**2. Neuroimmune and neuroendocrine communications: aging, metabolic syndrome and diabetes mellitus**

Aging is a universal factor for metabolic and immune disorders in humans and related diseases, including DM [6]. So, analysis of the reciprocal effect of neuroendocrine factors and immunological processes at the system level, human organs and tissues is very important. It is the basis for the development of processes of aging and the emergence of DM formation of mechanisms at cellular and molecular levels.

The maintenance of the homeostasis of nervous and immune systems is carried out by comparable number of cellular elements. The integration of nervous and immune systems is due to the presence of neuronal processes, receptors and neurotransmitters in the nervous system, as well as the presence of highly mobile cell elements and cytokines in the immune system [7]. The search of opportunities of the influence to immune processes through the central nervous system in the order to prevent of aging and metabolic disorders is based on fundamental laws of hierarchical organization of regulatory system, the presence of humoral signals in cell populations, the points of application of the effect in tissues and organs. The information in the nervous system is encoded in the sequence of electrical impulses and in the architecture of neuronal interactions, in the immune system information is stored in stereochemical configuration of molecules and receptors involved in lymphocyte interactions. There was evidence of a common receptor apparatus in the immune system to neuromediators and nervous system to endogenous immunomodulators. Immunological active neuroendocrine substances - thymosin, triiodothyronine (T3) and thyroxine (T4), protimosin, endogenous regulator of protimosin, parathymosin, oxytocin, Th-I antigen and vasoactive intestinal peptide have been found both in the brain and in the thymus, they play significant role in the aging of human immune system [8]. The greatest number of studies are devoted to the participation of interleukin 1 (IL-1), in immunoregulation at the level of immunocompetent cells and in regulation of functions. Interleukin 2 (IL-2) also exerts various effects on the immune and nervous systems mediated by affinity binding to the corresponding cell surface receptors. The activating effect of IL-2 on lymphocytes and macrophages is manifested in the enhancement of the antibody-dependent cytotoxicity of these cells with parallel stimulation of the secretion of tumor necrosis factor α (TNF-α). IL-2 induces proliferation and differentiation of oligodendrocytes, affects the reactivity of the hypothalamus neurons and increases the level of adrenocorticotropic hormone (ACTH) and cortisol in the blood, which together form a stable mechanism of neuroimmune and neuroendocrine network interactions. Cells that are targets for the action of IL-2 are T-lymphocytes, natural killers (NK), and macrophages. IL-2 causes the functional activation of these cell types and the secretion of other cytokines, for example, increases the production of NK cells by interferon γ (IFN-γ) [9]. There are data about the production of nervous cells of IL-1, IL-6 and TNF-α, which are critical components in the development of chronic inflammation with destruction of β-cells of the pancreas in DM type 2 [10]. It is known that glucocorticoids (GCs), androgens, estrogens and progesterone suppress immune responses, and growth hormone (GH), T4 and insulin have a stimulating effect [11, 12]. Cells of the immune system transmit transmembrane signal to receptors for GCs, insulin, GH, estradiol, testosterone, betaadrenergic agents, acetylcholine, endorphins and enkephalins [13]. All of above-mentioned hormonal factors are involved in the formation of metabolic and immunological changes in conditions of aging and DM. For example, the exogenous administration of contra-insular hormones T3 and T4 alters functional activity of the immune system. This action is realized through cytoplasmic and nuclear receptors in immune cells [14, 15]. The theory of aging suggests that life expectancy has negative relationship with metabolic rate, which is regulated by hormones of energy metabolism. Experimental hypothyroidism increased life expectancy in young rats, whereas hyperthyroidism shortened life expectancy. Several mutant mice in long life experiment had reduced or almost absent thyroid function [16–18]. Hypothyroidism can affect life expectancy by reducing the intensity of metabolism, body temperature and oxygen consumption, resulting in a decrease in the generation of free oxygen radicals and associated oxidative damage in cells. Subclinical hypothyroidism is associated with a reduction

There is significant increase of the prevalence of DM in the Russian Federation. According to the Federal Register of Diabetes Mellitus, at the end of 2016, 4.35 million outpatients with DM (3% of the total population) were registered in Russia, of whom 92% (4 million people) had type 2 DM, 6% (255,000 people) - type 1 DM and 2% (75,000 people) -other types of DM. Actual number of patients with DM remains underestimated, since only identified and reported cases are considered. The results of the large-scale Russian epidemiological study NATION confirmed that only 50% of type 2 DM cases are diagnosed. Actual number of patients with DM can be at least 8-9 million people (about 6% of the population) in Russia [4]. Because of the lack of timely diagnostics of DM, some patients do not receive necessary therapy and have higher risk of the developing of such complications of DM as retinopathy, nephropathy, ischemic heart disease, cerebral ischemia, peripheral angiopathy. These complications are responsible for most cases of disability and mortality of DM. Today, DM is considered as the cause of accelerated aging [5]. Twenty percent of middleaged people and 35% of the population of older persons are characterized by varying degrees of impaired glucose tolerance (IGT) and symptoms of insulin resistance. An increase in the frequency of obesity and sedentary lifestyle and the major risk factors for type 2 DM suggests that the prevalence of DM in the world will increase. The management of this disease becomes difficult for persons aged 60, 70 and 80 years. The risk of complications, such as ischemic heart disease, increases with age, as well as damage with age of organs of vision, hearing

The modern stage of the development of researches in the field of DM and aging is interrelated and involves the use of unified technological platforms for molecular diagnostics and pharmacology of stages of aging and DM. Unified technological platforms presuppose the performing of comparative genomic and proteomic studies, the results of which allow to study interrelated pathogenesis of aging and DM. Also new technological platforms are necessary for the development of new prophylaxis and treatment of these interconnected pathological states. The analysis of data from comparative genomic and proteomic studies allows the formation of unified molecular pathological pathways of DM and aging. The chapter presents new technological platforms for the early identification and the development of

**2. Neuroimmune and neuroendocrine communications: aging, metabolic** 

Aging is a universal factor for metabolic and immune disorders in humans and related diseases, including DM [6]. So, analysis of the reciprocal effect of neuroendocrine factors and immunological processes at the system level, human organs and tissues is very important. It is the basis for the development of processes of aging and the emergence of DM formation of

The maintenance of the homeostasis of nervous and immune systems is carried out by comparable number of cellular elements. The integration of nervous and immune systems is due

and physical activity, can amplify in the presence of DM.

anti-aging and anti-diabetic agents.

140 Diabetes and Its Complications

**syndrome and diabetes mellitus**

mechanisms at cellular and molecular levels.

in mortality in women, which was found in families with long life expectancy and is due to polymorphism of the receptor to thyroid stimulating hormone (TSH) [19]. An important fact is that subclinical hypothyroidism is often recorded with type 2 DM [20].

of DM development. Lipostatic theory postulates the existence of a feedback mechanism

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The theory predicts the presence of chemical signal produced in adipose tissue, which controls food behavior, physical and metabolic activity [31]. In 1994, leptin was discovered, that is, produced by adipocytes, moves with blood to the brain and acts on the hypothalamic receptors, suppressing the appetite [32]. Decreased leptin concentration leads to the development of obesity and is considered as one of the factors of the pathogenesis of type 2 DM. There is an increased level of cortisol, heat release, the restriction of growth, the lack of reproductive function, unlimited appetite and insulin resistance in mice with the ob/ ob genotype. Leptin receptors belong to the family of cytokine receptors of class 1 and are present in the hypothalamus, fatty tissue, liver, skeletal muscles, pancreas, ovaries, prostate, placenta, kidneys and lungs. Leptin reaches the arcuate nuclei of the hypothalamus, interacts with its receptors in centers of hunger and satiety and reduces appetite. The binding of leptin activates the release of adrenaline, which increases the level of cAMP and the activity of protein kinase A through the adrenergic α-3 receptors, and triggers the synthesis of thermogenin, which converts mitochondria of adipocytes into unconjugated state [33].

In the arcuate nuclei of the hypothalamus, energy consumption is controlled by two types of neurons: orexigenic neurons stimulate the appetite by producing and releasing neuropeptide Y (NPY), which acts on the next neuron sending the brain a signal to eat. The concentration of NPY in the blood rises during fasting. It is the high level of peptide NPY that causes obesity in mice od/od and db/db [34]. Anorexigenic neurons of arcuate nuclei of the hypothalamus produce α-melanocyte-stimulating hormone (α-MSH). The release of α-MSH results in the next neuron sending a signal to the brain to stop eating. Mutations in the melanocortin receptor, which is expressed in the brain cells and plays a role in the regulation of appetite, lead to the appearance of obesity and type 2 DM [35]. Insulin acts on the hypothalamic receptors, suppressing appetite by inhibiting the release of NPY by the orexigenic neurons and also stimulating the production of MCH by anorexigenic receptors, reducing food intake and increasing

thermogenesis. Leptin makes the liver and muscle cells more sensitive to insulin.

was found.

Adiponectin—a protein, consisting of 224 amino acids, is encoded by the ADIPOQ gene and secreted by adipocytes under the action of insulin. Adiponectin regulates energy homeostasis, has anti-inflammatory and anti-atherogenic effects. Its level decreases with obesity and is associated with glucose metabolism. Adiponectin increases the absorption of fatty acids by myocytes and the rate of β-oxidation of fatty acids in muscles, blocks the synthesis of fatty acids and gluconeogenesis in hepatocytes and stimulates the absorption and metabolism of glucose in muscles and the liver. These effects of adiponectin are provided by increasing the level of cAMP and activating cAMP-dependent protein kinase. A low level of adiponectin is characteristic for obesity, DM and cardiovascular diseases [36]. The similarity of adiponectin to TNF-α

TNF-α is one of the key pro-inflammatory cytokines, secreted by macrophages and released by adipose tissue cells. One of the main targets of TNF-α is the adipocytes themselves, where it blocks the transcription of several genes and activates the expression of others. These effects

between the amount of fat stored by the body, nutritional behavior and fat burning.

Most of the data indicate the role of insulin as one of the growth factors that support the readiness of lymphoid cells to realize the response to an antigen. The stimulating effect of this hormone is manifested mainly in conditions of the pathology of the immune system with DM. Proliferative activity of lymphoid cells is reduced in patients with insufficient insulin production; first of all, functions of T cells suffer [21]. Antagonistic pleiotropic hypothesis of aging suggests that some pathological pathways that are evolutionarily necessary for the development of the human body and reproductive function become unfavorable with aging of the human body. For example, the increase of the ratio of GH / insulin-like growth factor-1 (IGF-1) is necessary for the growth and maturation during puberty. GH secretion decreases with age, resulting in a corresponding decrease in IGF-1 concentration. Low levels of IGF-1 in the human body are associated with an increased risk of developing type 2 DM [22].

GCs are the most studied and effective participants in pathological changes in neuroimmunoendocrine network interactions that occur in patients with DM. Genes that are targets of GCs are responsible for the synthesis of protein molecules involved in virtually all parts of immunological process in DM [23]. GCs inhibit the synthesis of IL-1, TNF-α, granulocytemacrophage colony-stimulating factor (GM-CSF), IL-3, 4, 5, 6, 8 and reduce the induction of NO synthase, which leads to the decrease of NO synthesis and pro-inflammatory effect through cyclooxygenase, phospholipase A2, endothelin-1, involved in cardiovascular remodeling in aging and DM [24, 25]. On the other hand, GCs enhance the synthesis of proteins that have an anti-inflammatory effect, including the synthesis of lipocortin-1, which inhibits the activity of phospholipase A2 and the production of leukotrienes (C4, D4, E4), as well as prostaglandin E2 and leukotriene B4 [26]. GCs are inducer of type II receptors for IL-1, which has an anti-inflammatory effect. GCs inhibit the enhanced TNF-α transcription of the IL-8 gene [27]. Feedback in neuroendocrine interaction is carried out by cells that originate from lymphocytes through the hypothalamic-pituitary-adrenal system.

So, the nervous, immune and endocrine systems fulfill their specific functions with the help of identical mechanisms and are interrelated.

Insulin resistance is the main component of the metabolic syndrome and is very often found in elderly patients. Abdominal obesity, which is often found with human aging, is the main cause of insulin resistance and metabolic syndrome [28]. Aging is also associated with an increase in the level of proinflammatory cytokines that interact with insulin. Cytokines are isolated from adipose tissue, and cytokine synthesis increases with age, it is associated with aging. It has been shown that the synthesis of cytokines increases by aging cells [29]. Glucostatic theory was formulated by J. Mayer, who described a feedback system that maintains the level of glycemia. In accordance with this theory, the hypothalamus controls the absorption of nutrients through receptors that respond to changes in glycemia [30].

The interaction of metabolic disorders and the distribution of adipose tissue in the human body constitute links in the vicious circle that can accelerate the aging process and the onset of DM development. Lipostatic theory postulates the existence of a feedback mechanism between the amount of fat stored by the body, nutritional behavior and fat burning.

in mortality in women, which was found in families with long life expectancy and is due to polymorphism of the receptor to thyroid stimulating hormone (TSH) [19]. An important fact

Most of the data indicate the role of insulin as one of the growth factors that support the readiness of lymphoid cells to realize the response to an antigen. The stimulating effect of this hormone is manifested mainly in conditions of the pathology of the immune system with DM. Proliferative activity of lymphoid cells is reduced in patients with insufficient insulin production; first of all, functions of T cells suffer [21]. Antagonistic pleiotropic hypothesis of aging suggests that some pathological pathways that are evolutionarily necessary for the development of the human body and reproductive function become unfavorable with aging of the human body. For example, the increase of the ratio of GH / insulin-like growth factor-1 (IGF-1) is necessary for the growth and maturation during puberty. GH secretion decreases with age, resulting in a corresponding decrease in IGF-1 concentration. Low levels of IGF-1 in

the human body are associated with an increased risk of developing type 2 DM [22].

lymphocytes through the hypothalamic-pituitary-adrenal system.

of identical mechanisms and are interrelated.

receptors that respond to changes in glycemia [30].

GCs are the most studied and effective participants in pathological changes in neuroimmunoendocrine network interactions that occur in patients with DM. Genes that are targets of GCs are responsible for the synthesis of protein molecules involved in virtually all parts of immunological process in DM [23]. GCs inhibit the synthesis of IL-1, TNF-α, granulocytemacrophage colony-stimulating factor (GM-CSF), IL-3, 4, 5, 6, 8 and reduce the induction of NO synthase, which leads to the decrease of NO synthesis and pro-inflammatory effect through cyclooxygenase, phospholipase A2, endothelin-1, involved in cardiovascular remodeling in aging and DM [24, 25]. On the other hand, GCs enhance the synthesis of proteins that have an anti-inflammatory effect, including the synthesis of lipocortin-1, which inhibits the activity of phospholipase A2 and the production of leukotrienes (C4, D4, E4), as well as prostaglandin E2 and leukotriene B4 [26]. GCs are inducer of type II receptors for IL-1, which has an anti-inflammatory effect. GCs inhibit the enhanced TNF-α transcription of the IL-8 gene [27]. Feedback in neuroendocrine interaction is carried out by cells that originate from

So, the nervous, immune and endocrine systems fulfill their specific functions with the help

Insulin resistance is the main component of the metabolic syndrome and is very often found in elderly patients. Abdominal obesity, which is often found with human aging, is the main cause of insulin resistance and metabolic syndrome [28]. Aging is also associated with an increase in the level of proinflammatory cytokines that interact with insulin. Cytokines are isolated from adipose tissue, and cytokine synthesis increases with age, it is associated with aging. It has been shown that the synthesis of cytokines increases by aging cells [29]. Glucostatic theory was formulated by J. Mayer, who described a feedback system that maintains the level of glycemia. In accordance with this theory, the hypothalamus controls the absorption of nutrients through

The interaction of metabolic disorders and the distribution of adipose tissue in the human body constitute links in the vicious circle that can accelerate the aging process and the onset

is that subclinical hypothyroidism is often recorded with type 2 DM [20].

142 Diabetes and Its Complications

The theory predicts the presence of chemical signal produced in adipose tissue, which controls food behavior, physical and metabolic activity [31]. In 1994, leptin was discovered, that is, produced by adipocytes, moves with blood to the brain and acts on the hypothalamic receptors, suppressing the appetite [32]. Decreased leptin concentration leads to the development of obesity and is considered as one of the factors of the pathogenesis of type 2 DM. There is an increased level of cortisol, heat release, the restriction of growth, the lack of reproductive function, unlimited appetite and insulin resistance in mice with the ob/ ob genotype. Leptin receptors belong to the family of cytokine receptors of class 1 and are present in the hypothalamus, fatty tissue, liver, skeletal muscles, pancreas, ovaries, prostate, placenta, kidneys and lungs. Leptin reaches the arcuate nuclei of the hypothalamus, interacts with its receptors in centers of hunger and satiety and reduces appetite. The binding of leptin activates the release of adrenaline, which increases the level of cAMP and the activity of protein kinase A through the adrenergic α-3 receptors, and triggers the synthesis of thermogenin, which converts mitochondria of adipocytes into unconjugated state [33].

In the arcuate nuclei of the hypothalamus, energy consumption is controlled by two types of neurons: orexigenic neurons stimulate the appetite by producing and releasing neuropeptide Y (NPY), which acts on the next neuron sending the brain a signal to eat. The concentration of NPY in the blood rises during fasting. It is the high level of peptide NPY that causes obesity in mice od/od and db/db [34]. Anorexigenic neurons of arcuate nuclei of the hypothalamus produce α-melanocyte-stimulating hormone (α-MSH). The release of α-MSH results in the next neuron sending a signal to the brain to stop eating. Mutations in the melanocortin receptor, which is expressed in the brain cells and plays a role in the regulation of appetite, lead to the appearance of obesity and type 2 DM [35]. Insulin acts on the hypothalamic receptors, suppressing appetite by inhibiting the release of NPY by the orexigenic neurons and also stimulating the production of MCH by anorexigenic receptors, reducing food intake and increasing thermogenesis. Leptin makes the liver and muscle cells more sensitive to insulin.

Adiponectin—a protein, consisting of 224 amino acids, is encoded by the ADIPOQ gene and secreted by adipocytes under the action of insulin. Adiponectin regulates energy homeostasis, has anti-inflammatory and anti-atherogenic effects. Its level decreases with obesity and is associated with glucose metabolism. Adiponectin increases the absorption of fatty acids by myocytes and the rate of β-oxidation of fatty acids in muscles, blocks the synthesis of fatty acids and gluconeogenesis in hepatocytes and stimulates the absorption and metabolism of glucose in muscles and the liver. These effects of adiponectin are provided by increasing the level of cAMP and activating cAMP-dependent protein kinase. A low level of adiponectin is characteristic for obesity, DM and cardiovascular diseases [36]. The similarity of adiponectin to TNF-α was found.

TNF-α is one of the key pro-inflammatory cytokines, secreted by macrophages and released by adipose tissue cells. One of the main targets of TNF-α is the adipocytes themselves, where it blocks the transcription of several genes and activates the expression of others. These effects can lead to insulin resistance, chronic inflammation with systemic consequences for the body. Many genes transcribed by TNF-α are activated by the transcription factor in NF-κB adipose tissue cells.

researchers to determine whether the presence of mutation carrier makes the elderly more secure or more vulnerable to the effects of damaging factors. Topol et al. perform study compared genetic sequencing in healthy volunteers, aged 80 years, and persons whose death has been linked to diseases associated with aging, including type 2 DM [40]. Scientists are finding that healthy people have an extremely low probability of genetic variations associated with the development of the disease. This fact proves the idea that protective genes play major role in the successful aging people. Therefore, the identification of molecular bases of protective effect would develop similar medicines, including effective means of preventing type 2 DM. Barzilai et al. sequenced several candidate genes of centenarians, including a variant gene that modifies the mechanism of cholesterol metabolism [41]. Scientists have sequenced genes of IGF1, its receptor and have identified mutations that are unique to women aged 100 years [42]. Calorie restriction increases life span and reduces age-related deterioration of work systems and physiological responses of age-related diseases, including with the development of DM. Restriction of caloric intake in animals in the experiment leads to a decrease in the level of glucose and insulin in the blood plasma and

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Genetic analysis identified several genes that affect life span and associated with damage to the pituitary development, the decrease of the secretion of GH, food intake and apoptosis. The work of these genes converges in the region of the IGF-1 receptor pathway and reproduces many effects of limiting calorie intake. Although *dwarf* mice having the defect in the synthesis of GH or the IGF-1 signaling pathway are also characterized by an increase of life expectancy, people with signaling defects associated with GH are prone to the development of diseases associated with aging. One of the targets of IGF-1, the signal pathway within the cell, is the repression of proteins responsible for stress resistance, including SOD and heat shock proteins, as well as a decrease in IGF signaling can increase life expectancy by increasing the expression of genes responsible for stress resistance. The mutation of the receptor to IGF-1, a phosphorylation target (p66 Shc), also increases the life span without affecting other organs and systems. When Shc is activated, the levels of intracellular oxygen radicals increase, suppressing the factor FKHRL1, which is involved

Let us consider the scheme of molecular pathological pathway insulin/IGF-1 in humans,

IGF-1 and IGF-1R provide the activity of proliferative signaling system that stimulates growth in many cell types and blocks apoptosis. In vivo, IGF-1 acts as an immediate response to effects of many growth factors and GH. One of the components of IGF-1, mitogenic signaling, is associated with the tyrosine kinase receptor via Shc, Grb2 and Sos-1, activating the RAS and MAP kinase cascade (raf, Mek, Erk). The end point of the MAP kinase pathway is the modification of the activity of transcription factors, such as the activation of ELK transcription factors. The serum response factor (SRF) and AP-1 provide mitogenic activity of many growth factors. IGF-1R signals for cellular survival and growth in response to IGF-1 and IGF-2. IGF-1R activates three signaling pathways that converge on the phosphorylation process of the BAD protein and block apoptosis. The first pathological pathway is activated by the

where mechanisms of aging and the appearance of type 2 DM are converging.

reduces inflammatory responses and the intensity of oxidative stress.

in apoptosis (**Figure 1**).

The peroxisome proliferator-activated receptors (PPARs) alter gene expression, affecting the metabolism of fats and carbohydrates in response to changes in lipid levels in food. Ligands of these transcription factors are fatty acids and their derivatives. PRAPs act on the nucleus of the cell by forming heterodimers with another nuclear receptor—retinoid X receptor (RXR) that binds to regulatory regions of DNA. PPARs include genes necessary for β-oxidation of fatty acids and the formation of ketone bodies during fasting and stimulate the expression of genes encoding proteins that provide β-oxidation and dissipation of energy due to the formation of mismatched mitochondria. In mice with non-functioning receptor, leptin-activated PPAR-γ prevents the development of obesity by stimulating the synthesis of proteins involved in the cleavage of fatty acids and thermogenesis [37].

Ghrelin is a peptide hormone consisting of 28 amino acids produced by P/D1 cells of mucous membrane of the fundus of the stomach. Ghrelin receptors are expressed by neurons in the arcuate nucleus and ventromedial hypothalamus, here the processes associated with the action of ghrelin are mediated: stimulation of the production of releasing hormones, increased appetite, changes in the level of glucose and lipid metabolism, regulation of secretion and contractions of walls of the gastrointestinal tract [38]. It stimulates the release of GH. The concentration of ghrelin in the blood increases before eating and falls immediately after its intake. The concentration of ghrelin in the blood plasma increases with age, which contributes to weight gain in people as they age [39].

Consequently, numerous biomedical studies have proved the key role of neuroimmuneendocrine interactions in the human body, which trigger the universal molecular pathological pathways in the development of aging and DM.
