Peptide Self-Regulation of Living Systems (Facts and Hypotheses) - Shatayeva, L. K. 2003

Peptide Regulation of Aging
Molecular Mechanisms of Aging

Despite the multi-tiered hierarchy, all mechanisms of Homeostasis regulation fundamentally serve a single purpose: they coordinate the processes of Biosynthesis within the body's Cells by modulating Gene Expression. According to modern concepts, homeostasis in multicellular systems is regulated via neuroendocrine and immunological mechanisms. The Role of neural and Hormonal Influences on the processes that enable the Organism to maintain the constancy of its internal environment has been studied most extensively (Homeostasis, 1981). It is well established that the nervous and endocrine systems modulate immune function through Neurotransmitters, Neuropeptides, and Hormones, whereas The Immune System interacts with the neuroendocrine system via cytokines, immunopeptides, and immunotransmitters. The immune system ensures the preservation of the genetic constancy of the cellular composition, meaning it acts as one of the homeostatic mechanisms maintaining the integrity of the organism (Immunophysiology, 1993).

A fundamentally important factor in The Development of age-related pathology is the marked decrease in the synthesis of numerous regulatory Peptides and the corresponding reduction in the sensitivity of target cells to them (Kasków et al., 1999; Khavinson et al., 2001a). Given the wide spectrum of biological activities exhibited by these substances (Ashmarin, Obukhova, 1986), it can be hypothesized that such changes in their production lead to the disruption of all links in peptide regulation and to the gradual decline of physiological Functions in the Aging organism. Peptide Hormones participate in The regulation of aging through various Mechanisms of action—endocrine, neurocrine, paracrine, and autocrine (Korneva, Shtikhnek, 1988). For instance, the endocrine MECHANISM OF ACTION is characteristic of hypothalamic releasing hormones. Research has shown that elderly men produce less gonadotropin-releasing hormone (luteinizing hormone-releasing hormone), while the Leydig cells in the Testes exhibit a blunted response to pituitary gonadotropins. In aged rats, the response of hypothalamic neurosecretory cells—which synthesize GnRH—to NMDA receptor excitation is impaired. The resulting failures in peptide regulation lead to an age-related decline in luteinizing hormone secretion by adenohypophyseal cells, which culminates in severe Menstrual cycle disorders and menopausal syndrome (Sahu, Kalra, 1998).

In addition to the decreased synthesis of peptides, many target Cells and Tissues also exhibit a diminished receptor-mediated perception of them. For example, The Effect of exogenously administered substance P on Neurons of The Nucleus tractus solitarius in aged rats is significantly less pronounced than in young ones. This is apparently related to the observed reduction in the number of NK-1 receptors (which are specific to substance P) in this Brain region. A diminished efficacy of substance P on airway smooth Muscle has also been demonstrated. A significant role in these phenomena may be played by the age-related decrease in The amount of mRNA required for the Synthesis of the substance P precursor, preprotachykinin A. Other studies have demonstrated that in aged mice, the stimulatory effects of bombesin, gastrin-releasing peptide, and the active cholecystokinin fragment CCK-8 on lymphocyte chemotaxis are either inhibited or entirely absent. Furthermore, during aging, gastrin-releasing peptide and CCK-8 show a reduced ability to stimulate the cytotoxic activity of natural killer cells. With advancing age, the level of vasoactive intestinal peptide in the ganglion stellatum also declines, and the response of porcine Small Intestine smooth muscle to VIP is impaired (Erlwanger et al., 1999; Khavinson, 2001a).

When analyzing the dynamics of peptide growth factors during aging, contradictory changes emerge. For instance, the synthesis of basic fibroblast growth factor, which is essential for the repair of neurons and their processes, decreases significantly with age, whereas the level of platelet-derived growth factor, conversely, increases. Aging is also accompanied by an elevation in tumor necrosis factor levels. Such disorganization in The production of peptide growth factors can lead to numerous adverse consequences. One prominent example is the alteration in the Structural and functional Organization OF THE Extracellular matrix in venous walls under these conditions, subsequently leading to the development of varicose Veins (Drubaix et al., 1998).

A unique feature of peptide-mediated homeostasis regulation is Polypeptide Processing, which allows peptidases to be activated to generate—at the right place and time—the precise amount of short peptide fragments possessing higher biological activity than the parent compounds. A marked decrease in The activity of cellular endo- and ectopeptidases has been established in aging animals. Concurrently, significant quantities of peptides that resist the available Complement of peptidases are produced and accumulate within cells. However, the precise causes of peptide accumulation in aged cells and their biological role remain fully unresolved (Dzjaliashvili, 1989).

Thus, involutional changes during aging lead to the impairment of Organ and tissue functions, which at THE CELLULAR LEVEL is primarily manifested in disrupted Synthesis of specific Proteins. Furthermore, unlike mature organisms, aging human bodies contain lower levels of hormones, Vitamins, ATP, and Cholesterol. The analysis of a broad spectrum of age-related disorders in peptide homeostasis regulation reveals a clear overarching trend: aging is accompanied by an almost total decline in the Synthesis and Secretion of regulatory peptides, as well as a diminished sensitivity of target cells to them. Numerous research findings indicate that this reduction in the synthesis and secretion of peptide BIOREGULATORS is specifically tied to impairments in their paracrine and autocrine mechanisms of action, which in turn accelerates the aging processes within the organism.

Age-related changes in any organ are the result of both intrinsic processes and reciprocal influences from other Organs. The Thymus—the central organ of the immune system (Khavinson, Zhukov, 1992)—and the Pineal Gland, which regulates the neuroendocrine system (Khavinson, Golubev, 2002), are key organs whose involution largely determines the rate at which aging processes develop. Let us examine the characteristic disruptions in regulatory and functional processes within these organs and certain other body systems.

Thymus (Glandula Thymus)

Age-related involution of the thymus is characterized by the most pronounced changes compared to other organs. Furthermore, the functional involution of the thymus begins much earlier than its morphological manifestations are registered. This involutional process starts During the first year of life, and according to some data, even before birth (Polyakova et al., 2001). The relative mass of the thymus is maximal at birth, but subsequently decreases progressively due to the faster growth rate of overall body mass. Following Puberty, the absolute mass of the thymus decreases exponentially, predominantly at the expense of the cortical layer and to a lesser extent the medullary layer, with both being replaced by connective and adipose tissue. Concurrently, Hassall's corpuscles atrophy, the regular arrangement of epithelial cells is disrupted, the total lymphocyte count diminishes, and macrophages containing various inclusions and cellular debris, along with plasma and mast cells, accumulate. Because the thymic microenvironment plays a crucial role in the "education" and functional activity of T cells, Cell membrane damage, the disruption of cellular microenvironment integrity, and T-cell dysfunction strongly correlate with one another. The ultrastructure of secretory epithelial cells and lymphocytes changes with age (Bellamy, 1973). There is a drop in the levels of thymic hormones circulating in the Blood, which exert a marked influence on the development and functioning of T- and, to some extent, B-lymphocytes, as well as on various types of immunological reactions (Hirokawa, 1977). Starting from the age of 20, the concentration of serum thymic factor in human blood undergoes a gradual decline, culminating in its complete disappearance by ages 50–60. However, the levels of thymosin-a1 and thymopoietin apparently drop much earlier—a process that begins around 10 years of age (Bodey et al., 1997).

With advancing age, substantial alterations are observed in both the functional and phenotypic profiles of T cells. In fact, the two most characteristic signs of declining Immunity are phenotypic shifts and a reduced T-cell response. One of The most significant changes noted in the T-cell population with age is an imbalance in their ratios: a decrease in the proportion of naive T cells and an increase in the proportion of memory T cells. Additionally, evidence points to a decreased frequency of early signal Transduction events, suppression of activation-induced intracellular phosphorylation, and a diminished cellular proliferative response to T-cell receptor stimulation (Ginaldi et al., 1999; Pawelec et al., 1999).

Changes in the immune system associated with thymic involution impact overall systemic homeostasis (Petrov, Khaitov, 1975). During aging, the thymus's capacity to contribute to the terminal differentiation of lymphocytes declines. The Atrophy of the thymic cortex is accompanied by a drop in the immune system's production of numerous secretory factors—including thymopoietin, thymosin a₁, thymulin, and thymic humoral factor—which leads to the suppression of immune responses. Nevertheless, thymic involution does not drastically alter the number of circulating lymphocytes in the blood. The age-related involution of the thymus, which occupies a pivotal position in the immune system, contributes to an increased incidence of malignancies, lowered resistance to infections, and a higher frequency of autoimmune disorders (Ouyang et al., 2000).

Occasionally, immune system weakening is observed long before the onset of old age, which is often predetermined by intensive Chemotherapy, particularly Antibiotics, used in treating infectious diseases during youth. Under such conditions, the organism's natural immune potential is reduced or suppressed, and genetic mechanisms cannot restore it because defective or recessive traits are most commonly inherited. In isolated cases, the third generation (the grandchildren of immunocompromised individuals) inherits homozygosity for recessive Mutations (Rapoport, 1996).

Epiphysis (Pineal Gland)

Melatonin (N-acetyl-5-methoxytryptamine, see Fig. 2), one of the primary Hormones of the pineal gland, possesses a uniquely broad spectrum of action. It serves as a key regulator of biological rhythms, participates in visual function, lowers cholesterol levels, enhances the body's resistance to stress and heavy loads, and helps normalize blood pressure. Melatonin modulates the state of intracellular messengers and/or membrane Ion Channels. By binding to cytoplasmic receptors, melatonin regulates gene expression. Furthermore, the melatonin molecule exhibits antioxidant and anticarcinogenic properties. A distinctive feature of melatonin production by the pineal gland is its pronounced daily cyclicity, with peaks occurring during nighttime hours. As the organism ages, these nocturnal peaks of melatonin secretion decline, which has numerous consequences for the neuroendocrine system—primarily concerning reproductive functions and stress responses—as well as for the immune system, carcinogenesis, and circadian rhythm regulation (Khavinson, Golubev, 2002). The principal morphological manifestations of involutional changes in pineal Structure include a reduction in the total number of pinealocytes, a decrease in their RNA concentration, and an increase in cyst formation within the gland. Additionally, calcium concretions form within the pineal gland during aging. It is hypothesized that this occurs due to an age-related decline in Ca⁺⁺-ATPase activity, ultimately leading to cell death. With advancing age, functional sympathetic denervation develops in the pineal gland. For instance, in rats, the concentration of ß-adrenergic receptors drops, the capacity to upregulate adrenoreceptors in response to adrenergic denervation is lost, and immunoreactivity for Tyrosine hydroxylase—a marker enzyme of catecholaminergic axons—significantly decreases. Generally speaking, disturbances in the noradrenergic systems external to the pineal gland that stimulate its secretory activity contribute substantially to the age-related hypofunction of the gland (Chazov, Isachenkov, 1974).

However, at the age when a marked reduction in nighttime melatonin secretion peaks occurs, the pineal gland does not exhibit degenerative changes of the same severity (unlike the thymus, where the decline in factor production is directly linked to the degeneration of the organ itself). Age-related involution of the pineal gland is more functional than organic in nature, making the potential restoration of its functions highly probable.

Gonads

In addition to the thymus and pineal gland, the Reproductive System is directly implicated in the aging process, and The rate of sex hormone production largely determines a person's biological age. This is particularly pronounced in women as a complex symptom complex known as the Climacteric, where aging runs parallel to an increase in blood gonadotropin levels and enhanced excretion of non-classical phenolic Steroids. From a biological standpoint, the climacteric is a necessary and inevitable mechanism that removes aging individuals from the reproductive process, which is advantageous for species preservation. Clinical evidence demonstrates shared manifestations of the climacteric in both women and men. This allows it to be considered, in essence, a physiological syndrome caused by age-related shifts in hormonal and general METABOLISM, and primarily by the age-related decline in gonadal function. In men, it occurs later than in women, proceeds less noticeably, and merges seamlessly with the signs of senescence. There is a drop in testosterone levels, which correlates with an elevated concentration of cholesterol and atherogenic Lipids in Blood Plasma. Androgen deficiency manifests particularly clearly in structural and functional alterations of testosterone's primary target organs—the Prostate Gland and Seminal Vesicles, which are directly dependent on androgenic stimuli. Disrupted testosterone metabolism within prostate tissue promotes the local accumulation of dihydrotestosterone, ultimately leading to the development of adenoma and prostate Cancer (Finch, Kirkwood, 2000).

Blood Vessels

According to modern concepts, atherosclerosis is the primary age-related vascular pathology (Chebotarev et al., 1982). For a long time, the "lipid theory" was considered the main mechanism behind atherosclerosis; however, the discovery in 1980 of an endothelium-derived relaxing factor—nitric oxide (NO)—prompted a revision of existing views regarding atherogenesis. This led to the hypothesis of primary endothelial dysfunction and a multifactorial theory framing the development and progression of atherosclerosis as a multi-organ systemic process (Furchgott, Zavadski, 1980). It is now established that inflammatory-like reactions play a significant role in the Pathogenesis of atherosclerosis. The synthesis of numerous growth factors involved in forming atherosclerotic lesions occurs in the endothelium, and their production is upregulated by inflammatory mediators. Destructive changes in the vascular wall form the basis for the development of aneurysms, mural and occlusive thrombi, and intramural hemorrhages.

Age-related changes in ocular tissues follow the general laws of The Cardiovascular system's aging, yet they possess distinct features driven by the structural and functional Specificity of the visual analyzer and the presence of autoregulatory mechanisms in its blood supply system. Diminished Blood Circulation and transcapillary metabolism promote the development of dystrophic changes in the retina. Such processes are similarly rooted in Metabolic Disorders of specific proteins within the retinal pigment epithelium and other retinal layers. During the progression of age-related pathology in older individuals, the lens tissue becomes clouded, the retina is damaged, Connective Tissue mass increases, and The structure of Collagen fibers alters (Rumyantsev, 1983; Trofimova, Khavinson, 2002).

In Chapter 1, when discussing Tissue-Specific Regulatory Peptides, it was demonstrated that the integrating and coordinating function of peptide self-regulation at THE MOLECULAR LEVEL is performed by the brain, i.e., the Central Nervous system. Investigations into normal aging similarly reveal the leading role of the central nervous system and the brain in self-regulatory processes at the level of the entire organism.

Brain

Brain aging represents one of the most dramatic processes in ontogenesis. Senile Changes in the central nervous system begin quite early, with initial manifestations appearing as early as after the age of 30. They are characterized by a reduction in the number of Nerve Cells and diminished cerebral blood flow, which is accompanied by a decrease in brain mass and an expansion of the free space between the cranial bones and brain tissue. However, the loss of neurons is not the decisive factor in declining nervous system function. Of greater importance is the preservation of functional connections between neurons, which are maintained via neurotransmitters interacting with specific receptors. It has recently been experimentally proven (Reichardt et al., 2001) that normal aging involves a sequential decoupling of the brain's neuronal regulatory systems. In this process, alterations in signaling cascades at the nuclear level appear first, followed by disruptions in the structural and Functional Properties of synaptic membranes leading to their degradation, and subsequently by memory disorders. Furthermore, in old age, certain brain structures (nucleus caudatus, putamen) exhibit decreased levels of serotonin, norepinephrine, and dopamine. These impairments are also associated with memory decline, slowed reaction speeds, and reduced tolerance to everyday loads.

During normal aging, age-related changes frequently manifest as attention deficits, particularly when processing auditory-verbal information. Other cognitive functions (intelligence, speech) are not significantly impaired. Attention and memory disorders in old age typically do not progress, or do so extremely slowly. Rapid progression of cognitive impairment in older age is a sign of brain pathology. Neurodegenerative diseases serve as a reflection of involutional processes in the central nervous system, with Alzheimer's disease (AD) and Parkinson's disease (PD) being the most prominent.

Alzheimer's disease is characterized by a triad of morphological features, which includes the presence of ß-amyloid plaques (senile plaques), neurofibrillary tangles, and extensive destruction of Nervous Tissue, particularly in the hippocampus and Cerebral Cortex (Dickson, 1997). An important biochemical mechanism of AD is a progressive cholinergic deficit in neurotransmitter systems. The pathological mechanisms of AD also involve oxidative stress and the accumulation of free radicals, which in turn can lead to excessive Lipid Peroxidation, the disruption of neuronal membrane integrity, and the gradual death of brain cells. In recent years, the concept that oxidative stress is the "primary culprit" in neuronal destruction during AD has become increasingly dominant.

Parkinson's disease is a major neurodegenerative disorder characterized by the progressive degeneration of dopamine-producing neurons in the substantia nigra of the Brainstem. The destruction of these catecholaminergic neurons is accompanied by a range of sensory and motor impairments leading to tremor, rigidity, and akinesia. Estimates indicate that in patients with overt Parkinson's disease, the dopaminergic neuron population is depleted by at least 80%. In most cases, the initial signs of Parkinson's disease precede the appearance of frank parkinsonian symptoms by 5–10 years (Olanov, Tatton, 1999). According to the free-radical theory of Parkinson's disease, dopaminergic neurons are destroyed due to a relatively high frequency of exposure to reactive oxygen species, particularly H₂0₂ (hydrogen peroxide), which is produced during both enzymatic (via monoamine oxidase) and non-enzymatic (driven by auto-oxidation) degradation of dopamine. Oxidative stress not only destroys dopaminergic neurons but also impairs mitochondrial Oxidative Phosphorylation, leading to reduced energy production by these Organelles and, ultimately, neuronal cell death.

The preceding sections outlined current Perspectives on the age-related involution of vital organs and systems. Aging is an inevitable process, yet it can be delayed by extending the period of active life. This constitutes the primary objective of gerontology.

Studies investigating age-related involution have yielded data indicating that extending a healthy, productive lifespan is entirely feasible (Frolkis, Muradyan, 1988). For instance, it was previously believed that the thymus virtually ceases to function by the time a person reaches mid-adolescence (14–16 years of age). However, recent research suggests that the adult thymus can indeed contribute to T-cell reconstitution. Furthermore, the extrapolation of experimental data regarding the age-related dynamics of the cellular microenvironment suggests that the complete depletion of the reticuloepithelial tissue of the thymus and its thymocytes may only occur around 120 years of age (Bodey et al., 1997). Similar encouraging results have been obtained for other organs. As noted above, the human pineal gland does not undergo pronounced degeneration during age-related involution. Interesting findings have also emerged from studies on the human corneal endothelium across different age groups (Robert et al., 2001). Human corneal endothelial cells were found to be capable of incomplete polyploidization of mitotic cells—a variant of normal cell proliferation characteristic of long-lived, slowly proliferating tissues. The age-related increase in the number of polyploid cells in the corneal endothelium points to the activation of adaptive mechanisms during age-related involution.

Thus, there is good reason to believe that the body possesses endogenous mechanisms capable of ensuring a longer and, crucially, a healthier life (Yakovlev et al., 1990). To extend the period of active life, it is essential to identify these mechanisms and develop ways to modulate them. The most promising approach in this direction may lie in discovering and developing Methods to correct age-related pathology, aimed at slowing down and reversing the impairments in the synthesis, secretion, and reception of biologically active molecules that drive the involution of organs and tissues.