length of telomeres. Laboratory "Archimedes" makes a test that allows you to estimate the average telomere length of cells in the leukocyte fraction of peripheral blood by the method of polymerase chain reaction (PCR) (Fig. 6.).
Fig. 6. An example of a peripheral blood test for measuring telomere length of peripheral blood leukocytes
The result is presented as a telomere index (T / S or so-called (thousand nucleotide repeats)) and compared with the indices of the studied population in the same age range. The calculated index represents the average length of telomeres, the index evolves, changes over time and age of a person. As a consequence, a high telomere index is a signature of young cells, while a low telomere index is senescent cells.
A person's gender and geographic origin are among the main factors affecting the length of their telomeres. Also, telomere length is significantly influenced by oxidative stress, body mass index, alcohol and tobacco consumption, physical inactivity and unhealthy diet. Age and heredity are important factors in telomere length, but lifestyle and environment are still the main factors.
Monitoring the dynamics of the telomere index is today part of the global diagnosis of a patient, which consists of 4 main factors: prognosis, prevention, personalization, and participation.
In modern medicine, telomere length is considered as an indicator of global biological aging or specific aging of individual systems. That is why the length of telomeres can and must be correlated with pathologies associated with human aging.
New technology in the study of telomere length and the use of the innovative drug "Telomerol" are invaluable tools in your daily medical practice, and this is why: it is easy to estimate the biological age of a patient and make a prognosis; diagnostics of cardiovascular diseases, such as: atherosclerosis, hypertension, obesity, diabetes mellitus; use in the treatment of chronic diseases; diagnostics of the individual risk of metabolic disorders; use in the treatment of infertility: violation of gametogenesis, violation of the nuclear reaction of spermatozoa, violation of the frequency of aneuplodia, increase in reproductive age, both in men and women; stem cells: assessment of their quality control and characteristics; use in the treatment of obesity: the formation of an individual diet and nutrition for the patient; short telomeres indicate the likelihood of developing cancer cells in a patient; managing the age, aging process of your patient: functional medicine, personalized medicine, preventive medicine. Telomerol has an individual effect on each patient, since critically short telomeres are restored in the body, which is why you and your patient will see the effect from those organs and systems that are in the worst condition.
The clinic of Professor Kalinchenko in Moscow, perhaps one of the very first in Russia, began to widely use in its clinical practice the determination of telomere length in patients with age-associated diseases (since 2014) and to prescribe first cycloastrogenol (TA-65), and today - Telomerol ... Our own 4-year experience in this area of anti-aging medicine, based on the examination and treatment of more than 120 patients with the use of telomerase activators, allows us to draw some preliminary conclusions regarding the place of these drugs in complex Anti-Aging Medicine and pathogenetic anti-age medicine.
First of all, it is necessary to apply the principle of rational justification of the appointment of these drugs, based on the mandatory preliminary laboratory diagnosis of telomerase activity, which is reflected in the telomere length of the chromosomes of peripheral blood leukocytes. This is understandable, since with initially unknown enzyme activity, the results of therapy with telomerase activators can be very unpredictable. All patients are different, which makes them different levels of metabolism, different features of the hormonal and metabolic background and indicators of homeostasis of the body, etc., in other words, therapy with telomerase activators should be phenotypic, patient-targeted, and if the rate of biological aging, assessed along the telomere length, the patient corresponds to age, then it is obvious that the appointment of telomerase activators is advisable to recommend to the patient for the prevention of age-associated diseases and colds, to maintain good health and appearance, to regulate the sleep-wake system and during mental stress and stress. In other words, telomerase activators are not a “universal elixir of youth,” but they certainly occupy the main place in the modern concept of a person's transition from HOMO SAPIENS to HOMO LONGEVUS, when a person in adulthood fully retains mental and physical activity, vigor.
In our opinion, the main indication for discussing the prescription of telomerase activators, additional to the ongoing pharmacotherapy, is the discrepancy between the biological and passport age of the patient, revealed on the basis of a laboratory test of the telomere aging rate in combination with subjective and / or objective insufficiency of the effect of previously prescribed and ongoing pathogenetic therapy.
On the other hand, when laboratory signs of a decrease in telomerase activity are detected (rapid telomere shortening, which does not correspond to biological age), additional prescription of telomerase activators is an expedient and pathogenetically substantiated component of complex anti-age therapy. According to our own observations, the appointment of Telomerol allows you to suspend the processes of accelerated biological aging, reliably lengthening telomeres by the end of the first month of treatment by an average of 10–20%. Our clinical experience in the use of telomerase activators is based on the use of these drugs, both in monotherapy and as part of the “Health Quartet” treatment and prophylactic concept. The drugs have shown almost equal effectiveness, but since the therapeutic and prophylactic concept of the "Health Quartet" is aimed at complex therapy of the whole organism, telomerase activators still showed the most pronounced effectiveness here. This is completely logical, since all components of the "Health Quartet" (sex hormones, vitamin D, Omega-3 PUFAs and antioxidants) are in fact indirect telomere activators, therefore, the therapeutic effectiveness of the "Health Quartet" + Telomerol combination significantly exceeds the effectiveness of monotherapy with each of them individually by an average of 20-30%. Already during the first months of therapy, most patients notice a significant improvement in mood, restoration of the circadian rhythm, an improvement in overall well-being, and even a feeling of inner harmony. Of course, the clinical use of Telomerol in Russia has just begun, so evidence-based studies are not so large, but they already exist, so today we are talking about its efficacy and safety. all pharmacotherapeutic options available today to ensure the quality of life for our relatives, friends and patients, and telomerase activators today are a vivid example of how one of the most proven fundamental theories of cell aging (telomerase theory) is already being implemented in the daily clinical practice of doctors a wide variety of specialties.
Conclusion. Modern diseases of the XXI century, alas, to which all residents of the metropolis are exposed, prevent a person from living long and high quality. The revision of medicine, which Zalmanov A.S. called for. back in 1963, in his revolutionary for that time book "The Secret Wisdom of the Human Body", today it is all the more ripe. Today, a doctor of each specialty must be guided by the new concept of "anti-aging medicine", as every doctor of the 20th century was guided by infectious diseases that have become less relevant in the 21st century. All patients with any age-associated aprioir pathology have oxidative stress, therefore, the use of effective and safe antioxidants with long-term intake of antioxidants should become a clinical norm and have the character of constant lifelong intake, since the intensity of oxidative stress and its negative metabolic consequences only increase with age. Taking into account the deteriorating indicators of all aspects of modern human health in the 21st century, early diagnosis and timely correction of all pathological processes that accelerate cellular and systemic aging are becoming the prerogative of clinical medicine, among which the key ones are age-related hormonal deficiencies / imbalances and oxidative stress, leading to a more rapid shortening of telomeres. cells, which together determines the acceleration of cellular and systemic aging and rejuvenation of most age-associated diseases. However, this process in skilled hands can be quite easily controlled, especially since for the pathogenetic pharmacotherapeutic management and prevention of accelerated aging and age-associated pathology, there are already unique and effective drugs with powerful pathogenetic anti-age effects, including synthetic telomerase activators (cycloastrogenol and regulatory peptides) may very soon take their rightful place in the arsenal of a modern doctor. The main thing in this case is the skill of the doctor, skillfully and according to the indications to apply them, so that everyone finds "their" patient.
18 January 2010Summary
On April 18, 2007 in Palermo, Italy, an international conference "Pathophysiology of aging, longevity and age-associated diseases" was held. In this report, we provide background information on the most important issues discussed. While aging must be seen as an unavoidable endpoint in the life history of every individual, deepening knowledge of the mechanisms of aging provides the basis for developing many different strategies to alleviate the symptoms of aging and prolong youth. Thus, a better understanding of the pathophysiology of aging and age-associated diseases is necessary to provide every person with a real chance to live a long and disease-free final stage of life.
Most cancers develop in patients over the age of 65. The incidence of cancer with aging increases sharply in both sexes: after 65 years, the incidence of cancer is 12-36 times higher than in the age group 25-44, and 2-3 times higher than in people aged 45-65 years. It should be noted that 70% of cancer-related deaths occur in men and women aged 65 and over, while 35% of cancer-related deaths in men and 46% in women occur after age 75. The relationship between aging and cancer is the same for almost all forms of cancer and is well described by a multistage model of carcinogenesis. Therefore, aging itself should be considered not as a determining factor in the development of cancer, but as an indirect marker of the duration of exposure to significant carcinogenic factors. On the other hand, according to a recent revision of the relationship between cancer and inflammation, inflammatory cells and cytokines found in the tumor area are likely to stimulate tumor growth and progression. Moreover, the predisposition to cancer and the severity of the course of the disease may be associated with functional polymorphism of genes encoding inflammatory cytokines. When genetic damage is compared to a match that kindles a fire, some types of inflammation can provide "fuel to keep the flame". Thus, the reason for the increase in the incidence of cancer in old age may well be the well-known pro-inflammatory status of the organism associated with aging.
At the conference, the role of oncogenes in the development of human cancer was highlighted by the authors of works devoted to the study of epithelial tumors of the human thyroid gland that developed from follicular or parafollicular cells. Follicular cell tumors represent a wide range of pathological changes (from benign adenomas to differentiated papillary and follicular carcinomas and undifferentiated anaplastic carcinomas), which makes them a good model for studying the correlation between specific genetic damage and histological phenotype. Follicular adenomas often appear in the presence of mutations in one of the three genes of the ras family: HRAS, KRAS, and NRAS. Mutations in the G-stimulating protein (gsp) and thyrotropin receptor (TSH-R) genes trigger the formation of hyperfunctioning benign tumors (toxic nodes and adenomas). The two different types of differentiated thyroid carcinomas differ not only in morphology but also in behavior; in addition, they are associated with mutations of different oncogenes: papillary carcinoma - with rearrangement of the RET or TRK genes, and follicular carcinomas - with mutations of one of the three oncogenes of the ras family. The p53 tumor suppressor gene is often associated with anaplastic thyroid cancer. The RET gene is a classic example of a gene whose various mutations can lead to the development of different neoplastic phenotypes. Somatic rearrangements, often caused by chromosomal inversions (rotation of a chromosome region by 180 °), activate the oncogenic potential of the RET gene in human papillary thyroid cancer cells. Such changes occur in the cells of almost 50% of papillary tumors and represent the superposition of the 3'-tyrosine kinase domain of the RET gene, encoding a protein receptor, usually not expressed by follicular cells, and the 5'-domain of one of the ubiquitously expressed genes, resulting in the formation of several types of chimeric RET / PTC genes characteristic of papillary thyroid cancer. Such ubiquitous genes perform the activation and dimerization functions required for the constitutional activation of RET / PTC proteins. Point mutations of the stem cell RET gene are the cause of the development of syndromes of type 2 familial multiple endocrine neoplasia (MEN II), represented by (a) familial medullary thyroid cancer, (b) MEN IIA, and (c) MEN IIB. A common characteristic of these diseases is the presence of medullary thyroid cancer, formed by parafollicular C-cells. RET gene point mutations can also occur in somatic cells, leading to the development of sporadic medullary thyroid cancers and pheochromocytomas. Detailed information on the specific mutations in the RET gene that underlie the development of malignant tumors of the human thyroid gland greatly facilitates the treatment of these diseases.
Immunological aging
Many health-threatening disorders of the functioning of innate and acquired immunity in the elderly have been described, which led to the emergence of the term "immunological aging". On the other hand, immunological aging is rather a complex process that includes many changes caused by the evolution and restructuring of the organism, rather than a simple gradual fading of the functioning of the entire system. However, elderly people often have significantly reduced certain immunological parameters and, conversely, a good functioning of the immune system is closely related to the state of health. Recent observations indicate that immunological aging is not accompanied by an inevitable progressive decline in the functioning of the immune system, but rather is the result of rearrangements leading to the suppression of a number of functions, while the effectiveness of other functions does not change or even increases. It is important to note the fact that age-associated changes in the immune system are directly or indirectly involved in the development of increased susceptibility of the elderly to infectious, autoimmune and oncological diseases, as well as in reduced immunological reactivity during vaccination. The same applies to the pathogenesis of the most important age-associated diseases, such as cardiovascular and neurodegenerative diseases, as well as diabetes and osteoporosis: there is an important immune component in the pathogenesis of all these diseases. In addition, innate immunity appears to be relatively well preserved during aging, compared to the younger and more complex clonotypic immune response, which is more strongly influenced by aging.
Aging of clonotypic immunity is largely the result of changes in the state of T cells. It is believed that chronic antigenic load is the main cause of immunological aging, affecting human life expectancy by reducing the number of naive (not interacting with antigens) T cells and filling the resulting immunological niche with memory T cells and T cells that have already encountered antigens. effectors. This lifelong chronic antigenic load affecting the immune system is the cause of the chronic inflammatory status characteristic of old age. The progressive decrease in the number of naive CD4 + and CD8 + T-lymphocytes occurs in parallel with the growth of the population of CD28- memory T-cells with the aging phenotype, that is, demonstrating a progressive shortening of telomeres and a reduced ability to replicate. The second fundamental aspect of immunological aging is the progressive aggravation of the proinflammatory status, characterized by increased levels of inflammatory cytokines and inflammatory markers that are predictors of morbidity and mortality. This chronic pro-inflammatory condition is caused by chronic antigenic load (bacteria, viruses, fungi, toxins, mutated cells), constantly stimulating the mechanisms of innate immunity and, apparently, contributing to the development of typical age-associated diseases (atherosclerosis, dementia, osteoporosis, neoplasias), in development of which a significant role belongs to immune and autoimmune factors.
It has been suggested that chronic viral antigenic stimulation may be the cause of aging-specific modifications of lymphocyte populations, including the clonal expansion of CD8 + T-lymphocytes specific to viral antigens, expressing the phenotype of memory cells and in some cases accounting for up to a quarter of the entire population of CD8 + T cells. ... In a recent work, the authors estimated the quantitative ratio of populations of CD8 + T cells with different phenotypes in the blood of elderly people of two age groups: from 90 to 100 years old and over 100 years old. The cell phenotype was assessed using tetramers of the major histocompatibility complex HLA-A2 HLA-B7 antigens containing epitopes specific to the Epstein-Barr virus (EBV) and cytomegalovirus (CMV). The data obtained showed that in elderly people, these viruses induce quantitatively and qualitatively different immune responses mediated by CD8 + T cells. The relative and absolute number of CD8 + cells specific for the three epitopes of the Epstein-Barr virus was small, and these cells were predominantly represented by the CD8 + CD28 + phenotype. On the other hand, during cytomegalovirus infection, different levels of CD8 + T cells, specific to two epitopes of the virus, were recorded in the blood of different people. In some individuals, the populations of these cells not expressing the CD28 molecule were extremely large. For a more detailed study of the roles of cytomegalovirus infection and the immune system, scientists recently examined 121 people aged 25 to 100 years, 18 of whom were seronegative and 118 were seropositive to this cytomegalovirus. The results of the analysis of the obtained showed that individuals infected with cytomegalovirus were characterized by a more pronounced decrease in the number of naive CD8 + T cells, while the decrease in the number of naive CD4 + T cells did not depend on the presence of CMV infection. The decrease in the number of naive CD8 + T-lymphocytes was accompanied by a progressive increase in the population of CD8 + CD28 + effector cells, especially pronounced in CMV-infected individuals. Age-associated accumulation of cells with the CD4 + CD28- phenotype was observed only in infected individuals, while these cells were practically absent in CMV-negative subjects. Peripheral blood mononuclear cell samples were stimulated with peptide combinations containing fragments of amino acid chains that completely covered the sequences of cytomegalovirus pp65 and IE-1 protein molecules. As a result, responsive cells expressing interferon-gamma (IFN-gamma +) appeared in both CD8 + and CD4 + lymphocyte populations. At the functional level, all individuals showed age-associated accumulation of CMV-specific (IFN-γ +) CD8 + cells, while the growth of the population of PP65-specific CD4 + cells occurred only in people over 85 years of age. At the same time, most of the cells specific to cytomegalovirus CD8 + (IFN-gamma +) and 25% of CD4 + (IFN-gamma +) expressed the cytotoxic degranulation marker CD107a (Sansoni et al., Accepted for publication). These data support the hypothesis that chronic cytomegalovirus infection underlies pronounced changes in the ratio of lymphocyte subpopulations, affecting not only CD8 +, but also CD4 + cells and, possibly, contributes to the development of age-related pro-inflammatory status that accompanies most age-associated diseases.
The study of the immune response in healthy elderly people has shown that immunological aging affects not only the responses of T cells, but also various aspects of innate immunity. Perhaps the most detailed studies of age-related changes in the innate immune system have focused on so-called natural killer (NK) cells. These cells, as well as polymorphonuclear leukocytes and macrophages, are components of innate immunity, and represent the body's main defense system responsible for the spontaneous destruction of tumor and virus-infected cells. Natural killer cells do not have T-cell receptors and express the CD56 and CD16 molecules on their membrane. In addition, they have two alternative mechanisms of cytolysis: direct spontaneous cytotoxicity directed against various tumor cells, and indirect Fc receptor mediated cytotoxicity against antibody coated targets (antibody dependent cell mediated cytotoxicity). A finely balanced complex of signals from numerous activating and inhibiting receptors controls their effector functions. These receptors provide the ability of cells to quickly detect potentially dangerous cells in their environment. In the case of a shift in the equilibrium of the signaling complex towards activation, natural killer cells begin to secrete cytokines and / or release cytotoxic substances contained in cytoplasmic granules. In humans, one of the activating receptors expressed by NK cells, as well as T-gamma-delta cells and CD8-alpha-beta T cells, is the NKG2D molecule. As ligands, this receptor recognizes UL16-binding protein 1 (ULBP1), ULBP2, ULBP3, ULBP4, as well as MICA and MICB - chains of MHC I antigen molecules. On the surface of healthy cells, these ligands are absent or are present in insignificant amounts, but their expression can be induced by viral or bacterial infections. Several works were devoted to the study of the ability of natural killer cells at the early stages of the development of the infectious process to regulate the development of the acquired immune response through the production of cytokines, usually synthesized by type I T-helper cells, or through the activation of dendritic cells. In addition, co-cultivation of natural killer cells and antigen-activated T cells showed that in response to the production of interleukin IL-2 by activated T cells, human NK cells begin to secrete interferon-gamma. In contrast, there is little evidence of physical interactions between natural killer cells and cells that mediate acquired immune responses, especially CD4 + cells. Natural killer cells stimulate acquired immunity through the production of type 1 or 2 cytokines or chemokines. The secretion of these factors by activated NK cells affects the differentiation of B and T lymphocytes. More and more data obtained by scientists indicate the direct participation of natural killers in the maturation of dendritic cells. At the same time, the potential role of direct cell-to-cell interactions between natural killer cells and T-lymphocytes, in particular CD4 + T-lymphocytes, has not yet been studied. There is evidence that human activated natural killer cells are able to stimulate TCR-dependent proliferation of resting autologous CD4 + T cells in peripheral blood through a process that involves the co-stimulatory molecules of the immunoglobulin and tumor necrosis factor (TNF) superfamilies. These data indicate the existence of a previously unknown mechanism of the relationship between innate and acquired components of the immune system.
Results from a 1987 quantitative analysis of cells expressing the NK phenotype showed that the number of circulating peripheral blood NK cells in healthy individuals over 70 years of age is higher than in young and middle-aged people. The growth of the population of NK cells in the peripheral blood of elderly people clearly correlates with age and a decrease in the number of T-lymphocytes, which supports the theory that an increase in the number of natural killer cells compensates for a decrease in their cytolytic activity. The cytolytic activity of peripheral blood lymphocytes is approximately proportional to the relative content of NK cells in the blood sample. However, it turned out that after incubation with K562 cells, the cytolytic activity of natural killer cells is the same for both young people and exceptionally healthy elderly individuals selected according to the SENIEUR protocol, despite the twice higher content of effector cells in the blood of the latter. In any case, isolated or cloned NK cells from elderly people showed reduced cytolytic activity per cell. These results confirm the data according to which, after binding to the target cell CD16 +, the cell of an elderly donor exhibits, on average, two times lower cytolytic activity than the cell of a young person. However, the natural killer cells of the elderly do not differ significantly from the cells of young individuals either in their ability to bind to a target, or in their intracellular content, or in the distribution and utilization of perforin. Therefore, it is obvious that some other factors are responsible for the decrease in the cytolytic activity of natural killer cells in the elderly. In fact, the ability of NK cells to transform a receptor-mediated signal into an effector response associated with the ability to synthesize secondary messengers after stimulation with K562 cells decreases significantly with age. The main biochemical defect underlying this phenomenon appears to be an age-associated slowdown in PIP2 hydrolysis and a decrease in the rate of IP3 formation after stimulation of natural killer cells by K562 cells. Since the density of surface receptors involved in recognition and adhesion, as well as the ability of NK cells to form complexes with target cells, practically does not change with age, it can be assumed that impaired signaling in these cells occurs at stages remote from the moment of receptor binding.
A growing body of scientific evidence suggests that the immune, endocrine and nervous systems are highly interconnected and interact with each other through circulating cytokines, hormones and neurotransmitters. Many hormones and trace elements have an important effect on the homeostasis of the immune system and the maintenance of a constant body composition. Aging-related reductions in adipose tissue and muscle and bone mass, combined with an increased risk of malnutrition and vitamin and trace mineral deficiencies, are major contributors to the development of disease states and a decrease in the resistance of older people to infectious diseases. A pronounced relationship was found between the amount and cytolytic activity of natural killer cells and the content of vitamin D in the blood serum, which corresponds to the data according to which the intake of vitamin D by the elderly has a pronounced effect on the activity of NK cells, increasing the level of interferon-alpha in the blood. Anthropometric parameters used to estimate the volume of adipose and muscle tissue also correlate with the number and activity of natural killer cells, and indicators of the volume of adipose tissue - with the level of vitamin D in blood serum. Another important result is the identification of a strong correlation between the number of NK cells and the concentration of zinc in the blood serum, which is necessary for the implementation of many homeostatic reactions of the body, including oxidative stress, and many functions of the body, including effective immune responses. In addition, the intake of zinc aspartate led to an increase in the concentration of zinc ions in the blood of people with an initially low content of this element in the blood serum and stimulated the cytolytic activity of their natural killers, which indicates a softening of the pro-inflammatory status (characterized by high levels of pro-inflammatory cytokines and, possibly, chemokines) and the development of more balanced immune responses mediated by type 1 and 2 helper T cells. Because of the strong relationship between micronutrient and vitamin deficiencies and immunodeficiency in older adults (an increased risk of infectious disease, as evidenced by the high rate of nonresponsiveness to influenza vaccine among malnourished older adults), these results highlight the paramount importance of nutritional assessment in clinical trials. health conditions of the elderly.
Age-associated inflammatory diseases
The individual aging rate of the whole organism or any organ system may vary depending on genetic characteristics, history of the course of the disease, random factors, etc. The immune system is no exception. Disorders of homeostasis and functioning of the immune system (especially the main immune cells - CD4 + lymphocytes) underlies or at least is one of the causes of the development of Alzheimer's disease and rheumatoid arthritis. These diseases refer to conditions that accelerate aging (shorten life expectancy) of a person. The question arises: is the aging of CD4 + cells of people suffering from these diseases accelerated? The main tasks of CD4 + lymphocytes are the production of a large number of various cytokines and periodic proliferation, which ensures the formation of clones of effector cells and memory cells. It is known that for CD4 + lymphocytes of patients with rheumatoid arthritis, as well as for cells of healthy elderly people, signs of aging are characteristic, including relatively short telomeres, a decrease in the number of CD28 molecules expressed on the surface, a decrease in the frequency of proliferation, etc. To study the probability of accelerated aging For CD4 + lymphocytes from patients with Alzheimer's disease and rheumatoid arthritis, the researchers used a new flow cytometric technique to assess the frequency of cell proliferation. This technique is based on the labeling of cells with carboxyfluorescein-succinimide-ether and a complex mathematical analysis of the data obtained, which makes it possible to determine the number of proliferating lymphocytes with a high degree of accuracy, as well as to evaluate the dynamic parameters of proliferation, including the timing of the cell cycle, in particular the time of transition from the G0 phase. in phase G1. The obtained results showed that the CD4 + cells of patients with rheumatoid arthritis (especially young people) do not differ from the cells of healthy elderly people in these parameters, thereby confirming the assumption of their premature aging. At least one of these parameters (duration of the G0 – G1 transition) correlates with the level of CD28 expression on the surface of lymphocytes, which, in turn, depends on the regulatory activity of the proinflammatory cytokine, tumor necrosis factor. There is also the Klotho gene (a protein product of which is sometimes called the "aging hormone"), which contains a regulatory sequence that is supposedly responsive to tumor necrosis factor. His study showed that both the transcriptional activity of the gene itself and the content of the Klotho protein in the cell are significantly reduced in the CD4 + cells of patients with rheumatoid arthritis, regardless of their age, and do not differ from those of the cells of healthy elderly people. As expected, the enzymatic activity of beta-glucuronidase attributed to the Klotho protein (presumably involved in the hydrolysis of steroid glucuronides) is reduced in CD4 + lymphocytes of patients with rheumatoid arthritis and healthy elderly people, which may be one of the factors determining the inflammatory status characteristic of both groups. ... Using the same methodology to study the CD4 + cells of patients with Alzheimer's disease revealed a quasi-opposite pattern. The values of the dynamic parameters of proliferation, including the timing of the cell cycle and the G0 – G1 transition, of lymphocytes in typical elderly patients with Alzheimer's disease corresponded to those obtained in the study of cells in healthy young people. Obviously, this feature is due to the effect on the cells of the beta-amyloid peptide. An interesting fact is that the CD4 + cells of patients with Alzheimer's disease show a more pronounced response to beta-amyloid than cells of healthy people. Perhaps one of the factors that determine this phenomenon are genetic differences, such as different variants of genes of the histocompatibility complex. In short, these data indicate that rheumatoid arthritis is responsible for the accelerated aging of CD4 + lymphocytes, whereas Alzheimer's disease does not affect the aging of these cells, which, however, show abnormalities.
DNA damage repair
50 years ago, when the free radical theory of aging was first proposed, the damaging effects of reactive oxygen species (ROS) were actively studied and recognized as the most important factor in the aging process. However, the theory of expendable soma (or the theory of disposable soma), which appeared 20 years later, redirected the attention of specialists to the potential role of mechanisms that neutralize the damaging effects of ROS in maintaining cell viability and repairing damage, the effectiveness of which is due to both genetic characteristics and environmental factors. In this context, poly (ADP-ribosyl) ation, a post-translational modification of protein molecules caused by DNA damage, is of particular interest. Poly (ADP-ribosyl) ation catalyzes the enzyme poly (ADP-ribose) polymerase-1 (PARP-1), the substrate of which is NAD +. PARP-1 activation, triggered by DNA strand breaks, is functionally associated with mechanisms of DNA damage repair and is a factor in the survival of cells under conditions of low and medium genotoxic stress. More than 10 years ago, a positive correlation was described between the ability of mononuclear blood cells to poly (ADP-ribosyl) ation and the lifespan of various representatives of the mammalian class. The results of a subsequent comparative analysis of the purified recombinant molecules of human and rat PARP-1 showed that this correlation is partly explained by the differences in the genetic sequence coding for this enzyme that have arisen during evolution. This observation is in excellent agreement with the results of a study of various strains of knockout mice with gene defects that provide DNA repair by removing nucleotides, which have recently appeared in the literature. These results demonstrate the critical importance of DNA repair for the functioning of the mechanisms that ensure the longevity of the body. To further explore the role of DNA repair and poly (ADP-ribosyl) ation in aging, Bürkle's scientists have recently developed an improved method for quantitatively analyzing DNA cross-linking and breaks in living cells using an automated guided alkaline unweaving method. fluorescence (automated fluorescence-detected alkaline DNA-unwinding (FADU) assay). They also developed a new method for monitoring poly (ADP-ribose) formation in living cells using liquid cytometry, based on the approach used for permeabilized cells.
Longevity
Improvements in the quality of social conditions, medical care and quality of life have led to an improvement in the health status of the population as a whole and, consequently, to a decrease in morbidity and mortality, which has led to an increase in life expectancy. In the 70s, a gradual decrease in mortality (by 1-2% per year) of individuals over 80 years old was observed in all industrialized countries, which led to an increase in the number of people who reached the age of 100, about 20 times. These centenarians are a group of people who have benefited from delaying the onset of diseases that are a common cause of death in much younger people. Data on the genetics of human longevity, mainly obtained from studies with the participation of people who have crossed the 100-year milestone, indicate the following: individuals aged 100 years and older, as well as long-lived siblings are the best choice when studying the patterns of human longevity, so how they have an extreme phenotype, that is, qualities that allowed them to avoid death in infancy, death from infectious diseases before the antibiotic era, and death as a result of age-associated complex diseases. The 100-year-old model is not just an addition to well-studied model organisms. Human studies have revealed characteristics of aging and longevity (geographic and sex differences, the role of antigenic load and inflammation, the role of mtDNA variants) that have not been disclosed in the study of aging processes in animal models. All phenotypic features of centenarians of two age groups (90-100 years old and over 100 years old) correspond to the hypothesis according to which the essence of the aging process lies in the “restructuring” or progressive adaptation of the long-liver's organism to external and internal damaging agents acting on it for several decades, according to most not foreseen by evolution. This adaptation process, which can be considered a Darwinian process occurring at the somatic level under the influence of evolutionary pressure, may explain why the same gene polymorphism can have different (beneficial or harmful) effects at different age periods. Demographic data indicate that longevity is provided by various combinations of genes, environment and random factors, and their influence can differ quantitatively and qualitatively depending on the geographical area, as well as that population-specific genetic factors play a role in the phenotype of longevity ... The combined and integrated use of new high-performance strategies based on the use of powerful computers will significantly accelerate the identification of new genes that ensure human longevity.
It is widely believed that the existence of more or less centenarians is mainly due to the mortality rate between the ages of 80 and 100 years. In fact, the low mortality rate in this age group suggests that more people will survive the centenary. Therefore, to determine the longevity of a population, demographers use the mortality rate at the age of 80-100 years, and not the relative number of centenarians (100 years and older) in the population. Of great interest is Sardinia (the second largest Italian island), which is home to a large number of centenarians, especially a geographical area in which male mortality after 80 years is lower than anywhere in the region and throughout Italy. This zone covers several municipalities in the center of the island and extends to the south of the province of Nuoro, where male deaths from cardiovascular disease and cancer are particularly low. The study of populations genetically isolated due to cultural and historical reasons, origin and demographic parameters is considered the best method for analyzing and mapping interrelated multifactorial traits. The situation observed in Sardinia has drawn the attention of researchers to the larger Italian island, Sicily. First, they wanted to identify geographic areas homogeneous in terms of low mortality rates for males and females over 80, and examine the region-specific causes of death in older people. Secondly, to compare Sicily and Sardinia in order to identify analogies and find the reasons for such longevity. As reference periods, scientists have chosen the time intervals from 1981 to 1990 and from 1991 to 2001. According to the 2001 census, at that time Sicily was divided into 390 municipalities and Sardinia into 377 municipalities. Selected for the study, respectively, 386 and 363 municipalities at the time of the beginning of the municipal analysis (1981) had similar characteristics from a geographic point of view. The calculation of standardized mortality rates (SRS) of people over 80 years old (for general mortality and mortality due to specific reasons), according to generally accepted epidemiological rules, was carried out by municipalities. When creating geographic maps, the researchers used kernel density estimators for nonparametric density estimates. The kernel density functions are averaged ATP values calculated as a spatial moving average for several municipalities bordering the municipality in question. The results obtained indicated the existence of a region in Sicily, for which, to the same extent as for the famous region of Sardinia, male (but not female) longevity is characteristic (Fig. 1).
Mortality rates in the municipalities of Sicily - among men (left) and women (right) over 80 years old between 1994 and 2001.
Mortality rates are color coded from blue (lowest) to red (highest).
The mortality rate among women in the "blue" zones is higher than the average for Italy.
Both areas under consideration are sparsely populated, occupy a small area and do not have contaminated areas. Thus, the authors concluded that longevity is typical for men living in small cities in ecologically clean zones and, most likely, is due to certain working conditions and lifestyle, including limited consumption of alcohol and tobacco, as well as nutrition according to the principles of called the "Mediterranean diet". Accordingly, both regions (both Sicily and Sardinia) are characterized by low mortality from cancer and cardiovascular diseases. Longevity appears to be less prevalent in women due to slightly different living and working conditions and lower educational levels, which results in less access to disease prevention and health facilities. The reason that longevity is characteristic of residents of small settlements has been known for a long time - it is the better health status of older people who have strong social support from the family, which is especially typical for families with adult daughters.
Final comments
In conclusion, it should be noted that aging should be considered as an inevitable stage in the life of every individual, however, the emergence of new information about the mechanisms of aging makes it possible to work out various strategies for slowing down the aging process. Thus, a better understanding of the pathophysiology of aging and associated diseases is necessary to ensure that all people have a real chance to live a long and disease-free final stage of life.
Bibliography to Article .
Translation: Evgeniya Ryabtseva
Portal "Eternal Youth"
Primary care physician
Age-associated conditions (geriatric syndromes) in the practice of a general practitioner at a polyclinic
^ I.I. Chukaeva, V.N. Larina
Department of Polyclinic Therapy, Faculty of General Medicine, Pirogov Russian National Research Medical University, Ministry of Health of the Russian Federation, Moscow
The article discusses the geriatric syndromes that are most common in the practice of a general practitioner at a polyclinic. Etiological factors, peculiarities of pathogenesis, clinical picture and prevention of senile asthenia and sarcopenia are discussed. Key words: geriatric syndromes, elderly patient, senile asthenia, sarcopenia, falls.
More than half of the patients who seek help from the general practitioner of the polyclinic are elderly and senile persons. Such patients require a different approach to assessing the state of health, monitoring and treatment in connection with the changes in the body that develop in the process of physiological aging.
Aging is associated not only with an increase in the number of diseases, polypharmacy, but also with the development of a number of geriatric syndromes, reflecting the morphofunctional age-related evolution in different organs and systems of the aging organism.
Geriatric syndromes
Most of the conditions that geriatricians deal with in everyday clinical practice are classified as geriatric syndromes, but the concept of the latter remains poorly understood (Table 1).
The term "geriatric syndrome" is used to distinguish clinical
Contact information: Vera Nikolaevna Larina, [email protected]
conditions in elderly and senile persons other than the category of "disease". Geriatric syndromes are multifactorial conditions that form in response to a decrease in the functioning of many organs and systems.
Despite their heterogeneity, geriatric syndromes have many features in common:
Widespread among people of the older age group;
Table 1. Geriatric syndromes and diseases
Dementia conditions (Alzheimer's disease,
senile psychosis)
Sleep disturbance
Decreased hearing, vision
Cataract
Urinary incontinence
Fecal incontinence
Osteoporosis
Movement disorder
Malnutrition
Dehydration
Violation of thermoregulation
Dizziness
Sarcopenia
Senile asthenia
Rice. 1. Relationship between geriatric syndromes and outcomes (adapted from).
General risk factors (age, decreased cognitive status, functional disorders, decreased activity / mobility) and pathophysiological mechanisms underlying their development;
A negative impact not only on the quality of life with further disability, but also on the prognosis (Fig. 1).
In addition to the above, geriatric syndromes are characterized by some clinical features. Firstly, each geriatric syndrome has many risk factors for development as a result of age-related changes in systems and organs. Second, diagnostic approaches aimed at identifying the underlying cause of a particular geriatric syndrome are often ineffective, burdensome, dangerous, and costly. And finally, it is necessary and expedient to treat the clinical manifestations of geriatric syndromes, even in the absence of a definitive diagnosis or a cause underlying its formation.
Unfortunately, geriatric syndromes do not receive the necessary attention in routine therapeutic practice. This situation may be due to the lack of awareness of general practitioners and general practitioners of the outpatient level about the presence and consequences of geriatric syndromes; focusing on the complications of concomitant pathology, which is often present in persons of the older age group (acute cerebrovascular accident, cardiac
heart failure, rhythm and conduction disturbances), and not on the general state of health of the patient.
Doctors have an idea of an elderly person as having many diseases and needing to prescribe a large number of drugs, which, of course, matters. However, in old age, it is often not the presence of the disease itself that is important, but the extent to which it limits the daily activity of a person and increases his dependence on the close environment. The quality of life, including in severe cases of the disease, can improve over time, despite the impossibility of the patient recovering and returning to his previous normal activities. This is due to the high adaptability of a person to clinical symptoms, which makes it possible to consider his quality of life at a satisfactory level even in the absence of positive dynamics of the clinical state.
Thus, according to the Russian project "Crystal", in which 462 outpatients aged 65 to 74 years and 452 patients aged 75 years and older took part, the main problem of older people was a decrease in functional activity and quality of life. Every 4th patient is partially dependent in his daily activities on a stranger.
In 1976, B. Isaacs introduced the term "giants of geriatrics", which includes changes that are present in weakened persons of the older age group: decreased vision
General Medicine 1.20sh1
Primary care physician
Etiology / risk factors
Potential mechanisms Frailty phenotype
Chronic Intermediate
inflammation
Musculoskeletal
Endocrine Cardiovascular Hematopoietic
Weakness Weight loss Waste
Decreased activity
Delayed activity
Rice. 2. Pathogenesis of senile asthenia.
and hearing loss, imbalance and falls, urinary and fecal incontinence, cognitive decline. The data accumulated to date have made it possible to revise and change the concept of the leading components of geriatrics. J. Moley considers senile asthenia and sarcopenia as new "giants of geriatrics".
Senile asthenia
An extreme manifestation of age-related changes that lead to involutive processes in the body and organ damage against the background of polymorbidity is the syndrome of senile asthenia. Senile asthenia in modern geriatrics is the leading and most significant condition in terms of its consequences. Senile asthenia is considered as a result of the accumulation of natural age-related processes, the accumulation of various diseases and is a characteristic of the health status of older patients.
Senile asthenia is defined as a biological syndrome characterized by an age-associated decrease in the physiological reserve and functions of most organs, which leads to
a decrease in the ability to respond to external and internal stressful influences, as well as to adverse functional and medical consequences. Senile asthenia and disability have much in common, but not all persons with disabilities suffer from senile asthenia, and about 70% of persons with senile asthenia do not have a disability.
The true prevalence of senile asthenia has not been established, since it depends on the age of the patients and the criteria for its assessment. According to various sources, the frequency of senile asthenia in the population is approximately 5%, among people aged 65-75 years - 25%, among people aged 85 years and older - 34%. Age, female sex, low level of education and socio-economic status, loneliness, cardiovascular diseases, obesity are considered as the leading factors in the formation of senile asthenia. Chronic inflammation, presumably, is a key pathogenetic process that contributes to the formation of senile asthenia, both directly and indirectly, through other systems of the body (Fig. 2).
Geriatric syndromes
Since today there is no "gold standard" for the definition of senile asthenia, the most widespread and international recognition has received the "phenotype of senile asthenia" described by L. Fried et al. ... According to this description, senile asthenia is a complex condition and is determined by a combination of five indicators:
1) weight loss (sarcopenia);
2) a decrease in the strength of the muscles of the hand (confirmed with a dynamometer);
3) severe fatigue (the need to make efforts in the implementation of daily activities);
4) slowing down the speed of movement;
5) a significant decrease in physical activity.
In the presence of three or more indicators, senile asthenia occurs, in the presence of one or two indicators - senile preasthenia.
Also of interest is a fairly simple screening validated FRAIL scale for detecting senile asthenia in wide clinical practice (Table 2). If there are three or more positive answers, they talk about senile asthenia, one or two - about preasthenia.
Since the clinical manifestation of senile asthenia is heterogeneous, weakness is considered as its most frequent precursor, and the addition of slowness, decrease in physical activity precedes exhaustion and loss of body weight in most older persons.
Most often, with senile asthenia, the musculoskeletal, immune and neuroendocrine systems are affected. Aging leads to heterogeneity in the size of muscle fibers with a predominant loss of type I fibers, a uniform decrease in the number of muscle fibers of types I and II, and a decrease in the number of myosatellitocytes - the main source of physiological and reparative regeneration of skeletal muscle tissue.
Table 2. FRAIL scale
Acronym Description
Fatigue Fatigue (feeling tired most of the time in the last 4 weeks)
Resistance Endurance (difficulty or inability to climb a flight of stairs)
Ambulation Movement (difficulty or inability to walk a block)
Illness Diseases (there are more than 5 diseases)
Loss of weight Loss of body weight (loss of more than 5% of the previous weight in the last 6 months)
In addition, adipose tissue accumulates and redistributes in the aging body, the amount of intercellular fluid, lean body mass (skeletal muscles, visceral organs), muscle mass and strength (sarcopenia) decreases, thermoregulation and innervation of muscle tissue is impaired with a decrease in its endurance.
In the process of aging, sympathetic tone increases and steroid dysregulation increases, the sensitivity of peripheral tissues to insulin, the intensity of metabolic processes, appetite and gustatory sensitivity to food decrease, a syndrome of "fast saturation" is formed, in which the volume of food intake decreases due to the increased sensitivity of the centers of saturation of the oblong brain. As a result of these processes, malnutrition syndrome is formed, which, along with the high activity of pro-inflammatory cytokines, contributes to the formation of age-associated sarcopenia.
Sarcopenia
Sarcopenia is not only an inevitable consequence of aging, but also the most important pathogenetic factor in reducing muscle strength, mobility, and changes in posture.
Primary care physician
Table 3. Factors involved in the pathophysiological process of sarcopenia
Factor Loss of muscle mass Loss of muscle strength
Decreased physical activity Yes Yes
Decreased testosterone levels Yes Yes
Atherosclerosis Yes Yes
Increased levels of proinflammatory cytokines Yes Yes
Decreased food (protein) intake Yes No
Vitamin D deficiency No Yes
Mitochondrial dysfunction No Yes
Decreased levels of growth hormone and insulin-like growth factor-1 Yes No
Decreased levels of growth factor and differentiation-1 Yes No evidence
Table 4. Questionnaire SARC-F for screening sarcopenia
Component Question Score, points
Strength How much difficulty do you have to lift and carry the 4.5 kg weight? No - 0 Some - 1 Pronounced or not able - 2
Walking assistance How much difficulty do you have when walking around the room? No - 0 Some - 1 Expressed, in need of help or not able to - 2
Getting up from a chair How much difficulty do you have when getting out of a chair or bed? No - 0 Some - 1 Pronounced or not able to do it without assistance - 2
Climbing stairs How much difficulty do you experience when climbing a span of 10 steps? No - 0 Some - 1 Pronounced or not able - 2
Falls How many times have you fallen in the last year? Not once - 0 1-3 times - 1 4 times or more - 2
and the formation of imbalance with the syndrome of falls, osteopenia and changes in metabolic processes in the body.
The term "sarcopenia" was introduced into the literature by I. Rosenberg in 1995. Sarcopenia was defined as age-related pathological muscle loss and was seen as a predictor of decreased body function. Later, in 2012, T. Manini and B. Clark noted that sarco-
singing is the loss of muscle strength, not mass, which leads to functional impairment in old age.
Nowadays, the term "sarcopenia" is used mainly to describe age-related changes in skeletal muscles and implies the loss of muscle mass, strength and functional ability of a person with a further loss of the ability to self-care due to age-related changes in hormonal status.
Table 5. Causes of falls in old age
Group List
General Decreased body position control, gait disturbance, weakness, decreased muscle
strength in the limbs, visual impairment and vestibular apparatus, slowing down of reaction
Specific drugs that cause dizziness or body imbalance
Visual impairment, cataracts, retinal degeneration
Meniere's disease, Parkinson's disease
Vasovagal reactions when coughing, urinating, defecation
Hypoglycemia
Violations of the rhythm and conduction of the heart
Alcohol intake
Tendency to orthostatic hypotension
External influences: uncomfortable shoes, walking on uneven surfaces, harsh sound,
tremors, etc.
tus, central and peripheral nervous system, inflammatory reactions, a decrease in the density of the capillary network of skeletal muscles. The factors involved in the pathophysiological process of sarcopenia are presented in table. 3.
For the timely detection of muscle dysfunction in old age, a simple questionnaire SARC-F (sluggishness, assistance in walking, rise from a chair, climb stairs, falls) has been proposed (Table 4). A score> 4 is a predictor of sarcopenia and poor prognosis.
Sarcopenia is one of the reasons for the development of senile asthenia. However, not all persons with senile asthenia have sarcopenia, and not all persons with sarcopenia have senile asthenia, which certainly serves as a basis for further study of this problem.
Falls, especially repeated ones, are considered as one of the components of senile asthenia syndrome and occur in 30% of people over 65 years old and in 40% of people over 80 years old. Gait disturbances with a slowdown in walking speed, unsteadiness in posture, shortening of stride, shuffling are components of senile asthenia and often contribute to falls.
Falls lead to skeletal injuries and fractures, which are the 6th leading cause of death in older people. In addition to this, falls worsen the functional state, mobility, increase the risk of repeated hospitalizations, they are associated with the formation of an anxiety-depressive state, fear of repeated falls. In this regard, older people try not to leave their homes, which leads to an increased risk of loss of social independence.
It should be noted that the risk of falls in an elderly person and the peculiarities of walking are not taken into account and underestimated by medical workers, especially at the outpatient stage. According to a survey of American primary care physicians, only 37% of them asked patients for a history of falls.
Literature data and clinical experience indicate the need to include an assessment of the risk of falls in the elderly, since it is in this way that it is possible to realistically predict the occurrence of fractures. In this case, the following factors should be taken into account: muscle strength of the lower extremities, post-ural stability / lateral balance, degree of visual impairment, cognitive
General Medicine 1.20sh1
Primary care physician
disorders, the simultaneous use of several drugs. Skeletal muscle function and muscle strength balance are assessed in the chair lift and tandem walk tests, as these tests have been shown to be associated with a high risk of falls. The causes of falls in old age are presented in table. 5.
Cognitive impairment
Cognitive impairment is a deterioration in comparison with the individual norm of one or more cognitive functions, which are formed as a result of the integrated activity of different parts of the brain.
Cognitive functions are complexly organized functions that carry out the process of rational cognition of the surrounding world: attention, memory (the ability to capture, store and reproduce information), perception of information, thinking, speech and praxis (voluntary purposeful motor action).
In the process of aging of the body, cognitive functions often decrease: cognitive deficits of varying severity are observed in the form of impairments to cognitive functions up to the development of dementia. Dementia is a chronic pronounced disorder of the higher integrative functions of the brain, primarily cognitive, as well as emotional, which is accompanied by social / professional maladjustment. Arterial hypertension, chronic heart failure, acute cerebrovascular accident, hyperlipidemia, obesity, genetic predisposition, low intellectual activity at a younger age and an unhealthy lifestyle are risk factors for the development of cognitive impairment. The latter not only reflect the general disadvantage, but also indicate a high risk of developing disabilities and
poor prognosis. This is especially true of the so-called cognitive senile asthenia, described in 2008 and combining cognitive impairment and senile asthenia syndrome.
What you need to pay attention to when examining
an elderly patient on an outpatient basis?
When taking anamnesis, it should be remembered that decreased appetite, chronic pain, dehydration, dementia, depression, urinary incontinence, pressure sores, insomnia, locomotor falls, cognitive impairments, hearing and visual impairments contribute to the formation of senile asthenia.
During a physical examination, it is necessary to identify factors such as decreased memory, attention, episodes of decreased mood, depression, deterioration in vision, hearing, and muscle strength.
Laboratory tests include a complete blood count (hemoglobin content) and urine, biochemical blood test (glucose and albumin levels, lipid profile, kidney and liver function); if necessary, it is possible to determine markers of inflammation, the level of vitamins B, B12, folic acid, iron, ferritin, thyroid-stimulating hormone. Monitoring of laboratory parameters is necessary to monitor the course of chronic diseases that occur in a patient.
Instrumental studies are indicated for the timely identification of the consequences of senile asthenia, in which, due to polymorbidity, many organs and systems are damaged (cardiovascular, respiratory, genitourinary, digestive, etc.).
Patients without senile asthenia are usually under the supervision of a general practitioner / general practitioner who carries out standard preventive and therapeutic-diagnostic measures. Patients with preasthenia and asthenia should be referred to a geriatrician for assessment.
Geriatric syndromes
health status - a comprehensive geriatric assessment in order to identify elderly and senile people who need not only medical, but also social assistance.
The purpose of a comprehensive geriatric assessment, which is an interdisciplinary diagnostic process, is to identify medical and psychological problems, functional abilities, create a coordinated treatment plan and long-term patient follow-up. A comprehensive geriatric assessment includes the following components:
Information about the patient and social status: family history, living conditions (nature and safety of the place of residence), the presence of family and relatives (care of the close circle), financial situation, alcohol abuse, the need for social support and protection, including hospitalization in social institutions of a stationary type;
Physical status: identification of geriatric syndromes, for example, falls, urinary incontinence, malnutrition, hypomobility, etc.;
Functional status: activity in daily life; mobility (gait speed); functional potential assessment using questionnaires; identifying the degree of involutive changes in organs and systems, assessing the quality of life;
Mental health indicators: age-associated changes in mental status (cognitive impairment, dementia, or depression); psychological personality traits.
What should a primary care physician / general practitioner know and be able to do?
1. Know what senile asthenia is.
2. Assess age-related changes in organs and body systems.
3. Be able to conduct a geriatric examination (questionnaires, scales) or assess the functional state of an elderly person.
4. To identify the syndrome of senile asthenia and other geriatric syndromes.
5. Determine the indications for consultation with a geriatrician.
7. Correctly interpret the conclusion of the geriatrician.
8. Take an active part in drawing up and implementing an individual plan for monitoring and treating a patient, taking into account the recommendations of a geriatrician (at home - as needed): at least 1 visit in 3 months for a nurse and 1 visit in 6 months for a doctor.
9. If necessary, arrange a consultation with a geriatrician at home.
Prevention of the development of senile asthenia and other geriatric syndromes
Senile asthenia, sarcopenia, falls, cognitive impairment are geriatric conditions of high medical and social significance, since they are not only the most widespread, associated with high morbidity and disability, but also reversible conditions with their timely detection and preventive and therapeutic measures.
The reversibility of senile asthenia is of particular interest in its study, and with timely detection of this condition, it is possible to slow down the progression of disorders of body functions, reduce susceptibility to external influences and improve the patient's quality of life. In addition, prevention of senile asthenia can delay up to 5% of deaths in older patients. Approaches to the management of an elderly person with senile asthenia are presented in table. 6.
Primary care physician
Table 6. Algorithm of management of an elderly person with senile asthenia
Fatigue Fatigue Screening for depression, sleep apnea, hypothyroidism, anemia, hypotension Elimination of sleep apnea; determination of the levels of thyroid-stimulating hormone, hemoglobin, vitamin B12; blood pressure control
Resistance Endurance Ambulation Movement Sarcopenia Exercise, aerobic exercise: 3-5 times a week. Introduction to the diet of protein, vitamin B (if necessary)
Illness Diseases Review drug therapy for side effects to exclude their influence on the development of asthenia For example, anticholinergic, psychotropic, antihypertensive, hypoglycemic drugs
Loss of weight Weight loss Anorexia drugs; alcohol addiction; diseases of the oral cavity; digestive disorders; dementia; depression; hyperthyroidism, hyperglycemia, hypercalcemia; salt-free, hypoglycemic, hypocholesterol diet + Increased calorie intake
There are data proving a slowdown in the progression of sarcopenia with the use of certain drugs: an angiotensin-converting enzyme inhibitor perindopril, an activator of fast troponin complexes in skeletal muscles tirasemtiva and a P-agonist / antagonist espindolol, which should be taken into account when managing patients of the older age group.
The letters that make up the word FRAILTY (senile asthenia) help determine the plan for preventing this condition:
F (food intake maintenance) - control of the food intake;
R (resistance exercises) - physical activity;
A (atherosclerosis prevention) - prevention of atherosclerosis;
I (isolation avoidance) - avoidance of social isolation (loneliness);
L (limit pain) - relief of pain;
T (tai chi or other balance exercises) - performing physical exercises (especially aimed at training balance);
Y (yearly functional checking) - regular medical check-ups.
Diet control includes
yourself a balanced diet with low
Regular physical activity has a cardioprotective effect, reduces age-related decline in muscle mass and bone density, improves functional activity and improves quality of life. For persons of the older age group, on an individual basis (if possible), walking, physical education (exercises in the initial standing position and when moving, including aerobics, gymnastics) are useful; a ride on the bicycle; mobile outdoor activities.
Elderly and old people need balance training (balance) to reduce the risk of falls and fractures, including individually tailored exercise programs with a gradual increase in muscle strength, dancing, walking, teaching the patient to stand and sit correctly, keeping his back straight. Fall prevention activities are extremely important in general clinical practice.
To prevent falls, it is necessary to: regularly check visual acuity,
Geriatric syndromes
pick up glasses; do not abuse sleeping pills (impaired coordination of movements and increased dizziness); install special crossbars in the bathroom for support, use non-slip rubber mats; create good lighting in the apartment; do not walk around the apartment in the dark; do not leave the house on ice (or move only with a stable cane); do not use stepladders or chairs to reach anything.
Encouraging participation in psychological education courses on the basis of social protection centers, in amateur art groups, visiting health groups, doing housework and at their summer cottage, support and understanding of the close environment (family, relatives, neighbors, friends) contribute to the social activity of the elderly person.
Regular medical examinations are necessary for the timely detection of deviations in health, correction of the existing one or selection of a new therapy according to indications. In order to avoid un-
favorable consequences, it is important to identify changes at the preasthenia stage.
Conclusion
Geriatric syndromes increase the vulnerability of an elderly person to external influences and worsen the quality of life, leading to disability. It is important to remember that senile asthenia characterizes the functional status and state of human health, its determination allows identifying older people who are at risk of adverse outcomes. In this regard, when managing an elderly and senile patient, the therapist should assess age-related changes in organs and systems, pay attention to the presence of geriatric syndromes / diseases in the patient, determine the indications for consultation with a geriatrician and take part in the preparation and implementation of an individual observation plan and treatment of the patient, taking into account the recommendations of the geriatrician.
The list of references can be found on our website www.atmosphere-ph.ru
Geriatric Syndromes in a Primary Care Setting I.I. Chukaeva and V.N. Larina
The article deals with the most common geriatric syndromes in a primary care setting. The authors discuss etiology, pathogenesis, clinical course and prevention of frailty and sarcopenia. Key words: geriatric syndromes, elderly patient, frailty, sarcopenia, falls.
Knigp publishing house "Atmosphere"
Functional diagnostics in pulmonology: Monograph / Ed. Z.R. Aisanova,
A.V. Chernyak (Series of monographs of the Russian Respiratory Society, edited by A.G. Chuchalin)
The monograph of the fundamental series of the Russian Respiratory Society summarizes the world and domestic experience on the whole range of problems associated with functional diagnostics in pulmonology. The physiological foundations of each method for the study of pulmonary function and the peculiarities of the interpretation of the results are described. The international experience in the use and interpretation of various methods of functional diagnostics of pulmonary diseases is generalized, including relatively few used in our country, but extremely necessary in the diagnosis of functional tests: measurement of lung volumes, assessment of the diffusion capacity of the lungs and the strength of the respiratory muscles, out-of-laboratory methods for determining the tolerance of patients with bronchopulmonary pathology to physical activity, etc. 184 p., Ill., Tab. For pulmonologists, therapists, general practitioners, family doctors, as well as for specialists in functional diagnostics.
480 RUB | UAH 150 | $ 7.5 ", MOUSEOFF, FGCOLOR," #FFFFCC ", BGCOLOR," # 393939 ");" onMouseOut = "return nd ();"> Dissertation - 480 rubles, delivery 10 minutes, around the clock, seven days a week
Zhaboeva Svetlana Leonovna. Organizational and methodological foundations for modeling personified programs for the prevention of age-associated diseases and assessing their effectiveness: dissertation ... Candidate of Medical Sciences: 02.14.03 / Zhaboeva Svetlana Leonovna; [Place of defense: Peoples' Friendship University of Russia] .- Moscow, 2017.- 290 With.
Introduction
Chapter 1. Strategies for the prevention of major noncommunicable diseases. Medical and social problems of population and the prospects for personalized prevention (an analytical review of the works of modern domestic and foreign authors) 17
1.1. Analysis of the activities of medical organizations in the implementation of preventive programs: assessment of the results achieved, medical and social problems
1.2. Age-associated diseases: definition, relevance and social significance 43
1.3. Justification of the transition from population strategies in preventive activities to personalized approaches in the implementation of programs for the prevention of age-associated diseases 48
Chapter 2. Material and research methods 54
Results of our own research
Chapter 3. Opportunities for the implementation of preventive programs for age-associated diseases in medical organizations of public and private forms of ownership
3.1. Analysis of the main indicators of health and the dynamics of the appealability of the adult population to medical organizations 71
3.2. Expert assessment of the material and technical base, service and economic components, the effectiveness of management of medical organizations in the implementation of preventive programs 84
3.3. Medical-organizational analysis of the professional activities of doctors in the implementation of preventive programs 87
3.4. The role and place of preventive care in the goals and objectives of medical organizations 103
Chapter 4. Assessment of the quality of life of patients with age-associated diseases 109
4.1. Characteristics and hierarchy of age-associated diseases 110
4.2. The relationship of age-associated syndromes with major noncommunicable diseases 114
4.3. Study of the quality of life of middle-aged and elderly patients with established age-associated diseases 119
Chapter 5. Medical and organizational analysis of preventive programs implemented in medical organizations 125
5.1. Expert assessment of prevention programs implemented on the basis of public and private medical organizations 125
5.2. Analysis of the reasons for patients' referrals to medical organizations 129
5.3. Studying the opinion of middle-aged and elderly patients on preventive programs implemented on the basis of medical organizations 134
Chapter 6. Implementation of personalized preventive programs in medical organizations - assessment of management approaches 137
6.1. Analysis of the main characteristics of medical organizations and personnel for the implementation of programs of personalized prevention of age-associated diseases from the point of view of management 137
6.2. Organizational and methodological principles of training medical personnel in the implementation of preventive care for patients with age-associated diseases 147
Chapter 7. Justification of the principles of creating personalized programs for the prevention of age-associated diseases and the assessment of their medical and economic efficiency 155
7.1. Creation of prognostic scales for the effective implementation of personalized programs for the prevention of age-associated diseases 157
7.2. Development of an algorithm for the introduction of personalized prevention services for age associated diseases 165
7.3. Model of implementation, implementation and evaluation of the effectiveness of personalized prevention services age of associated diseases 174
7.4. Assessment of the medical and economic efficiency of introducing a model of personalized prevention of age-associated diseases in middle-aged and older people as a result of participation in preventive programs 183
Conclusion 199
List of abbreviations and conventions 213
Bibliography 214
Introduction to work
Relevance and degree of elaboration of the research topic. The main
the priority of the state policy of the Russian Federation today
is the preservation and strengthening of public health by improving the quality and
the availability of medical care, the introduction of high-tech
treatment methods, the promotion of a healthy lifestyle and an emphasis on
disease prevention (Chazova I.E. et al., 2004; Nazarova I.B., 2003; Kontsevaya
A.V. et al., 2008; Bykovskaya T. Yu., 2011; Vyalkov A.I., 2012; Medvedskaya D.R., 2013;
Pozdnyakova M.A. et al., 2015; Busse R. et al., 2008; Kirkwood T.B., 2013). On the
over the past decades, the search, development,
improvement and implementation of new methods in the system
health care, various models of management of medical
organizations in order to improve the efficiency of their work (Korotkov Yu.A. et al.,
2011; Martynov A.A. et al., 2014; N.V. Pogosova et al., 2014; Andreeva O.V. With
et al., 2015; Marshall K.L., 2014). The reforms carried out have resulted in
significant positive changes in public health indicators in most regions of the Russian Federation (Vishnevsky A.G., 2008; Kiseleva L.S., 2010; Dimov A.S. et al., 2011; Glushakov A.I., 2013; Yagudin R. H. et al., 2015).
However, the results achieved are still lower than the projected indicative indicators outlined by the Strategy for the Development of Healthcare of the Russian Federation for the long-term period 2015-2030. (Lysenko I.L. et al., 2014; Resolution of the Cabinet of Ministers of the Republic of Tatarstan No. 1029 dated December 25, 2014). treatment of diseases, whereas prevention and sanology not enough attention is paid (Oganov R.G. et al., 2003; Boytsov S.A., 2012; Boytsov S.A. et al., 2013; Pogosova N.V. et al., 2014; Boytsov S.A. et al., 2015). The situation is aggravated by the fact that, according to UN forecasts, in the period from 2000 to 2050, the world's population aged 60 and over will more than triple: from 600 million to 2 billion, which will be more than 1/5 of the world's population. , and in a number of countries, including Russia, the proportion of such people will reach 35% (United Nations Development Program, 2009; “Executive Summary: World population aging 1950–2050”, 2001; Cook J., 2011; Mc Intyre D., 2014). This demographic change has a number of consequences for public health, therefore, the reform of the health care system should take into account the prospective changes in the age composition of the population (Andreeva O.V. et al., 2015; Olshansky S.J. et al., 2012).
At the same time, clinical and epidemiological data show that today more than 10% of middle-aged people have functional signs characteristic of people of older age groups, which reflects the presence of population processes of premature aging (Ilnitskiy A.N., 2007; Anisimov V.V. N., 2010; Boytsov S.A. et al., 2013; Delcuve G.P., 2009; P. Lloy-Sherlocketal., 2012). Moreover, experts note that along with the general accelerated aging of the population, there is an accumulation of an unfavorable comorbid background.
(Belyalov F.I., 2011; Vertkin A.L. et al., 2013; Akker M. et all., 1998; World Health Organization, 2001; Karlamangla A. Et all., 2007; Kessler RC et all., 2007 ; LordosE.F. Et all., 2008; RobertsH.C. Et all., 2011): the acquisition of so-called new diseases: "diseases of civilization" or "new world non-infectious pandemics", such as diabetes mellitus, cardiovascular, oncological and cognitive diseases, depression, osteoporosis, diseases of the genitourinary system, erectile dysfunction in men, etc., which leads to a decrease high-quality, active life of a middle-aged and older person (Vertkin A.L., 2013; Markova T.N. et al., 2013; Akhunova E.R., 2014; Korkushko O.V. et al., 2014; Groot V. et all ., 2003; Weel C. et all., 2006; Morisky DE et all., 2013). Disorders in the health and well-being of the elderly and older people limit their independence, impair the quality of life and hinder the ability to take an active part in family and community life (Burton L.A. et all., 2010). Therefore, health promotion and disease prevention measures throughout life can prevent or delay the onset of non-communicable and chronic diseases (Boytsov S.A. et al. 2013; 2015; Seeman TE et all., 2010; Crimmins EM et all., 2011) ... In addition, it is advisable to introduce measures for early detection and, if necessary, treatment of noncommunicable diseases not only to minimize these consequences, but also to reduce the cost of providing primary health care, because people with diseases, especially in advanced stages, require appropriate care and support services for a long time, which, according to experts, will eventually cost the state 2-3 times more (Son I.M. et al., 2006; Prokhorov B.B. et al., 2007; Rimashevskaya N.M., 2007; Shemetova G.N. et al., 2014). The problem of disability and mortality of the population due to non-communicable diseases should not be neglected, which, according to experts, also causes significant economic damage to the state (Oganov R.G. et al., 2003; Hoover DR etall., 2002; Dillaway HE et all., 2009; Leeuwenvan KM etall., 2015; Oliver D. et all., 2015). In our opinion, “all this dictates the need to create an effective medical prevention service in Russia, aimed primarily at preventing diseases associated with age” (Zhaboeva S.L. et al., 2015; Zhaboeva S.L. et al. ., 2016). At the same time, most authors emphasize that it will not be possible to solve this problem by means of population prevention, therefore, it is necessary to actively introduce means of personalized prevention into the work of medical organizations (Lakhman E.Yu., 2005; Malykh O.L. et al, 2010; Boytsov S. A., 2012; Golubeva E.Yu., 2014; Kononova I.V. et al., 2014; Hansson L. et al., 2008; Eklund K. et all., 2009).
Meanwhile, a number of unresolved problems are noted: there is no normative documentation regulating the activities of a doctor in the field of preventive activities, the main directions and volumes of services for the provision of personalized prevention of age-associated diseases have not been determined, the prognostic needs of the population in this type of care have not been studied, there are no standards and regulations, limited clinical recommendations for the provision of personalized preventive care to the population (Kartashov
I.G., 2007; Oganov R.G. et al, 2009; Baklushina E.K. et al., 2010; Andreeva O.V. et al., 2014; Krivonos O.V., 2014; Mc Kee M. et all., 2002; Nussbaum M.C., 2015).
All of the above testifies to the timeliness of the
research on the development and implementation of organizational and scientific methods for the prevention of age-associated diseases based on a personalized approach. This is especially relevant in the context of socio-economic reforms, modernization of health care and new trends in meeting the needs of the population in maintaining and strengthening their own health.
Objective- scientific and methodological substantiation, development and assessment of the effectiveness of medical and organizational technologies of personalized programs for the prevention of age-associated diseases, introduced at the regional level.
Research objectives:
Conduct an expert assessment of the activities of public and private medical organizations in the implementation of preventive programs.
To study the prevalence of age-associated diseases, to assess the incidence of polypathology among middle-aged and older patients.
To assess the impact of the main geriatric syndromes on the quality of life of middle-aged and older patients as potential consumers of personalized preventive programs.
Determine the readiness of public and private medical organizations to participate in the implementation of preventive programs.
To study the level of training of medical personnel involved in the implementation of preventive programs and develop a training program for the prevention of age-associated diseases within the framework of continuing medical education.
To develop prognostic scales for the early detection of age-associated diseases and the development of personalized prevention programs.
Scientifically substantiate the models of personalized programs for the prevention of age-associated diseases and evaluate their effectiveness in the context of private medical organizations.
Scientific novelty of the research. For the first time in the dissertation - from modern positions
public health, organization, management and economics of health care -
a study was made of the possibilities of implementing preventive age-related programs
associated diseases in medical organizations of state and
private forms of ownership. It has been shown that non-state medical
organizations today have the greatest advantage: financial,
personnel, material and technical, organizational and administrative and temporary
resources create the prerequisites for increasing the total coverage of the population
preventive care. The ranking of geriatric
symptom complexes, such as cognitive deficits, sarcopenia, malnutrition, hypomobility, decreased vision, etc., in relation to which implementation is required
personalized prevention programs, taking into account their importance, showed a significant deterioration in the quality of life of patients with the listed syndromes.
For the first time, on the basis of a medical-organizational analysis, it is shown that
timely
initiation of prevention programs for age-related
diseases, especially in middle-aged people, because the formation of leading medico-social geriatric syndromes begins on average 10.4 ± 1.38 years earlier than they are recorded in real medical practice.
For the first time - based on the identification of potential components of interest and motivation, as well as the initial level of knowledge of medical personnel (therapists, general practitioners, gynecologists, endocrinologists) - a training program for the prevention of age-associated diseases has been developed, proposed and tested within the framework of continuing medical education, which made it possible to improve the professional level of students in the field of theory and practice, diagnosis and prevention, legal issues and social problems of premature aging.
It has been proven that the developed and implemented models of personalized prevention of age-associated diseases can increase the rates of early detection of non-communicable diseases (arterial hypertension by 6.8%, type 2 diabetes by 11.2%, hypothyroidism by 18.9%, chronic venous insufficiency by 32.2%), which leads to an improvement in healthy life expectancy (for women aged 45 by 6.9 years, at the age of 65 by 4.8 years; for men by 3.2 and 1.7, respectively) ...
For the first time - based on the calculation of the heuristic indicator of lost years of life as a result of premature death and disability (DALY) for the middle and senior groups in gender refraction - the medical and economic efficiency of the implementation of the developed model of personified prevention of age-associated noncommunicable diseases was determined. On the basis of the experiment, it was shown that the number of years of “defective life” (if preventive programs were not applied) were reduced by an average of 27.8 ± 3.7% (the sum of potential life years lost due to premature death (disability) was: for men of the middle age group - 2.08 years; for women of the middle age group - 1.38 years; for men of the older age group - 0.6 years; for women of the older age group - 0.31 years), which corresponds to 30,430 rubles savings per year for 1 patient undergoing a prophylaxis program in a private medical organization.
Theoretical and practical significance of the research. The results of the dissertation can be used to increase the degree of involvement of private healthcare organizations in the provision of preventive services to the population. The introduction of personalized prevention programs focused on the prevention of conditions of medical and social significance will help to increase the coverage of the population with preventive care and improve the quality of primary health care. Developed principles of creation and
implementation of personalized prevention programs provide an opportunity
to form target groups of patients seeking medical services in
private healthcare organizations that should be screened for age
associated syndromes of medical and social significance and requiring
supplement population prevention programs with personification
preventive care. It is advisable to use the results of the work in
public and private healthcare organizations in order to increase
quality of preventive care, early detection of such age-
associated pathologies such as cognitive disorders, hypothyroidism, sarcopenia, age-related decrease in vision, etc., improving the functional parameters and quality of life of patients, improving the parameters of the quality of life. The results of the study will contribute to the integration of various “blocks” of preventive programs (population and personalized), which, in turn, will increase the quality and volume of implementation of preventive programs to the population, improve the quality of life of patients with identified geriatric syndromes and increase the expected healthy life expectancy.
The results of this dissertation research are used in the practice of healthcare organizations of the Republic of Tatarstan; The Kabardino-Balkarian Republic; Republic of Belarus; in the scientific and educational activities of the St. Petersburg Institute of Bioregulation and Gerontology of the North-West Branch of the Russian Academy of Medical Sciences; Department of Faculty Therapy, Belgorod State National Research University, Ministry of Education and Science of the Russian Federation; at the Department of General and Medical Practice, Gerontology, Public Health and Healthcare of the Faculty of Medicine of the Federal State Budgetary Educational Institution of Higher Education "Kabardino-Balkarian State University named after HM. Berbekov "; Belarusian Republican Gerontological Public Association.
Research methodology and methods. To carry out the work was used
a set of methods, including epidemiological, analytical,
psychological, statistical and sociological methods, as well as - the method of expert assessments, economic analysis and organizational and functional modeling, which made it possible to solve the assigned tasks. Analysis of risk factors and prevalence of non-communicable diseases was carried out according to the STEPS method recommended by WHO. The basis for this study was state outpatient clinics and private medical organizations in the city of Kazan.
Provisions for Defense:
The introduction of personalized prevention services for age-associated diseases in non-governmental medical organizations that have financial, personnel, material and technical, organizational, administrative and time resources will lead to an increase in the provision of preventive care to the population (with an optimistic forecast - by 17.26%; with a pessimistic forecast - by 6.44%).
Study of the prevalence of major geriatric syndromes (sarcopenia,
hypomobility syndrome, cognitive deficit, malnutrition syndrome and visual impairment syndrome) in middle-aged and older people - taking into account gender, age, presence and severity of concomitant non-communicable diseases with simultaneous determination of the correlation dependence of their occurrence - is the basis for creating models of personalized preventive programs age -associated diseases.
The developed prognostic scales are the basis for models of personalized prevention of age-associated diseases and allow, on the basis of dynamic observation, to assess the incidence of polypathology, to increase the rates of early detection of non-communicable diseases (arterial hypertension - by 6.8%, diabetes mellitus of the second type - by 11.2%, hypothyroidism - by 18.9%, chronic venous insufficiency - by 32.2%), improve the quality and duration of life.
Personalized prevention of age-associated diseases, carried out at earlier age periods (in middle-aged people), as well as the sequential implementation of procedures - identification of the leading geriatric syndromes and the risks of their development with the subsequent formation of target groups of patients, additional diagnostic measures, preparation of individual preventive programs - provides an improvement in healthy life expectancy (for women aged 45 - by 6.9 years, at the age of 65 - by 4.8 years; for men - by 3.2 and 1.7, respectively).
The introduction of the developed models of personalized prevention of age-associated non-communicable diseases in comparison with traditional population prevention leads to an improvement in patients' satisfaction with their health and makes it possible to improve the quality of life (on the SF-36 scale) by 9.8 ± 0.7 points, p0.05, reduce the sum of potential life years lost due to premature death (disability) by an average of 27.8 ± 3.7% (DALY average husband = 2.08; DALY average wife = 1.38; DALY female husband = 0 , 6; DALY pozh.zhen = 0.31), which will allow the state to save 30,430 rubles per year for 1 patient undergoing a prophylaxis program in a private medical organization.
The degree of reliability and approbation of the results. Research results,
presented in the thesis were reviewed and discussed
(presentations with reports) at the following scientific events: Regional scientific
practical conference "Social protection of the population and interaction with
medical services ”(Kirovograd, Ukraine, 2009); The Interregional
conference "Modern outpatient practice" (Novopolotsk, Belarus, 2010); scientific-practical conference "Modern approaches to population and individual prevention" (Seoul, Republic of Korea, 2014); at meetings of healthcare organizers of the Republic of Tatarstan (Kazan, 2013, 2014); International scientific and practical conference "Anti-aging medicine: moving into the future, keeping traditions" (Kazan, 2015), at the VII European Congress of the International Association of Gerontologists and Geriatricians (Ireland, Dublin 2015); II and III Republican scientific and practical conference "Topical issues
preventive medicine and provision of sanitary and epidemiological
welfare of the population ”(Kazan, 2016); V All-Russian Scientific and Practical
conference "Preventive medicine 2016. Innovative diagnostic methods,
treatment, rehabilitation of patients with diseases associated with age ",
(Moscow, 2016); V European Congress on Preventive, Regenerative and
Anti-Aging Medicine (St. Petersburg, 2016); IX-th Russian scientific
practical conference with international participation "Human health in the XXI
century "(Kazan, 2017). The dissertation was approved at an extended session
Department of Preventive Medicine and Human Ecology of the Federal
state budgetary educational institution of higher
professional education "Kazan State Medical
Publications. 58 papers have been published on the topic of the dissertation, including 29 articles (of which 20 are in scientific journals from the list of the Higher Attestation Commission of the Ministry of Education of the Russian Federation), 2 monographs, 2 textbooks and guidelines approved by the Presidium of the Eurasian Society of Gerontology, Geriatrics and Anti-Aging Medicine, 25 abstracts of reports.
The structure and scope of the thesis. The dissertation consists of an introduction, a main part consisting of seven chapters, conclusions, conclusions, practical recommendations, and a bibliography. The work is presented on 290 pages, contains 42 tables, 30 figures and a list of references, including 368 sources (including 117 in foreign languages).
Age-associated diseases: definition, relevance and social significance
To date, the world scientific literature provides convincing evidence, supported by many years of research on the effectiveness of the implementation of preventive measures in relation to risk factors for chronic non-communicable diseases among the population, such as hypertension, stroke, heart attack and diabetes mellitus. At the same time, all researchers note that the work on prevention and health promotion of the population does not give immediate results and has many "pitfalls".
Thus, in a number of works by researchers from the United States and Canada, it is noted that over the past 40-50 years, there has been a decrease in the mortality rate from stroke standardized by sex and age by more than 50%, and, to a slightly lesser extent in Europe, as a result of preventive programs. Other works provide convincing evidence that a 20% decrease in the prevalence of arterial hypertension and tobacco smoking can lead to a decrease in morbidity, including temporary disability and mortality from cardiovascular diseases by 15%, and this is equivalent to saving life. about 25 thousand people of working age annually. However, such results can be observed only after 5-10 years of daily preventive work with the population.
Preventive measures, together with monitoring the morbidity and mortality from CVD for 10 years under the name "WHO MOMSA Project", carried out by WHO, led to a decrease in mortality from coronary heart disease and a decrease in the impact of risk factors, both in men and women, by 75 and 65%, respectively. The rest of the changes in the samples, the authors of the project note, were associated with the provision of medical care, which provided "improved survival during the first four weeks after the event."
Preventive programs proposed by employees
Stanford University have also focused on reducing risk factors for hypertension, hypercholesterolemia, smoking, and overweight. More than 15 years of work resulted in a 24% reduction in the risk of myocardial infarction and cerebral stroke in the "experimental" cities compared to the "control" ones. Another preventive program "Oslo-Study", conducted in the USA, was focused on only one risk factor - adherence to permanent treatment of arterial hypertension. The resulting factor was the overall mortality rate (which decreased by 20-21%, mainly due to a decrease in mortality from CVD). The main conclusion reached by the authors of the program was that regular and effective treatment of arterial hypertension can reduce the risk of death from stroke in men 40-54 years old by almost 50%.
The UK-based EHLEIS project showed that the reduction in coronary heart disease mortality was due to an almost 58% reduction in population-wide exposure to risk factors. The remaining 42% were treatment-related (including 11% associated with secondary prevention, 13% with treatment for heart failure, 8% with primary treatment for acute myocardial infarction, and 3% with treatment for hypertension).
When assessing the results of the preventive program "North Karelia" from 1982 to 2005. in Finland, the organizers noted a decrease in the prevalence of risk factors: hypercholesterolemia, arterial hypertension and smoking, while the consumption of vegetables and fruits increased 2.5 times. The result of the implementation of this project was that over 20 years mortality from CVD decreased by 57%, from cancer of the respiratory tract - by more than 60%. A program carried out in the period from 1991 to 2002 in Poland, aimed at changing the diet of residents, led to a decrease in the death rate of residents of Warsaw from cardiovascular diseases by more than 50%. Compliance with a strict diet, combined with smoking cessation, led to a 13% decrease in cholesterol levels and was accompanied by a 47% decrease in the likelihood of myocardial infarction. At the same time, the authors of the program noted positive changes in the stereotype of the population's nutrition: a decrease in the consumption of saturated fatty acids by 19% and an increase in the consumption of polyunsaturated fatty acids by 32%.
In 2007-2010, in a number of countries of the world (China, Ghana, India, Mexico and South Africa), including Russia, under the auspices of the World Health Organization, a sample study of the health of the elderly was conducted SAGE4 (Study on global AGEing and adult health) [. In Russia, the sample consisted of 3418 respondents, and a comparison of the data on the prevalence of risk factors showed that Russia ranks first in terms of the amount of alcohol consumed per year (with the largest group being men aged 50-59); The second place is taken by obese Russian women (body mass index over 30 kg / cm2); III place after India and China in the prevalence of tobacco smoking (especially in the male population).
Expert assessment of the material and technical base, service and economic components, the effectiveness of management of medical organizations in the implementation of preventive programs
These changes in approaches to prevention are explained by the active work of a working group established in Canada in the late 1970s. It consisted of epidemiologists, methodologists and physicians providing primary health care and specialized medical care; It was headed by W. Spitzer. The team members were tasked with two main tasks: to determine the extent to which periodic medical examinations can contribute to the health of the population, and to develop a program of examinations that every Canadian citizen should undergo throughout their life. For 2 years, researchers collected data on the possibility of introducing preventive examinations for 78 diseases. Subsequently, it was concluded that annual medical examinations carried out without a specific purpose were useless. This data was published in 1979. Instead of mandatory periodic examinations by a group of experts, it was proposed to use certain combinations of targeted preventive interventions, which would be carried out during visits to the doctor for any other reason. As shown in the report, thanks to the use of this technology, a fairly complete identification of persons who can benefit from therapeutic and preventive interventions is achieved, and, at the same time, diagnostic studies are carried out purposefully, in limited groups of people. At the same time, risk groups were identified by age, gender, and the presence of behavioral risk factors. These suggestions are reflected in numerous clinical guidelines: for 19 diseases, clinical guidelines were proposed for the first time, and for 28 diseases, the recommendations were revised taking into account new information. Thus, the members of the working group found that regular preventive medical examinations aimed at diagnosing and subsequent treatment of predetermined diseases, as well as identifying and assessing risk factors affecting the population of different ages and sexes, are more effective than annual screenings carried out with assistance of everyday medical research methods.
The experience of colleagues in the development of clinical guidelines was adopted by domestic researchers, resulting in national guidelines for cardiovascular prophylaxis. The Guidelines provide up-to-date knowledge on three main strategies for the prevention of cardiovascular disease: population-based, high-risk, and secondary prevention. Much attention is paid by the authors of the recommendations to practical aspects - algorithms of preventive measures depending on the level of total cardiovascular risk, non-drug methods of preventing cardiovascular diseases and drug therapy that can improve the prognosis.
Quite often in the literature there are problematic articles containing questions devoted to calculating the effectiveness of the implemented diagnostic and therapeutic measures, while research work on assessing the effectiveness of preventive and screening programs is somewhat limited. This is probably due to the complexity of the assessment of ongoing preventive measures, which are described in a number of works. Difficulties such as lack of information and resources are noted by WHO experts when developing principles for the phased implementation of the STEPS monitoring system for the assessment and management of preventive strategies.
The transition from population-based preventive strategies to personalized ones is due to the fact that modern personalized medicine is based on the principles of preventive medicine, the content of which was most fully disclosed in the works of S. Auffray et al. (2010) and grew into the so-called “four Ps” medicine: predictive, preventive , personified and participatory - i.e. in medicine, aimed at predicting the disease before its symptomatic manifestation; a preventative illness; taking into account the individual, including genetic characteristics of a person; implying the active participation of the patient in identifying his genetic characteristics and preventive measures.
Conclusion: Currently, both domestic and foreign health care is going through a period of searching for new forms of organizing medical preventive care due to the fact that the existing mechanisms have practically reached their maximum in improving the quality of care and are mainly aimed at the population, and not at a specific individual. At the same time, consumers of medical services feel the need to receive better preventive medical care in terms of such parameters as accessibility, complexity, cost-effectiveness, achievement of the proper and desired quality of life, maximum adaptation in society, aesthetic component, and others. A rather promising niche for finding ways to improve the quality of care according to the specified criteria of patient needs can be the development of preventive programs focused on certain groups of consumers of services that are fundamentally different in any significant way.
The studies carried out in our country and abroad indicate the prospects of introducing a personalized approach in the provision of preventive care in modern socio-economic conditions based on a combination of the achievements of domestic medicine in the field of disease prevention and new trends in the field of meeting the needs of the population in maintaining and strengthening health.
Relationship between age-associated syndromes and major noncommunicable diseases
At the same time, it should be noted that against the background of a decrease in the number of visits to state polyclinics in the city of Kazan, there is a tendency to reduce the planned capacity of outpatient clinics in the city.
So, for the studied period (2010-2014), the planned capacity of city polyclinics decreased from 15672 to 15486 visits per shift, while in non-state polyclinics of the city), which fulfill the state task of providing outpatient care, there is a significant increase in this indicator with ZON visits per shift in 2010 to 3779 visits per shift in 2014 (Figure 3.5).
This fact testifies to the redistribution of the volume of medical care to the non-state healthcare sector of the city of Kazan.
In general, the provision of state-owned APUs over five years decreased by 20.4%: in 2010 it was 165.5 per 10 thousand of the population, and in 2014 this indicator was at the level of 131.7 per 10 thousand of the population.
Since the main volume of preventive work falls on the district therapeutic service of outpatient clinics, we carried out a retrospective analysis of its activities. So, at the beginning of 2014 in the city of Kazan there were 398 therapeutic sites (2010 -422) with an average number of attached population of 1929 ± 27 people (2010 - 1937 ± 31 people). The decrease in the number of therapeutic sites is explained by the expansion of the form of provision of primary health care to the population by general practitioners. So, if in 2010 there were 97 such sites in Kazan with an average population of 1825 ± 24 people served, then at the end of 2014 there were already 124 sites of general medical practice with an attached population of 1826 people. 191 general practitioners (2010 - 136 doctors) have a general practitioner certificate, i.e. 35% of general practitioners work as district doctors.
The summary analysis of visits to the district doctor and general practitioner in the city of Kazan showed that the proportion of preventive visits has a significant decrease, while the proportion of dispensary visits increases (Figure 3.6).
Figure 3.6. The structure of visits to the district doctor and general practitioner of state polyclinics in the city of Kazan (in%). So, at the end of 2010, the share of preventive visits in the total structure of visits was 7.9%, and in 2013 - 6.6%. The data presented in Figure 3.3 demonstrate a decrease in the share of home visits from 17.3% (2010) to 14.4% (2014) and preventive visits from 7.9% (2010) to 6.6% ( 2014), and an increase in the share of dispensary visits from 9.5% (2009) to 13.9% (2013), while the initial and repeated visits do not differ significantly.
The increase in the share of dispensary visits is primarily due to the implementation of federal target programs of the priority national project "Health". The decrease in the activity of medical care at home is noted due to the lengthening of the time of admission to the clinic. So the duration of admission was increased to 6 hours in two APUs of the city, to 5 hours - in ten APUs. In other APUs, lengthening the reception time is difficult due to a shortage of premises, which indicates a shortage of material and technical resources of outpatient clinics in the city of Kazan.
As part of this study, we conducted a study of outpatient cards and accounts-registers of appeals of the adult population to state ones (the sample included outpatient clinics in the city of Kazan: GAUZ City Polyclinic No. polyclinic No. 18 "- a total of 936402 calls, of which 151092 for preventive purposes, which is 16.14%) and non-governmental medical organizations conducting outpatient clinics (" Clinic of Youth and Beauty "," Polyclinic-Salvation ", Medical Center" Family health ”- a total of 178289 calls, while the share of calls for preventive purposes accounted for 18.91% of calls or 33709 in absolute terms) (Table 3.2).
Organizational and methodological principles of training medical personnel in the implementation of preventive care for patients with age associated diseases
The study identified the leading health problems that worried patients with diseases leading to the main medical and social syndromes, and which caused patients to turn to medical organizations.
The leading problem for which patients turned to government agencies with hypothyroidism was weakness (p 0.05). In addition, patients with hypothyroidism applied to nongovernmental medical organizations with complaints of hair loss on the head and eyebrows, symptoms of hirsutism, pastiness and looseness of the facial skin, eyelid swelling, dryness and peeling of the skin, pallor of the skin (p 0.05) (table 5.2).
Illness N Problems for which patients turn to state AAP Problems for which patients turn to non-state medical organizations (n = 226) O 0) Score 263 Weakness (p = 0.0004) Weakness (p = 0.0003) Pastosity and looseness facial skin (p = 0.0004) Puffiness of the eyelids (p = 0.0007) Hair loss on the head and eyebrows (p = 0.0015) Hirsutism (p = 0.0231) Dry and peeling skin (p = 0.0317) Pallor of the skin (p = 0.0412) a k noi un "nm 224 Dry mouth (p = 0.0016) Decreased vision (p = 0.0129) Dry mouth (p = 0.0017) Decreased vision (p = 0.0134) Dry lips (p = 0.0019) Trophic disorders of the lower extremities (p = 0.0028) Problematic wrinkles on the face (P = 0.0117) Dry mucous membranes and skin (p = 0.0184) Itching of the skin (p = 0.0206) Long-term wound healing (P = 0.0211) Calluses and cracks on the legs, hyperkeratosis (p = 0.0213) Recurrent skin infections (p = 0.0372) Diffuse hair loss (p = 0.0392) Fungal lesions nails and skin (p = 0.0394)
Chronic venous insufficiency 228 Increased veins in the lower extremities (p = 0.0065) Swelling of the lower extremities (p = 0.0100) Increased veins in the lower extremities (p = 0.0071) Swelling of the lower extremities (P = 0.0112) Vascular "stars" on the legs ( p = 0.0108) Cellulite (p = 0.0463)
O 0) oo3 238 Pain in the heart (p = 0.0011) Increased blood pressure (p = 0.0104) Pain in the heart (p = 0.0014) Increased blood pressure (p = 0.0115) Spots and xanthomas on the eyelids (p = 0.0108) Lipomas in different parts of the body (p = 0.0319)
Arterial hypertension 315 Dizziness (p = 0.0026) Headaches (p = 0.0106) Dizziness (p = 0.0027) Headaches (p = 0.0109) Edema of the eyelids (p = 0.0105) Face swelling (p = 0.0111) Telangiectasias and facial rosacea (p = 0.0293) Chronic diseases of the gastrointestinal tract 158 Unpleasant sensations in the abdominal region (p = 0.0026) Defecation disorders (p = 0.0026) Unpleasant sensations in the abdominal region ( p = 0.0024) Disorders of defecation (p = 0.0031) Dry skin (p = 0.0027) Loose skin syndrome Rosacea (p = 0.0027) Acne Allergic rash (p = 0.0027) Salty complexion (p = 0.0027) Dermatitis (p = 0.0027) Pigmentation (p = 0.0027) Psoriasis (p = 0.0027)
Dry mouth and decreased vision (p 0.05) were the leading problems in patients with diabetes for whom they applied to government medical organizations. In addition, patients with diabetes mellitus turned to non-governmental medical organizations with complaints of dry lips, problem wrinkles on the face, dry mucous membranes and skin, itching of the skin, diffuse hair loss, trophic disorders of the lower extremities, prolonged healing of wounds, calluses and cracked legs (hyperkeratosis), recurrent skin infections, fungal infections of the nails and skin (p 0.05).
In case of chronic venous insufficiency, patients applied to state medical organizations due to enlarged veins in the lower extremities and due to edema of the lower extremities (p 0.05), and, in addition, they contacted non-governmental medical organizations due to the presence of vascular "asterisks" on the legs and in connection with cellulite (p 0.05).
With atherosclerosis, patients turned to state medical organizations for pain in the heart area, high blood pressure (p 0.05), in addition to non-state medical organizations, they addressed, in addition, for spots and xanthomas on the eyelids, lipomas on various parts of the body (p 0 , 05).
Patients with arterial hypertension applied to state medical organizations for dizziness, headaches (p 0.05); in addition, non-state medical organizations were contacted for eyelid edema, facial swelling, telangiectasia and facial rosacea (p 0.05).
In chronic diseases of the gastrointestinal tract, the reason for contacting state medical organizations was unpleasant sensations in the abdominal region, defecation disorders (p 0.05), in non-state medical organizations the reason for contacting, in addition, was dry skin, sagging skin syndrome, rosacea , acne, allergic rash, sallow complexion, dermatitis, skin pigmentation, psoriasis (p 0.05).
As can be seen from the data presented in the table, patients with the same nosological forms did not combine their aesthetic problems into a single whole with problems related to health and physical condition. With problems of a somatic nature, they turned to state APUs, and with problems related to their appearance - to non-state ones.
We analyzed applications to non-governmental medical organizations. It turned out that among the patients who complained of hair loss, 24.2 ± 2.2% suffered from hypothyroidism, while only 4.6 ± 0.3% of patients had previously been diagnosed. Among patients with complaints of dry lips, 36.2 ± 2.4% suffered from type 2 diabetes mellitus, while previously only 12.9 ± 1.2% of patients had been diagnosed. Among the patients who applied for trophic disorders of the lower extremities, 28.3 ± 2.8% suffered from type 2 diabetes mellitus, while previously only 13.2 ± 1.0% of patients were diagnosed with chronic venous insufficiency of the lower extremities. It was established during the examination when contacting a non-governmental medical organization in 26.4 ± 2.1% of patients, it was established earlier in 13.8 ± 1.3% of people.
Consequently, a significant part of patients, when contacting non-governmental medical organizations, already had a somatic pathology, and in 44.3% of cases it was not diagnosed earlier. We analyzed the reasons why somatic pathology in these patients was not diagnosed earlier. Among the leading reasons, it should be noted such as the lack of suspicion of a somatic disease (67.2%), unwillingness to visit state polyclinics for diagnosis and treatment (53.5%), lack of time (34.0%). It should be noted that 72.4% of these patients belonged to the unorganized contingent of the population and did not undergo periodic medical examinations.
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