Age-related changes in nonspecific immunity - prolonging life

The great I.I. Mechnikov claimed: "Death before 150 years is a violent death."

We live in a potentially hostile world for us. Starting from the very first days of life, a person is surrounded by an environment containing countless infectious agents that lead a parasitic lifestyle and thereby ensure their existence. Most of these pathogenic organisms are not visible to the naked eye – these are numerous viruses, various bacteria and microscopic fungi. Natural protective barriers stand in the way of infection penetration into the human body, but if they are overcome, various immune defense mechanisms come into effect, which allow a person to fight pathogens and in most cases achieve victory. Therefore, it is difficult to overestimate the importance of the immune system for human health, quality of life and longevity.

In the internal environment of the body – this is blood, lymph, tissue fluid – there are cells and molecules specializing in protective function. Some of them are present in the human body even before meeting with foreign agents – whether they are molecules or pathogens, and it is they who form the so-called innate or nonspecific immunity. On the other hand, the internal environment of the body is also protected by mechanisms of a specific immune response, the action of which is selective and is realized only in relation to a specific antigen.

The realization of the immune response – the body's immunoreactivity – is a function of a highly specialized immune system. Nonspecific mechanisms of immunity, interacting and complementing each other, provide early and sufficiently reliable protection of the body from a variety of pathogens. As the infection develops, the nonspecific mechanisms of anti-infective protection are supplemented by antigen-specific immunity factors.

It should be noted that the functions of the immune system are subject to dynamic changes over time. Numerous facts indicate a decrease in the effectiveness of the functioning of the immune system with increasing age, as a result of which the incidence and mortality from infectious diseases increases tens and hundreds of times. The weakening and violation of the immune response is associated with an increase in the frequency of oncological and autoimmune diseases. It is obvious that an increase in the incidence rate in older age groups significantly reduces their quality of life.

The presence of a connection of various age-related pathological processes with defects of the immune system has led to the assumption that aging of the immune system may limit life expectancy. It is believed that changes in the functioning of the immune system is one of the main causes of aging. With age, the effectiveness of the immune system decreases, but various links of immunoreactivity with aging are disrupted to varying degrees.

Let us first focus on the features of age-related changes in nonspecific immunity. In the nonspecific protection of humans and animals from pathogenic and non-pathogenic foreign agents, cells capable of phagocytosis, as well as cells with cytotoxic activity - a special class of lymphocytes called natural (natural) killers - are of great importance.

The phagocytic cells circulating in the blood include neutrophil granulocytes (neutrophils) and monocytes. The cells exhibiting the ability to phagocytosis, which are present in various organs and tissues, include tissue macrophages, capillary endothelial cells, histiocytes, dendritic cells of lymph nodes.

Phagocytes capture, kill and digest phagocytosis objects. Monocytes/macrophages and some other human phagocytes are also capable of transmitting fragments of digested antigen to lymphocytes in combination with histocompatibility complex proteins localized on the outer membrane of the cell. This is the process of so-called antigen presentation, which is an absolutely necessary stage in the implementation of adaptive immunity.

A dynamic study of phagocytosis indicators in neutrophils showed that age imposes a certain limit on the absorption function of neutrophils: there is a decrease in the percentage of actively phagocytic cells (the indicator is the phagocytic index), this decrease is only partially compensated by an increase in their functionality due to the production of reactive oxygen species (the so-called "oxygen explosion"), at the same time it is possible inhibition of oxygen-independent killing mechanisms.

Age-related changes in the ability of macrophages to process antigen are also observed:  to induce a minimal immune response, macrophages need a large dose of antigen.

Numerous studies have shown that changes in the immune system begin long before any manifestations of aging of the body. Therefore, the detection of immune disorders is the most promising in terms of correcting its age-related changes and preventing aging.

Historical background

The phenomenon of phagocytosis was discovered and described by the great Russian scientist I.I. Mechnikov (1845-1916) during the observation of starfish larvae. In 1908 Ilya Ilyich Mechnikov, together with Paul Ehrlich, was awarded the Nobel Prize in Physiology or Medicine "for his work on immunity."

I. I. Mechnikov's works, including "Studies on Human Nature" and "Studies of Optimism", gave rise to several trends in modern gerontology. In his works on the mechanisms of aging, I.I. Mechnikov relied on the provisions he had previously developed on the role of phagocytosis in atrophy. He extended these provisions to the processes of senile atrophy ("struggle of macrophages" and "noble elements" of tissues). To explain the processes of tissue degeneration, Mechnikov proposed a theory of intoxication (poisoning) of the body as a result of bacterial infections carried by it, this theory of aging is currently not shared by science. The causes of aging are much more complex, and many factors are combined in them.

In the process of aging, which is not complicated by diseases, there is a natural change in the ratio of cellular populations of the immune system. At the same time, many researchers note that with age, not just the extinction of anti-infective protection occurs, but its adaptive restructuring. The significance and some age-related changes in the phagocytic system were described above. The innate immune system also includes other defense mechanisms, such as lysozyme, complement (a set of soluble protein factors in the blood), natural (or natural) killers (EC or NK cells, from the English natural killer - natural killers).

Information about age-related changes in the complement system is somewhat contradictory, but studies on groups of elderly volunteers have shown that, for example, the content of the C4 component in them is increased compared to young people. At the same time, there is evidence of a decrease in the concentration of lysozyme and the content of the C3 component of complement in the elderly. Thus, adaptive age-related changes in these components of innate immunity are not unambiguous and are multidirectional.

Weakening of the barriers of nonspecific antimicrobial immunity, as a rule, is manifested by an increase in the frequency of infectious diseases. The elderly and senile age are characterized not only by a decrease in antibacterial immunity, but also antiviral and antitumor protection, which is associated with cellular immunity reactions, in which natural killers play an important role. Natural killers in the human body carry out lysis of target cells independent of antibodies and complement.

Natural killers have been described in humans, monkeys, pigs, horses, guinea pigs, rats, mice and other animals. Virus-infected cells can serve as targets for natural killers, and in a number of viral diseases, an increase in their cytotoxic activity towards these cells is observed. It has been shown that natural killers are most active against tumor cells.

For a long time, it has been believed that the lytic action against target cells is a very important, but practically the only function of natural killers in maintaining genetic homeostasis. Further studies have shown that natural killers have not only effector, but also regulatory activity. The regulatory functions of natural killers are mediated by various mediators that they produce. These include interleukin-1, interleukin-2, alpha and gamma interferons, B-lymphocyte growth factor, colony stimulating factor.

In the elderly, there is an increase in the relative and absolute number of EC cells, which is associated with a decrease in the purity of T cells. This is especially true for centenarians, in whom EC cells take over the reactions of cellular immunity. On the other hand, researchers note a deficit in their functional activity. In particular, this concerns a decrease in the antitumor activity of EC, which is associated with violations of intracellular signaling. In addition to reducing toxicity in natural killers, a decrease in proliferative activity is also observed in response to stimulation by interleukin-2.

Thus, in the elderly and senile age, and in healthy people, and especially in people with various diseases, there are significant deviations in immunological parameters from the corresponding characteristics for people of the middle age group. We can assume that natural aging is the process of developing a balanced immunodeficiency affecting various parts of the immune system. In this regard, the cure of numerous senile ailments, the practical prolongation of human life are closely related to the need for a detailed assessment of the genetic and immune status of the patient, the search and use of na.on the basis of effective therapy, including adequate means of immunocorrection that affect the mechanisms of innate and adaptive immunity. In addition, some researchers recommend activating bone marrow hematopoiesis in combination with a full protein diet to activate the functions of nonspecific immunity (for example, phagocytosis), as well as using metabolic activators in combination with antioxidants. The discovery of new capabilities of the immune system, as well as the achievements of modern pharmacology, allow us to conclude that it is quite possible to delay the onset of aging, to mitigate the manifestations of diseases of the elderly, preventing the weakening of normal immune functions.

Acquired immunity arises due to the adaptation of the immune system to foreign elements that penetrate into the human body. Since microorganisms exist in many forms, the body has a wide range of anti-infective resistance and forms of immune response. Which of the forms of the immune response will be effective depends on the localization of the infection and the type of pathogen. The tasks of innate and acquired immunity are similar – to recognize the pathogen or other foreign material and to deploy a chain of reactions aimed at its elimination. But the main difference between these two types of immunoreactivity is that acquired immunity is highly specific to each specific pathogen. In addition, a repeated encounter with the pathogen does not lead to a change in innate immunity, but increases the level of acquired: the immune system, as it were, "remembers" the pathogen in order to subsequently prevent the infection caused by it.

The leading role in all reactions of acquired immunity belongs to lymphocytes. The main populations of lymphocytes are T-lymphocytes (T cells) and B-lymphocytes (B cells). The latter form antibodies whose molecules recognize foreign target molecules (antigens) and interact with them. These B cells help phagocytes in recognizing and destroying extracellular infectious agents, as well as natural (natural) killers in destroying cells infected with intracellular pathogens (for example, viruses). T-lymphocytes are represented in the form of different subpopulations and have a wide range of activities. There are helper T-lymphocytes – Tx - (helper helpers), which, in turn, are divided into type 1 T-helpers (Th1) and type 2 T-helpers (Th2). T-helpers secrete cytokines, which in some cases contribute to the production of antibodies by B cells, and in others activate macrophages to destroy intracellular microorganisms (Cytokines are mediator molecules, signaling molecules regulating activation, growth and differentiation of cells.) The third subpopulation is represented by cytotoxic T-lymphocytes (Tc), which recognize a specific antigen on the surface of virus-infected cells and destroy them before the virus begins to multiply. In addition to effector and regulatory functions, T- and B-lymphocytes perform the function of storing immunological information that the body receives throughout life. Due to the presence of T- and B-memory cells, the immune response is formed quickly and efficiently upon repeated penetration of the pathogen.

The body of a child and an elderly person, as well as being under stress, is much more vulnerable to immunological disorders. During the aging period, the immune system undergoes a number of adverse disorders. At the same time, changes associated with the distribution and functioning of T-lymphocytes, which play a central role in cellular immunity reactions, prevail.  To date, enough facts have accumulated indicating the existence of a link between the reactivity of the immune system and the health of the elderly.

Age-related weakening of the immune system functions is influenced by both exogenous and endogenous factors. The results of most studies indicate that the changes characteristic of aging in the T-cell population are due to age-related involution of the thymus (thymus gland). The period of the beginning of thymus involution coincides with the weakening of T-dependent immune functions. As a result, with increasing age, the output of differentiated mature T-lymphocytes decreases, and the endocrine function of the thymus weakens, i.e. the synthesis and secretion of polypeptide hormones of the thymus – thymosin, thymopoietin and thymulin. Since T-cell-mediated immunity is of great importance for protecting against tumors and infections, maintaining tolerance to its own antigens, and normal regulation of the immune response, it can be assumed that programmed thymus function involution plays an essential role in the pathogenesis of aging.

A number of in vivo and in vitro studies indicate age-related changes in the population composition of T-lymphocytes.  In various pathologies of the elderly and senile age, there is a violation of the normal balance between type 1 and type 2 T-helpers (Th1/Th2), in which one of the two subtypes of T cells has the greatest activity, and at the same time the spectrum of cytokines of one type prevails over the other. Also, with age, there is a dramatic shift towards memory T cells with a simultaneous decrease in the ability to generate naive T cells.  

As for functional changes, defects in functioning are noted at different levels. Firstly, the results of many studies indicate a decrease in the effectiveness of antigen recognition and further transmission of information necessary for its elimination. In addition, the ability to proliferate T cells from old individuals is usually reduced, and this defect concerns both a decrease in the number of cells and premature depletion of the clone's power. The next change concerns a decrease in the sensitivity of T cells to cytokines, for example, to interleukin-2 or interferons. This is explained either by a decrease in the binding of interleukin-2 to its receptor, or by disturbances in the transmission of the surface signal. As a result, the proliferative activity of elderly T cells is less enhanced by exogenous interleukin-2.

Thus, according to the available data, as well as in accordance with the immunological theories of aging, the immune dysfunction that develops with age determines the age-related decrease in resistance to infections and creates a predisposition to the development of autoimmune diseases and cancer.

The immunodeficiency condition accompanying old age can be realized both at the T- and B-cellular level. In the process of aging, not only the cellular link of immunity weakens, but also the humoral immune response to both autologous and exogenous antigens associated with the functioning of B-lymphocytes. Differentiation of the latter into plasma cells, accumulation of antibody-producing cells and antibodies - immunoglobulins of various classes IgM, IgG, IgA - determines the protective properties of the body in the fight against extracellular infections. At the same time, there is a systemic and mucosal (mucosal-associated) humoral immune response. The systemic immune response is formed when the antigen spreads through the bloodstream or lymphatic vessels and is associated with the accumulation of antibodies in the blood mainly of IgM and IgG classes, to a lesser extent - IgA. The mucosal type of humoral immune response is realized when the antigen enters the body through the mucous membranes, while the immune response is characterized by an increased content of secretory IgA in secretions and mucus, IgA also accumulates in the blood to a greater extent than IgM and IgG.

As noted in many works, age-related changes in humoral immunity are more difficult to detect. Studies of the effect of age on the ability of B-lymphocytes to differentiate into plasma cells and secrete antibodies give contradictory results, possibly due to the wide variability of these indicators characteristic of aging individuals. On the one hand, it is shown that these characteristics not only do not suffer with age, but increase. On the other hand, there is evidence that aging is associated with an imbalance in the production of immunoglobulins, and with age there is a decrease in the affinity of antibodies. It has been shown that with aging, there is a decrease in the concentration of IgM in the blood, i.e. the primary humoral response is reduced. The content of IgG and IgA tends to increase. An imbalance of immunoglobulins leads to a decrease in the effectiveness of antimicrobial protection, as a result of which the susceptibility to infections increases with age

As noted earlier, age-related changes in cellular immunity are associated with involutional processes in the thymus. However, they are not limited only to the T-cell link of immunoreactivity, but also have an effect on the B-cell link.  The decrease in the activity of T-lymphocytes in the development of a humoral immune response is explained by a significant decrease in the density of distribution of specific receptors on their surface by old age. With aging, the processes associated with proliferation, the formation of cytokines, lymphokines are disrupted, which affects the nature of the interaction between T and B cells, leading to a change in the spectrum of cytokines produced and a violation of the sequence of inclusion of genes controlling the synthesis of immunoglobulin chains. A number of authors note that the decrease in the helper function of Th2 cells observed in old age leads to a loss of the ability to maintain a sufficient level of IgG after immunization.

Violation of the normal balance between type 1 and type 2 T-helpers (Th1/Th2), followed by an imbalance of cytokines produced by them, leads to inadequate development of cellular and humoral links of immunity. The decrease in the humoral immune response observed in the group of elderly people, as it turned out, is a prognostic sign of health and vitality.

It has been established that the depletion of the immune system developing with age, manifested by a decrease in the number of T-lymphocytes and a violation of the differentiation of B-lymphocytes into antibody-producing plasma cells, contributes to the development of autoimmune diseases and malignant neoplasms.

Summing up a variety of observations on age–related pathology of immunity shows that with aging, changes in the immune system are characterized by two main groups of phenomena: a decrease in reactivity to foreign antigens, which is registered as immune deficiency, and the appearance of immune reactions against antigens of one's own body - the phenomenon of autoimmunity.

These changes are most likely due to regulatory disorders in the immune system. They lead to a limitation of the ability to maintain the constancy of the antigenic composition of the body, autoaggression against the components of one's own body and are closely related to the pathology that occurs at a late age.

Thus, in the elderly and senile age, both in healthy and, especially, in patients with various diseases, there are significant deviations of immunological parameters from the corresponding characteristics for people of the middle age group. We can assume that natural aging is the process of developing a balanced immunodeficiency, withering of all parts of the immune system. Diseases in old age aggravate the immunodeficiency characteristic of the elderly. In this regard, the cure of numerous senile ailments, the practical prolongation of human life are closely related to the need for a detailed assessment of the genetic and immune status of the patient, the search and use on this basis of effective therapy, including adequate means of immunocorrection. It is quite possible to delay the onset of aging, to mitigate the manifestations of diseases of the elderly, preventing the weakening of normal immune functions.

Normal immune response and undisturbed genetic regulation of immunoreactivity are a necessary condition for resistance to diseases and aging. Age-related changes in various parts of innate and adaptive immunity affect not only the number of different immunocompetent cells, but also the peculiarities of their functioning. Studies of the last few decades have shown that the vital activity of cells of the immune system is closely related to cytokines. Cytokines are protein or polypeptide products of immunocompetent cells that regulate intercellular and intersystem contacts. The study of the diverse effects of cytokines has shown that they are practically involved in all systemic reactions of the body: regulation of the immune response, hematopoiesis, proliferation, differentiation, survival and apoptosis of most cell types, inflammation, tissue regeneration. In addition, they are a link between the immune, nervous and endocrine systems. As a result, the significance of cytokines significantly goes beyond immunology.

At different stages of ontogenesis, cytokines can be characterized by different activity. Of particular interest is the study of the cytokine profile during aging, since age-related changes in the immune status are usually associated with the occurrence of specific diseases. Characterization of cytokine activity in elderly people allows not only to characterize the pathogenesis of the disease, but also to choose an appropriate therapeutic strategy that, in addition to the therapeutic effect, could improve the quality of life of an elderly person.

The cytokine balance in elderly and senile diseases affecting the bone, cardiovascular and endocrine systems has been studied in sufficient detail. So, rheumatoid arthritis and osteoarthritis are frequent companions of old age. These are typical autoimmune diseases, in the pathogenesis of which cytokines are involved. The most active representatives are RANK (receptor activator of NF-kb), RANKL (receptor activator of NF-kb ligand) and OPG (osteoprotegerin), belonging to the tumor necrosis factor superfamily (TNF-α, or TNF-α).

The normal state of bone tissue is maintained due to the functioning of several types of cells – osteocytes, osteoblasts and osteoclasts. At the same time, bone tissue remodeling (restoration) is carried out by osteoblasts, and resorption is carried out by osteoclasts. The balance between the activity of osteoblasts and osteoclasts allows you to maintain the bone system in a normal state, which, in turn, is due to certain processes at the molecular level.

The interaction of RANKL with its RANK recipe on the surface of osteoclasts leads to the activation of NF-kb, a nuclear transcription factor located in the cytoplasm in an inactive form. The subsequent induction of the expression of a number of genes leads to the activation of osteoclasts and the development of the inflammatory process. But RANKL also has an affinity for an OPG protein that is not bound to the membrane. Competition between OPG and the RANK receptor leads to a weakening of the interaction of RANKL with its receptor, as a result, the cascade of genes leading to the activation of osteoclasts is not triggered. Thus, thanks to OPG, the necessary balance is maintained between the activity of osteoblasts and osteoclasts. In elderly patients with rheumatoid arthritis, OPG expression is reduced, as a result of which bone resorption is observed, leading to the development of osteoporosis.

Anomalies of bone structure as a result of imbalance between osteoblastic bone formation and bone resorption by osteoclasts are also observed in Paget's disease. It has been shown that arthritis, fractures, osteoporosis, etc. are significantly more common in patients with Paget's disease, and the cytokine interleukin-6 (IL-6) has a significant effect on bone resorption. (Historical background: it is assumed that hearing loss, headaches and progressive hyperostosis of the frontal bone, observed in Ludwig van Beethoven, were the result of advanced Paget's disease.)

Insulin-like growth factor (IGF-1) is of great importance for bone and cartilage tissue. It promotes the activation of osteoblasts involved in the elongation and formation of bone during development, stimulation of proliferation and differentiation of chondrocytes. Along with growth hormone and parathyroid hormone, IGF-1 affects various aspects of bone anabolism. IGF-1 will perform an important function in regulating the metabolism of calcium phosphate, which is necessary for bone mineralization and normal skeletal development. In turn, the expression and activity of IGF-1 and its receptors is modulated by steroid hormones (estrogen, progesterone) and the cytokine interleukin-1 (IL-1).

Thus, dysregulation of cytokine levels, age-related changes in hormonal expression, changes in the activity of a number of proteins under the control of cytokines are the background against which diseases of senile age develop. Many age-related diseases, despite their different nature, have a common regulatory system, the molecular characteristics of which are largely determined by the properties of cytokines and their receptors.

By the end of the second millennium, the prevalence of cardiovascular diseases in highly developed countries had acquired the character of an epidemic. If at the beginning of the twentieth century, mortality from cardiovascular diseases was no more than 1%, then by the 60s it had grown to 50%, and according to forecasts, mortality from atherosclerosis in the coming years of the XXI century may reach 60%.

The technogenic nature of modern civilization, the development of high technologies, the penetration of electronic technology into all spheres of human existence, in addition to the advantages in the form of household comfort, sociability and information accessibility, have led to a qualitative change in the nature of human behavior. The need for physical labor has significantly decreased, the degree of inactivity has increased. However, having parted in most cases with hard physical labor, the current generation has not narrowed its nutritional needs. Thus, the total energy expenditure of a modern person does not reach 2900 kcal (2000-2900 kcal), and the total consumption of food calories exceeds 3000 kcal. As a result, daily consumption of an extra 150 kcal with food leads to the accumulation of 10 kg of fat for 18 months. It is shown that the balance of food calories is realized mainly through the ratio of atherogenic and non-atherogenic lipoproteins. This factor especially affects in old age, when a person's physical activity decreases and the likelihood of developing atherosclerosis increases.

Atherosclerotic vascular damage is caused by the formation of plaques, and these events begin already in the vessels of young people. Microscopic examination of the vessels showed that macrophages and modified smooth muscle cells accumulate under the externally intact endothelium (the inner lining of the vessels), the cytoplasm of which is filled with fat droplets. Further progression of the process depends on the genetic predisposition to this disease.

Experimental and clinical observations demonstrate an extraordinary variability of molecular and cellular events in atherosclerotic plaques. Nevertheless, to date, some molecular and biological aspects of the occurrence of atherosclerosis in the elderly and the reasons for the difficulties of its treatment have become clear. The theory of the immunological nature of atherosclerotic lesions has become a kind of continuation and complement of the classical ideas about the nature of atherosclerosis. It has been shown that the pathogenesis of the disease is inextricably linked with a violation of the balance of immunocompetent cells, the ratio of T-helper lymphocytes (Th1/Th2) and, as a consequence, with violations of the activity of cytokines produced by them.

The process of atherosclerotic vascular damage is based on intercellular interactions, primarily between the endothelium and leukocytes. It is this interaction that stimulates the synthesis of biologically active cytokines, adhesion molecules, coagulation and fibrinolysis factors, etc. An increase in the activity of these proteins is associated with the processes of thrombosis and atherogenesis.

It is known that there are so-called "squenager" receptors on the surface of macrophages that have affinity for low-density lipoproteins. During the progression of the disease, these lipoproteins accumulate in macrophages and monocytes located in the intima of the vessels (intima is the space located under the endothelium). Such intracellular accumulation of lipids is toxic, often leads to cell death and contributes to the formation and consistent increase of the atherosclerotic lesion zone.

Many factors contribute to the invasion of leukocytes into the intima of vessels: the expression of adhesion molecules both on leukocytes and on the endothelium, the activity of chemokines that ensure the migration of leukocytes to the focus of inflammation and their interaction with the endothelium, as well as the oxidation and capture of lipoprotein passively migrating at the vessel walls.

The migration of leukocytes into the intima of blood vessels occurs in stages. At the initial stage, the expression of selectins increases on the damaged endothelium, which affects the "adhesion" of leukocytes to the endothelium and their movement along the vascular wall. Then, under the action of chemokines (IL-8 and MCP-1), leukocyte integrins are activated on neutrophils (CD11b) and on T-lymphocytes (CD49d). Integrins promote prolonged contact of leukocytes with the vascular endothelium. The last stage is characterized in the migration of leukocytes between endothelial cells.

At the moment, some of the components of the pathogenesis of atherosclerosis attract particularly close attention, especially in connection with the need to develop new therapeutic approaches.

First of all, it is the chemokine MCP-1, an increase in the concentration of which contributes to the replenishment of the number of monocytes in the subendothelial layer and the subsequent development of atherosclerotic lesions. In knockout mice deficient in MCP-1 and its CCR-2 receptor, a significant decrease in the area of atherosclerotic damage was observed. The development of ways to block MCP-1 and its receptor together with a lipostable diet can prevent the development and increase in the size of atherosclerotic lesions.

An important role in the development of atherosclerotic plaque is also assigned to intercellular interactions involving CD40 and its CD40L ligand, which are expressed by activated T-lymphocytes infiltrating the intima of atherosclerotic vessels, as well as endothelial cells, macrophages and smooth muscle fibers. In animal experiments, it was shown that inhibition of the CD40-induced cellular response prevented the growth of plaques and the development of new ones. The creation of specific CD-40 antibodies can play a crucial role in preventing vascular damage.

Protection of the intima of the vessel from further damage should be reduced to a weakening of lymphocytic activity in the intima of the vessel, a decrease in the inflammatory reaction in the area of damage. This requires actions aimed at blocking the Th1 response and stimulating the synthesis of Th2 lymphocytes. In this regard, an important protective role in atherosclerosis is assigned to Th2-cytokine – interleukin-10 (IL-10). Its physiological activity was confirmed in an experiment: mice knocked out by IL-10 are 30 times more likely to develop atherosclerosis. Perhaps IL-10 will become the basis for the development of highly effective anti-atherogenic drugs.

Thus, the study of the molecular basis of the pathogenesis of atherosclerosis makes it possible to determine the strategy of correction of the disease and ways to create a new generation of drugs

Currently, diabetes mellitus belongs to one of the most common endocrine diseases. The scale of its spread is huge: according to the World Health Organization, there are currently about 100 million patients with diabetes mellitus in the world.

Depending on the pathogenesis of the disease, endocrinologists distinguish two main types of diabetes: insulin-dependent diabetes, or type I diabetes, and insulin-independent diabetes, or type II diabetes. Age differences in the clinical course of these types of disease are very significant. Therefore, type I diabetes is sometimes called juvenile, because it affects not only the elderly, but also children and young people. Older people are more characterized by type II diabetes, which most often develops at the age of 50-60 years, and the number of such patients is 14-16 times more. This is explained, first of all, by the peculiarities of the demographic situation - the global aging of the Earth's population. In this connection, this pathology is now considered as a problem of the elderly and senile age.

In type I diabetes, there is an absolute insufficiency of insulin, which is characterized by a progressive decrease in its synthesis and secretion, a decrease in blood content and occurs due to the destruction of insulin-secreting beta cells of the pancreas. Insulin-dependent diabetes is an autoimmune disease accompanied by a violation of the balance of Th1/Th2. The object of the immune attack are autoantigens – proteins expressed on the surface of beta cells. Both Th1- and Th2-lymphocytes and their mediators actively participate in the destruction of beta cells. The observed genetic predisposition to the development of type I diabetes is due to the presence of certain alleles of the main histocompatibility complex.

Type II diabetes is not an autoimmune disease and is characterized by relative insulin deficiency. Its pathogenesis is associated with disorders in the receptor system of peripheral tissue cells to insulin, provided that the beta cells of the islets of Langerhans of the pancreas function normally. In this case, there is also a genetic predisposition to the development of the disease. Most patients with insulin-dependent diabetes are characterized by obesity. An increase in glucose level causes complications of diabetes, which affect the functioning of the visual organs (retinopathy), nervous system (neuropathy), kidneys (nephropathy), bone system (ostepathy), also in patients there are signs that are associated mainly with old age: nocturia (stable predominance of the nocturnal part of diuresis over the daytime), orthostatic hypotension (reduction of blood pressure when moving to an upright position), etc.

Insulin receptors are found in almost all types of cells, but in different amounts. Most of them are in hepatocytes (liver cells) – up to 250,000 receptors per cell. In adipocytes (cells forming adipose tissue), their content is less – up to 50,000, and in monocytes and erythrocytes – even an order of magnitude less. At the same time, cells with different contents of insulin receptors react differently to the same concentration of insulin.

The insulin signaling system is a complex mechanism for regulating blood glucose levels, and the transfer (transduction) of the insulin signal includes many stages, some of which still require clarification. The insulin receptor (RI) is a tyrosine protein kinase (tyrosine kinase) that phosphorylates proteins by the amino acid tyrosine. Tyrosine kinase is a mandatory mediator of almost all pleiotropic actions of insulin. With a mutation that leads to the loss of the ability to autophosphorylate, the cells stop responding to insulin.

One of the main participants in the signal transmission from the surface into the cell (after the activation of the RI) are certain cytoplasmic proteins – the substrates of the receptor. There are several of them, the main one is RI–C1 (substrate 1 of the insulin receptor), as well as RI-C2, Shc and some proteins of the Stat family. They activate different signaling pathways.

Experiments on animal models have shown that in some cases mutations of the IRS-1 gene (the RI-C1 protein gene) led to obesity and the development of type II diabetes, and in other cases – to a weakening of glucose utilization. In knockout mice with the ISR-2 gene (the RI-C2 protein gene), progressive development of type II diabetes with concomitant insulin resistance was observed in all cases. At the same time, up to 80% of the beta cell mass was observed in animals compared to normal animals. But at the same time, glucose-induced insulin secretion by this mass of cells in mutant animals was higher than in the original ones. Perhaps this is the result of a kind of compensation for insulin resistance.

With the mediation of RI-C1, insulin activates another enzyme PHI-3-kinase (phosphatidylinositol-3-kinase), which is a link in the signaling pathway that stimulates the movement of the GLUT4 transporter protein into the plasma membrane, which provides transmembrane glucose transfer.

Insulin also activates the Ras signaling pathway. Ras superfamily proteins are involved in a variety of cellular processes. Ras activation is the final link of transmembrane signal transmission and the initial link of cytoplasmic and nuclear signaling pathways, which are implemented through a cascade of reactions involving protein kinases. Ultimately, the phosphorylated (active) form of PFGr-1 protein phosphatase bound to glycogen granules activates enzymes that accelerate glycogen synthesis (glycogen synthetase) or stop glycogen mobilization (phosphorylase kinase and glycogen phosphorylase). In such a long way, the insulin signal reaches one of the final effector links.

It should be noted that the components of the insulin signaling system work in different cells with different activity. In particular, RI-C1 is more important for the functioning of the insulin system in muscles and adipose tissue, while the activity of RI-C2 dominates in the liver. These signals are also necessary for the normal functioning of beta cells, they contribute to their growth and survival, which is especially important in the case of compensation for insulin resistance.

Thus, the decoding of the molecular mechanisms of the insulin signaling system in target cells indicates that the treatment of insulin-dependent diabetes should be aimed primarily at correcting disorders occurring in this system.

Portal "Eternal youth" www.vechnayamolodost.ru
22.01.2008