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Peptides of pineal gland and thymus prolong human life
Abstract
Researchers of the St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences and the Institute of Gerontology of the Ukrainian Academy of Medical Sciences (Kiev) clinically assessed the geroprotective effects of thymic (Thymalin) and pineal (Epithalamin) peptide bioregulators in 266 elderly and older persons during 6-8 years. The bioregulators were applied for the first 2-3 years of observation.
The obtained results convincingly showed the ability of the bioregulators to normalize the basic functions of the human organism, i.e. to improve the indices of cardiovascular, endocrine, immune and nervous systems, homeostasis and metabolism. Homeostasis restoration was accompanied by a 2.0-2.4-fold decrease in acute respiratory disease incidence, reduced incidence of the clinical manifestations of ischemic heart disease, hypertension disease, deforming osteoarthrosis and osteoporosis as compared to the control. Such a significant improvement in the health state of the peptide-treated patients correlated with decreased mortality rate during observation: 2.0-2.1-fold in the Thymalin-treated group; 1.6-1.8-fold in the Epithalamin-treated group; 2.5-fold in the patients treated with Thymalin plus Epithalamin as compared to the control. A separate group of patients was treated with Thymalin in combination with Epithalamin annually for 6 years and their mortality rate decreased 4.1 times as compared to the control.
The obtained data confirmed the high geroprotective efficacy of Thymalin and Epithalamin and the expediency of their application in medicine and social care for health maintenance and age-related pathology prevention in persons over 60 to prolong their active longevity.
... It is important to understand that the solution to the problems concerned with population ageing is only possible if all society members are aware that the citizen aged 65 and older constitute important potential for social development (3,4). As a rule, healthy people of older age are able to work till later age, compensating for the work force deficit caused by lower birth rate, thereby providing for the continuity of knowledge and experience of older generations. ...
... During the recent decade the achievements in theoretical and applied gerontology allowed implementing targeted regulation of age-related changes. Based on the latter, one of the priority tasks for modern gerontology is prevention of accelerated ageing and age pathologies, directed at increasing average life span, preserving active longevity and achieving species-specific human life span limit (4). ...
... Morphological and functional equivalent of ageing is involution of organs and tissues, and primarily those that are concerned with the main regulatory systems including the nervous, endocrine and immune ones. There are data available testifying to age hypoplasia, and in a number of cases, to the atrophy of the pineal gland, thymus, neuronal cortex and sub-cortex, retina, vascular wall and genitalia (4,31,32). ...
The current demographic situation in the world is characterized by an increase in average life expectancy, low birth rate, as well as an increase in the number of older and senior people, which is why our epoch is referred to as «the age of ageing». [...].
... On the molecular level, there was an obvious gap between multiple evidence of specific effects, caused by regulatory peptides in activation of gene tran- scription ( Khavinson et al. 2002a, c;Anisimov and Khavinson 2003;Sibarov et al. 2002Anisimov et al. 2003Djeridane et al. 2003;Kossoy et al. 2003;Khavinson and Morozov 2003;Labunets et al. 2004a, b), and limited schemes of the process underlying the selective binding of the transcription factor with specific DNA sites. Meanwhile non-specific binding of proteins with the DNA double helix was proved using physicochemical methods ( Riadnova et al. 2000). ...
... Taking into consideration the encouraging data testifying to high geroprotective activity of both natural tissue specific and synthetic peptide prepara- tions we have been concentrating our attention on studies of geroprotective activity of peptides in old and senile people in recent years (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004;Anisimov and Khavinson 2005;Khavinson and Malinin 2005;Goncharova et al. 2005;Kozina et al. 2007). Thus, annual treatment course with thymus and pineal preparations led to a reliable decrease in mortality (Table 3), to improvement of brain function and that of immune, endocrine, cardio-vascular systems, increased density of osseous tissue (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004). ...
... Taking into consideration the encouraging data testifying to high geroprotective activity of both natural tissue specific and synthetic peptide prepara- tions we have been concentrating our attention on studies of geroprotective activity of peptides in old and senile people in recent years (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004;Anisimov and Khavinson 2005;Khavinson and Malinin 2005;Goncharova et al. 2005;Kozina et al. 2007). Thus, annual treatment course with thymus and pineal preparations led to a reliable decrease in mortality (Table 3), to improvement of brain function and that of immune, endocrine, cardio-vascular systems, increased density of osseous tissue (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004). It is noteworthy that application of preparation of the thymus led to a twofold decrease in frequency of acute respiratory disease (Khavinson and Morozov 2003). ...
Twenty-five years of study have shown a wide spectrum of high biological activity of the pineal peptide preparation epithalamin. Long-term exposure to epithalamin was followed by an increase in the mean and maximum life spans and slower rates of aging of rats, mice, and D. melanogaster. Epithalamin increases pineal synthesis of serotonin, N-acetylserotonin, and melatonin and night pineal secretion of melatonin in adult and old rats. The pineal preparation decreases the luteinizing hormone and prolactin levels in adult male rats as well as the threshold of the hypothalamopituitary complex to feedback inhibition by estrogens in old female rats; it slows dawn age-related cessation of estrous function in rats and induces the recurrence of estrous cydes and fertility in old, persistently estrous rats. Epithalamin increases the levels of triiodothyronine and decreases thyroxine in serum of adult rats. It further decreases the levels of corticosterone in the serum of mice and increases the susceptibility of the hypothalamo-pituitary complex to the homeostatic inhibition of adrenocorticotropic function by glucocorticoids in old rats. Serum insulin and triglyceride levels in rabbits are decreased by epithalamin and the tolerance to glucose and diuresis are increased. With respect to immune function, it was found that T and B cell-mediated immunity in adult and old mice as well as the titer of thymic serum factor and the titer of thymosin-like compounds in old mice are stimulated by the pineal peptide preparation in the same way as the colony-forming activity of splenocytes in pinealectomized rats. Epithalamin inhibits spontaneous and induced carcinogenesis and is a potent antioxidant, decreasing lipid peroxidation and stimulating the activity of CuZn superoxide dismutase. The obtained results demonstrate a high efficiency of epithalamin therapy for prophylaxis of age-related pathology, including cancer, showing a new physiological way to slow down pathological processes and to extend human life spans.
... On the molecular level, there was an obvious gap between multiple evidence of specific effects, caused by regulatory peptides in activation of gene transcription (Khavinson et al. 2002a, c;Anisimov and Khavinson 2003;Sibarov et al. 2002Anisimov et al. 2003Djeridane et al. 2003;Kossoy et al. 2003;Khavinson and Morozov 2003;Labunets et al. 2004a, b), and limited schemes of the process underlying the selective binding of the transcription factor with specific DNA sites. Meanwhile non-specific binding of proteins with the DNA double helix was proved using physicochemical methods (Riadnova et al. 2000). ...
... Taking into consideration the encouraging data testifying to high geroprotective activity of both natural tissue specific and synthetic peptide preparations we have been concentrating our attention on studies of geroprotective activity of peptides in old and senile people in recent years (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004;Anisimov and Khavinson 2005;Khavinson and Malinin 2005;Goncharova et al. 2005;Kozina et al. 2007). Thus, annual treatment course with thymus and pineal preparations led to a reliable decrease in mortality (Table 3), to improvement of brain function and that of immune, endocrine, cardio-vascular systems, increased density of osseous tissue (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004). ...
... Taking into consideration the encouraging data testifying to high geroprotective activity of both natural tissue specific and synthetic peptide preparations we have been concentrating our attention on studies of geroprotective activity of peptides in old and senile people in recent years (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004;Anisimov and Khavinson 2005;Khavinson and Malinin 2005;Goncharova et al. 2005;Kozina et al. 2007). Thus, annual treatment course with thymus and pineal preparations led to a reliable decrease in mortality (Table 3), to improvement of brain function and that of immune, endocrine, cardio-vascular systems, increased density of osseous tissue (Khavinson 2002;Khavinson and Morozov 2003;Labunets et al. 2004a, b;Korkushko et al. 2004). It is noteworthy that application of preparation of the thymus led to a twofold decrease in frequency of acute respiratory disease (Khavinson and Morozov 2003). ...
The paper summarizes results of long-term research designed to elucidate mechanisms of aging and evaluate efficacy of peptide bioregulators for the prevention of age-specific pathology. Peptides obtained by up-to-date methods in Russia, USA, UK, Germany, Italy, Spain, and France are reviewed. A molecular model is proposed to describe complementary interactions of short-chain peptides with gene promoters underlying initiation of protein synthesis. Prospects for the use of peptide bioregulators to prevent premature aging of the employable population in Russia are discussed.
... Az immunrendszer és természetesen ennek központi eleme, a thymus alapvetően érintett a melatoninszint csökkenése által [3,36], és a pinealis involúció miatt bekövetkező melatoninszint-csökkenés parallel fut a thymus involúciójával [37], a thymusban történő melatoninszintézis csökkenésével. A szabad gyökök elleni védekezés és az immunrendszer tevékenységének csökkenése kedvez a jellegzetesen időskori megbetegedések fellépésének [38], miközben pinealis peptidek adagolása csökkenti a mortalitást [39]. Egyes kutatók feltételezik a thymus és a tobozmirigy funkcionális egységét [40,41], amit a thymus melatonintermelése is alátámaszt [42]. ...
... Mivel a felsőbb centrum a napi ritmus szabályozásában a suprachiasmaticus mag [33,48], feltételezhető, hogy az öregedési ritmus szabályozásában is részt vesz. Mindenesetre van olyan emberen észlelt megfigyelés, amely szerint melatonin és thymuspeptidek adagolása növelte az élettartamot [39], azonban az SCN hatását nem vizsgálták. Ugyancsak elmaradt a thymus endokrin részének, azaz hormonjainak (a peptideknek) alapos hatásvizsgálata állatkísérletekben az autoimmunitásra és élettartamra. ...
Thymus is an immunoendocrine organ, the hormones of which mainly influence its own lymphatic elements. It has a central role in the immune system, the neonatal removal causes the collapse of immune system and the whole organism. The thymic nurse cells select the bone marrow originated lymphocytes and destroy the autoreactive ones, while thymus originated Treg cells suppress the autoreactive cells in the periphery. The involution of the organ starts after birth, however, this truly happens in the end of puberty only, as before this it is overcompensated by developmental processes. From the end of adolescence the involution allows the life, proliferation and enhanced functioning of some autoreactive cells, which gradually wear down the cells and intercellular materials, causing the aging. The enhanced and mass function of autoreactive cells lead to the autoimmune diseases and natural death. This means that the involution of thymus is not a part of the organismic involution, but an originator of it, which is manifested in the lifespan-pacemaker function. In this case aging can be comprehended as a thymus-commanded slow autoimmune process. The neonatal removal of pineal gland leads to the complete destruction of the thymus and the crashing down of the immune system, as well as to wasting disease. The involution of the pineal and thymus runs parallel, because the two organs form a functional unit. It is probable that the pineal gland is responsible for the involution of thymus and also regulates its lifespan determining role. The data reviewed do not prove the exclusive role of pineal-thymus system in the regulation of aging and lifespan, however, calls attention to the suitability of solving this problem alone. Orv. Hetil., 2016, 157(27), 1065–1070.
... The discovery of the bioactivity of this extract and its first research were mainly led by V.K Khavinson and V.N Anisimov [2]. Since then, Epithalamin has been widely studied, including in clinical trials, showing a normalizing effect on the basic functions of the human organism and, as a result, establishing it as a geroprotective agent [3]. Despite the publication of several reviews of Epithalamin [4][5][6][7], to the best of our knowledge, none specifically concentrate on Epitalon. ...
Epitalon, also known as Epithalon or Epithalone, is a tetrapeptide, Ala-Glu-Asp-Gly (AEDG), which was synthesized based on the amino acids composition of Epithalamin, a bovine pineal gland extract, prior to its discovery in pineal gland polypeptide complex solution. During the last 25 years, this compound has been extensively studied using in vitro, in vivo, and in silico methods. The results of these studies indicate significant geroprotective and neuroendocrine effects of Epitalone, resulting from its antioxidant, neuro-protective, and antimutagenic effects, originating from both specific and nonspecific mechanisms. Although it has been demonstrated that Epitalon exerts, among other effects, a direct influence on melatonin synthesis, alters the mRNA levels of interleukin-2, modulates the mitogenic activity of murine thymocytes, and enhances the activity of various enzymes, including AChE, BuChE, and telomerase, it remains uncertain whether these are the sole mechanisms of action of this compound. Moreover, despite the considerable volume of research on the biological and pharmacodynamic characteristics of Epitalon, the quantity of physico-chemical and structural investigations of this peptide remains quite limited. This review aims to conclude the most important findings from such studies, thus presenting the current state of knowledge on Epitalon.
... Thymogen is implemented for treatment of pancreatic diabetes, influenza, and various inflammations. This peptide has a stressprotective and adaptogen effect, exerting a regulating effect on the level of neurotransmitters: dopamine, serotonin, norepinephrine, acetylcholine, GABA, glycine and endogenous opiates [5][6][7][8][9][10]. ...
... Forty years of experience, in the use of thymalin in the treatment of various viral and bacterial diseases accompanied by impaired immune system function, has proven its high clinical effectiveness [16][17][18]. One of the mechanisms of the immunomodulatory action of thymalin is considered to be the ability of this peptide preparation to influence the differentiation of human hematopoietic stem cells (HSCs). ...
The paper presents the results of a standard and complex treatment method using the peptide drug thymus thymalin in patients with COVID-19. One of the mechanisms of the immunomodulatory effect of thymalin is considered to be the ability of this peptide drug to influence the differentiation of human hematopoietic stem cells (HSCs). It was found that, as a result of standard treatment, patients in the control group showed a decrease in the concentration of the pro-inflammatory cytokine IL-6, C-reactive protein, D-dimer. The addition of thymalin to standard therapy accelerated the decline in both these indicators and the indicators of the T cell system. This has helped reduce the risk of blood clots in COVID-19 patients. The revealed properties of the thymus peptide preparation are the rationale for its inclusion in the complex treatment of coronavirus infection.
Graphical Abstract
Peptideswith potential biological activity against SARS-CoV-2 virus [29]. Note: Nitrogen atoms are shown in blue, oxygen atoms - in red, carbon atoms – in gray, hydrogen atoms – in white, and phosphorus atoms – in yellow
... The tetrapeptide Ala-Glu-Asp-Gly (AEDG) was constructed and synthesized of these amino acids [3,9]. The peptide AEDG had biological effects similar to those of PGPC, but in lower concentrations [1,[4][5][6]9,10]. Administration of PGPC or AEDG restored melatonin-forming function of the pineal gland in elderly people and in older monkeys [1,2], increased superoxide dismutase (SOD) activity, and decreased in the amount of LPO products, diene conjugates, and ROS [2,4,9]. ...
The polypeptide complex of the epiphysis and the peptide AEDG, constructed on the basis of its amino acid analysis, exert similar biological effects. Both bioregulators normalize melatonin synthesis in the pineal gland, functioning of the brain, eye retina, cardiovascular, endocrine, and immune systems; they also act as antioxidants, stress-protectors, and geroprotectors. Within the epiphysis polypeptide complex, free amino acids (3.26%), dipeptides (23.19%), tripeptides (50.72%), tetrapeptides (22.10%), and pentapeptides (0.72%) were revealed by mass spectrometry and HPLC. Peptide AEDG was detected among the tetrapeptides of the epiphysis polypeptide complex by selective reaction monitoring method. The biological effects of the epiphysis polypeptide complex are determined by the effect of its component AEDG.
... It seems likely a functional unity of pineal and thymus involution [79,124,128]. The functional unity is also supported by human experiments, when durable combined treatment with pineal and thymus peptides prolonged the lifespan [129]. ...
The thymus develops from an endocrine area of the foregut, and retains the ancient potencies of this region. However, later it is populated by bone marrow originated lymphatic elements and forms a combined organ, which is a central part of the immune system as well as an influential element of the endocrine orchestra. Thymus produces self-hormones (thymulin, thymosin, thymopentin, and thymus humoral factor), which are participating in the regulation of immune cell transformation and selection, and also synthesizes hormones similar to that of the other endocrine glands such as melatonin, neuropeptides, and insulin, which are transported by the immune cells to the sites of requests (packed transport). Thymic (epithelial and immune) cells also have receptors for hormones which regulate them. This combined organ, which is continuously changing from birth to senescence seems to be a pacemaker of life. This function is basically regulated by the selection of self-responsive thymocytes as their complete destruction helps the development (up to puberty) and their gradual release in case of weakened control (after puberty) causes the erosion of cells and intercellular material, named aging. This means that during aging, self-destructive and non-protective immune activities are manifested under the guidance of the involuting thymus, causing the continuous irritation of cells and organs. Possibly the pineal body is the main regulator of the pacemaker, the neonatal removal of which results in atrophy of thymus and wasting disease and its later corrosion causes the insufficiency of thymus. The co-involution of pineal and thymus could determine the aging and the time of death without external intervention; however, external factors can negatively influence both of them.
... This way senescence and biorhythmicity seems to be connected , influencing and maintaining the normal immune and endocrine status during aging [23]. It is possible that in this effect not only the melatonin is taking part, but other pineal or thymic peptides [24]. ...
The first observation on the relationship between the pineal gland and the immune system was done by the author of this paper in the late sixties and early seventies of the last century. After neonatal pinealectomy the thymus has been destroyed and wasting disease developed. Since that time a flood of experiments justified the observation and pointed to the prominent role of pineal in the regulation of the immune system. Melatonin, the hormone of the pineal gland stimulates immune processes acting to the immune cells' cytokine production, the haemopoiesis, and immune cell-target cell interactions. Melatonin receptors have been demonstrated and their localization and function were justified. Melatonin production by and melatonin receptors on (and in) the immune cells was proved. Melatonin agonists have been synthesized and the use of melatonin as adjuvant in the therapy of diseases connected to the immune system (cancers included) has been started. The paper summarizes the most important studies and discusses the interrelations of the data. The discussion points to the possibility of packed transport of the pineal hormone by the immune cells and to the adventages of local regulation by this transport.
... Being a major organ of the immune system, thymus plays a key role in the T cell immunity formation [1,2]. An overt lowering of thymus functional activity in humans can be traced from the beginning of puberty and is associated with an early involution of this organ [3,4]. Thymus involution is largely manifested by the reduced count of cortical thymocytes and mature T cells [1,5]. ...
The processes of differentiation, proliferation, and apoptosis were studied in a cell culture of human cortical thymocytes under the influence of short peptides T-32 (Glu-Asp-Ala) and T-38 (Lys-Glu-Asp). Peptides T-32 and T-38 amplified cortical thymocytes differentiation towards regulatory T cells, increased their proliferative activity, and decreased the level of apoptosis. Moreover, peptides under study stimulated proliferative and antiapoptotic activity of the mature regulatory T cells.
Immunoprotective,antioxidant,hepatoprotective effect of calf thymus extract and l-carnitine in aged male mice
Актуальной проблемой биологии и медицины является разработка новых технологий, применение которых способно замедлять процесс преждевременного старения и развитие возраст-ассоциированных заболеваний. Одним из важных направлений является изучение эффективности геропротекторных препаратов, препятствующих процессу старения и увеличивающих среднюю продолжительность жизни. Среди таких препаратов в настоящее время большое внимание привлекают пептидные биорегуляторы. Многолетние научные исследования показали, что особенно эффективными оказались лекарственный препарат эпиталамин (комплекс пептидов, выделенных из эпифиза мозга животных) и тетрапептид эпиталон (который содержится в этом комплексе). Введение указанных препаратов животным разных видов достоверно увеличивало среднюю и максимальную продолжительность жизни и уменьшало частоту возникновения спонтанных и индуцированных канцерогенами злокачественных опухолей. Клиническое изучение эпиталамина свидетельствовало об улучшении основных физиологических показателей у пациентов пожилого и старческого возраста и привело к снижению смертности в течение 15-летнего периода наблюдений. Анализ механизмов действия препаратов эпифиза в различных экспериментах показал возможность пептидергической эпигенетической регуляции экспрессии генов и синтеза белков у эукариот.
Development of new technologies aimed at prevention of early ageing and age-related diseases is a relevant issue of modern biology and medicine. Studying efficacy of geroprotective medicines, which hamper ageing and increase the average lifespan, has become a leading line of research. At present, peptide bioregulators hold a special place among such medicines. Multi-year studies have demonstrated a remarkable efficacy of Epitalamin (peptide complex isolated from animal pineal gland) and a tetrapeptide Epitalon (a part of this peptide complex). Administration of these peptide drugs to animals significantly prolonged the average and maximal lifespan and reduced the incidence of spontaneous and carcinogen-induced malignant tumors. Clinical studies of Epitalamin have demonstrated physiological improvement and decreased mortality rate in elderly and senile patients during a 15-year follow-up period. Analysis of mechanisms underlying the effect of pineal peptides in various experiments showed a possibility of peptidergic regulation for gene expression and protein synthesis in eukaryotes.
This review provides research data on drugs made on the basis of polypeptides isolated from different animal organs. They initiated the development of drugs of a peptide origin. Besides, a group of pharmaceuticals (peptide complexes), created at the Military Medical Academy named after S.M. Kirov (Thymalin, Epithalamin, Cortexin, Prostatilen, Retinalamin) under the supervision of V.Kh. Khavinson in the 80–90-ies of the 20th century has been described. At present, pharmacologists focus on isolation of short di-, tri-, tetrapeptides, identification of their primary structures and subsequent synthesis from amino acids (Thymogen, Vilon, Pinealon, Vesugen, Epitalon, Bronchogen, Cardiogen, etc.). The results of cutting edge investigations of peptide influence on various functions of an organism, gene expression and protein synthesis have been presented. A molecular mechanism of a peptide-DNA interaction has been depicted. Short peptides have been revealed to regulate gene expression, protein synthesis, chromatin state and promote telomeres elongation. Peptides regulate targeted differentiation of pluripotent cells and decrease their replicative ageing. Animals administered with peptides showed a decreased tumor incidence, normalized melatonin level and an increased average life span. To summarize the above, it is worth noting further prospects of studies aimed at creation of novel drugs on the basis of short peptides with targeted regulation of certain gene groups and protein synthesis which underlies the development of pharmacogenomics as fundamentals for future therapy.
Thymus is the central organ of immunity, which has a decisive role in the selection and removal of the autoreactive lymphocytes. The pineal gland influences the sustenance and function of thymus, the neonatal removal of thymus as well as pineal gland causes the total collapse of the immune system. Involution of pineal and/or thymus after adolescence permits the manifestation of autoimmune processes, causing the aging and determining the lifespan. Thymus involution is not a consequence of the general involution caused by the progressing age, but a prime mover of it. The pacemaker of aging could be in the suprachiasmatic nucleus of the brain, which is in neural and chemical contact with the the pineal body and the executor is the thymus, regulating the autoimmunity. From this aspect aging is caused by the continuous slow wearing of cells and organs by autoimmunity. A certain degree of autoimmunity is a natural process, which causes manifest disease if becomes enormously strong or directed towards a special organ or system. The velocity of the slow wearing as well, as the functional importance of the target organs determines the lifespan. Outer factors can not prolong the lifespan however, can shorten it by increasing thymic involution, consequently influencing autoimmunity.
The concept of frailty, a decrease in physical function and increasing vulnerability to morbidity and death, is central to the biological study of aging (Fried et al., 2001; Walston, 2004). Genetics, epigenetics, free radicals, aging, disease, and cellular bioenergetics have all been identified as causative elements in frailty. Study of these elements, and their relations, may allow us to develop dynamic models of the age related emergence of physical frailty at the population level (Dirks et al., 2006). A phenotype has been defined for physical frailty (Fried et al., 2001). An area where frailty is less completely studied is the central nervous system (CNS) where a phenotype has not been developed for cognitive "frailty". We attempt to develop such a model by examining the effects of loss of neuronal energetic capacity with age. To develop a model of frailty in the CNS the ability to parametrically describe changes in neuronal frailty and mortality must be examined in the context of the properties of cellular processes involved in energy production. Processes whose contribution to CNS frailty are to be examined include a) shortening of the telomere by oxidative stress, b) cellular bioenergetics involving mitochondrial enzyme, membrane and matrix structure, c) select genes silencing the expression of specific proteins, and d) genomic and non-genomic thyroid hormone (Triiodothyronine (T3)) regulation of mitochondrial structure and function, genesis and cell growth and differentiation. The role of environmental stressors, such as ionizing radiation (IR), in modifying certain rate parameters of cellular bioenergetics may suggest ways to better study and describe such mechanisms in humans.
This monograph highlights the gerontological aspects of the peptide regulation of gene expression. It focuses on the mechanisms of the geroprotective action of peptides related to chromatin activation, increase in telomerase enzyme activity, and elongation of telomeres in different cells. A key role in the initiation of the biological activity of peptide is its interaction with DNA which provides genetic stability and a normalization of the age-related metabolic shifts. Study of the genetic mechanisms of peptide action suggests a new concept which most comprehensively reflects on the evolutionary biological role peptide plays in the organism. The impact of peptides on the expression and structure of genes opens a new gate for the prevention of premature aging and age-related pathology which appears to be most promising in pharmacogenomics. This monograph narrates not only the theoretical aspects and experimental data, but also outlines new approaches to the prevention of aging and age-related pathology, thus addressing a wide readership of gerontologists, geneticists, molecular biologists, biochemists, and pharmacologists alike.
During the peptides activity mechanism investigation it was shown that short peptides regulate gene expression and protein synthesis. These peptides stimulated cell proliferation, differentiation and decreased cell apoptosis. This effect is the reason of increasing of various organs function. The peptides injection decreased the frequency of cancerogenesis and increased physiological resource of cells, tissues and organism till 20-42%. Peptides increased vital resource and decreased the mortality rate of elderly people.
This review describes the interplay between the thymus and pineal gland during their involution connected with aging. The data of a few studies on the effects of thymus peptides on the pineal gland and pineal peptides on the thymus are consolidated. Analysis of these data demonstrates that pineal peptides (epithalamin and epithalon) have a more pronounced geroprotective effect on the thymus as compared with those of the thymus peptides (thymalin and thymogen) on the pineal gland. The key processes involved in the restoration of the thymus function in its age-related involution by epithalamin and epithalon are the immunoendocrine mechanisms implemented at the level of transcription activation of various proteins.
We studied molecular mechanisms of immunoprotective effects of two dipeptides, AB-O and R-1, on cultured human and rat thymic cells. Both dipeptides were shown to increase the expression of lymphocyte differentiation marker CD5 in thymic cells. Dipeptide AB-O induced T-cells precursor differentiation towards CD4(+)T-helpers and its effect was weaker than that of dipeptide R-1. Dipeptide R-1 stimulates differentiation of CD5(+) cells to mature T-helpers and cytotoxic CD8(+) T cells and hence can be considered as a bioactive substance possessing immunomodulator and antiallergic activity.
This review considers the mutual influence of the thymus and pineal gland on each other during their involution. Research
data on the influence of thymus peptides on the pineal gland and of pineal peptides on the thymus is summarized. An analysis
of the data showed that pineal peptides (epithalamin, epitalon) had more a effective geroprotective effect on thymus involution
in comparison with the geroprotective effect of thymic peptides (thymalin, thymogen) on the involution of the pineal gland.
The key mechanisms of pineal peptides’ effect on thymus dystrophy is immunoendocrine cooperation, which is realized via transcription
activation of various proteins.
Keywordsepitalon–epithalamin–thymus–pineal gland–aging
The review comprises the results of author's long-term investigation in the mechanisms of aging and a role of peptide bioregulators in prevention of age-related pathology. A number of small peptides have been isolated from different organs and tissues and their analogues (di-, tri-, tetrapeptides) were synthesized from the amino acids. It was shown that long-term treatment with some peptide preparations increased mean life span by 20-40%, slow down the age-related changes in the biomarkers of aging and suppressed development of spontaneous and induced by chemical or radiation carcinogens tumorigenesis in rodents. Possible mechanisms of the biological effects of small peptides are discussed in the paper. The results of clinical applications of peptide preparation during the period of 6-12 years are presented as well.
Bovine pineal polypeptide extract (PPE) exerted an anti-tumor effect on mouse-transplantable tumors: mammary cancer (RSM), squamous cell cervical carcinoma (SCC), hepatoma-22a and lympholeukemia LIO-1, and had no effect on Harding-Passey melanoma and leukemia L-1210. It was shown that PPE possessed the ability to decrease the incidence of DMBA-induced mammary adenocarcinomas in rats. The daily administration of 0.5 mg PPE prolonged the life span of rats by 25% and failed to influence spontaneous tumor development. The arguments in favor of a possible mechanism of anti-tumor action of the pineal gland are submitted. It is suggested that the anti-tumor effect of PPE may occur when the syndrome of cancrophilia is induced by tumor transplantation or chemical carcinogens.
The low-molecular-weight polypeptide factors were obtained from bovine thymus (TF), pineal gland (PF) and anterior hypothalamus (AHF). Both TF and PF administration enhanced the rejection of skin allograft and stimulated the immunological response to sheep erythrocytes in adult CBA mice. Treatment of CBA mice with AHF increased the graft survival and inhibited antibody formation to sheep erythrocytes. Chronic TF or PF administration decreased spontaneous tumor development and prolonged the life span of female C3H/Sn mice. Administration of AHF failed to influence the life span and the tumor incidence of female C3H/Sn mice. The role of immunity and hormonometabolic shifts in mechanisms of both aging and the age-associated increase in cancer incidence are discussed.
The review on our own data on the effect of the pineal peptide preparation Epithalamin on free radical processes in rodents and humans is presented in this paper.
The activity of Cu, Zn-superoxide dismutase (SOD) was found decreased in the brain of aged rats (30 months old) by 46.8% as compared to young animals. Concentration of Schiff's bases in the brain also went down with age (by 13.6%), while the level of dien conjugates (DC) and protein peroxidation (PPO) remained unchanged. General antioxidation activity (AOA) in the brain also remained stable with age. The liver of aged rats showed significant increase of Schiff's bases (by 27.1%) and PPO products (by 109.2%) and considerable decrease of SOD activity. The level of DC and general AOA in the liver remained unchanged with age. Considerable elevation of protein and lipid peroxidation products contents was registered in the blood serum of aged rats. At the same time, general AOA and SOD activity remarkably decreased. The results obtained evidence from both significant age-related alterations in the activity of free radical processes in animal organism and organic peculiarities of their dynamics. Application of peptide drug epithalamin suppressed significantly the intensity of peroxide chemoluminescence in the blood serum (2.8-fold) and lipid peroxide oxidation (LPO) expressed in the considerably decreased DC contents (4,1-fold). The contents of Schiff's bases showed only a tendency towards decrease (by 14.4%, p > 0.05) and PPO level remained unchanged. Epithalamin administration was followed by considerable (by 36.6%, p < 0.01) increase of general AOA and increased SOD activity (by 19.7%) in males. Epithalamin decreased significantly the contents of conjugated hydroperoxides and ketodienes in tissues of D.melanogaster females, increased catalase activity in drosophila males and females, and increased SOD activity in males of D.melanogaster by 41%. Humans reveal significant age-related decrease of antioxidation defence indices.
Epithalamin administration to patients with age-related pathology eliminates imbalance in prooxidation and antioxidation systems.
We have investigated for 35 years the relationship between the neuroendocrine and the thymo-lymphatic, immune system. In the last decade we have shown that the pineal gland is a main adapter and fine synchronizer of environmental variables and endogenous messages into physiological modifications of basic functions. In particular the pineal gland itself seems to regulate, via circadian, night secretion of melatonin, all basic hormonal functions and also immunity. We have shown with several in vivo models that this fundamental role of the pineal gland decays during aging. Aging itself seems to be a strictly pineal-programmed event similar to growth and puberty. The continuation of our interventions with melatonin against the typical degenerative diseases of aging must be based on an accurate evaluation of its mechanisms of action. Melatonin being a ubiquitous molecule in nature, we suggest that it has acquired during evolution of the species numerous levels of activities. In fact, melatonin can be found in a large variety of cells and tissues, and bindings sites and “receptors” have been identified in many tissues and cells of the neuroendocrine and immune system. Therefore, the progressive understanding of the aging-programing role of the pineal gland also depends on studies of melatonin and its basic regulatory function. Our present studies will be described.
The 20 month-long treatment of female rats with daily doses of 0.1 or 0.5 mg of polypeptide pineal extract (PPE) per animal increased their lifespan by 10 and 25%, respectively, as compared with controls. At the age of 16--18 months, 38% of control rats exhibited persistent disturbances in estral function (constant estrus or repeated pseudogestations), whereas these disorders were observed in 7% of experimental animals only. After administration of PPE to 16--18 month-old female rats checked for sterility by a two-week mating, a second mating period resulted in gestation development in four out of 16 animals and deliveries, accordingly. While chronic treatment with PPE did not affect the rate of neoplasm incidence, the mean age of tumour detection in the control group was 697 days and in experimental groups it was 811 and 868 days, respectively. Certain aspects of the interrelationship of rate of ageing, lifespan and specific age pathology are discussed.
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Female SHR mice, aged 3.5 or 12 months, were exposed monthly to 5-day long courses of subcutaneous injections of 0.1 mg thymus-derived or pineal gland-derived polypeptide factors (TF and PF, respectively) or 0.9% sodium chloride solution (control). PF treatment increased life span of both young and middle-aged mice by 20% and 17%, respectively, and TF increased the life span only in young mice. Both factors when administered to young mice caused a decrease in both overall tumour incidence and incidence of mammary adenocarcinomas (TF, 1.8-fold decrease; PF, 2.6-fold decrease). TF administration to mature mice did not produce any antitumour effect, whereas PF possessed certain anti-tumour activity, but the response was far less pronounced than in young animals. The results obtained give additional evidence of the geroprotective and anti-tumour effect of thymus and pineal gland-derived peptide factors. The mechanisms of action of TF and PF and perspectives of clinical use of these agents as geroprotectors are discussed.
It was shown previously that epithalamin delays age-related changes in reproductive and immune systems and increases the life span of mice and rats. These effects could be mediated by stimulating influences of epithalamin on synthesis and secretion of melatonin and on free radical processes. A comparative study on the effect of epithalamin and melatonin on both the life span of Drosophila melanogaster (strain HEM) and on the intensity of lipid peroxidation and activity of antioxidative enzymes in their tissues was the main aim of this work. Melatonin and epithalamin was added to the nutrition medium (100 micrograms/ml) during 2-3rd age of larvas. For survival analysis the flies were passed (five coupes per vessel) each 3-7 days. Lipid peroxidation was evaluated as the level of ketodienes (KD) and conjugated hydroperoxides (CHP) in fly tissues at the age of 11 days. Activity of Cu, Zn-superoxide dismuatse (SOD) and catalase was evaluated as well. The mean, median and maximum life span (MLS) were estimated. Mortality rate (MR) was calculated as alpha in the Gompertz equation (R = Ro (exp alpha t) and mortality rate doubling time (MRDT) as in 2/alpha. These parameters in groups of male and female flies exposed to melatonin and in male flies exposed to epithalamin were no different from the parameters for controls. However, exposure to epithalamin was followed in females by a significant increase in mean life span (by 17%, P < 0.02), of median (by 26%), of MLS by 14% and by a 2.12 times decrease of MR (P < 0.01) and MRDT (by 32%) compared with female controls. The level of CHP and KD in the tissues of male control flies was 40 and 49% less than that in females and indirectly correlates with male life span. Exposure to melatonin was followed by a decrease in the level of CHP and KD in females and the deletion of sex differences in them. Exposure to epithalamin significantly decreased the level of CHP and KD in female flies compared to controls (2.3 and 3.4 times, respectively, P < 0.001). Exposure to melatonin failed to influence the activity of catalase in males but increased it in females by 24% (P < 0.02) and failed to influence SOD activity both in males and females. Exposure to epithalamin was followed by a significant increase in activity of catalse, 20% in males and 7% in females and by an increase in SOD activity in males (41%). Thus, it was shown that exposure to epithalamin significantly increases the mean life span and MLS of female D.melanogaster and slowed down their aging rate by 2.12 times. This effect is in good agreement with the inhibiting effect of epithalamin in lipid peroxidation processes in fly tissues.
Natural thymic peptides have been isolated from calf thymus by mild acid extraction. Pharmaceutical containing natural peptides (Thymalin) was put into practice as immunocorrector. One of the immunomodulatory molecules (L-Glu-L-Trp) has been isolated from Thymalin by reversed-phase high performance liquid chromatography. Pharmaceutical containing this agent (Thymogen) was designed on the base of synthesized dipeptide. A novel immunomodulatory dipeptide was synthesized and termed Vilon. Both natural and synthetic pharmaceuticals activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced the changes in intracellular composition of cyclic nucleotides and cytokine [interleukin (IL-2), interferon (IFN)] excretion of blood lymphocytes. Synthetic dipeptides activated neutrophil chemotaxis and phagocytosis. They had no influence on antioxidant response in thymocytes in comparison with natural peptides. Thymalin and Thymogen were used in persons with chronic pathology and immune dysfunction. The results indicate that thymic peptides participate in the regulating mechanisms of inflammatory processes as cytokine antagonists and show the difference between natural and synthetic products. It is important for the drugs designed to prevent immune dysfunction development.
Treatment with pineal peptide preparation epithalamin was followed by the increase of the mean lifespan of female D. melanogaster, SHR mice, C3H/Sn mice and LIO rats by 11-31% (P < 0.05). Ninety percent mortality as well as maximum lifespan were increased in fruit flies, C3H/Sn mice and rats. Mortality rate was decreased by 52% in D. melanogaster, by 52% in rats, by 27% in C3H/Sn mice. It did not change in SHR mice exposed to epithalamin. Treatment with the pineal peptide increased MRDT in flies, C3H/Sn mice and rats. It has been shown that epithalamin increased synthesis and secretion of melatonin in rats and inhibits free radical processes in rats and in D. melanogaster. It is suggested that antioxidative properties of epithalamin lead to increased lifespan of three different animal species.
It is clear, both empirically and theoretically, that the mechanisms of aging are multiple and complex. Nevertheless, single gene mutations and simple interventions such as calorie restriction have broad effects on the senescent phenotype. The major challenge is to unite highly reductionist analysis of molecular components with integrative model systems that can "put it all together." Two themes are developed. In the first, biochemical models are described that show how the network concept of cellular aging can be used to integrate multiple biochemical mechanisms that contribute to cellular instability. In the second theme, the role of intrinsic developmental chance is examined as a major factor contributing, in addition to genes and environment, to the divergence of the senescent phenotype. The implications of these themes for research strategies in molecular gerontology are discussed.
A technology has been developed for manufacturing of biologically active complex peptide preparations from extracts of different tissues. In particular, the pineal preparation (Epithalamin) augments the in vitro outgrowth of explants from the pineal gland but not from other tissues, the latter being stimulated by peptide preparations from respective tissues. Epithalamin increases melatonin production by the pineal gland of rats, improves immunological parameters in rats and mice, produces anticarcinogenic effects in different experimental models, stimulates antioxidant defenses, and restores the reproductive function in old rats. These effects are combined in the ability of Epithalamin to increase the lifespan in rats, mice, and fruit flies. Many of these effects are reproduced in clinical trials, which have demonstrated the geroprotector activity of Epithalamin in humans. Among the effects of the thymic preparation Thymalin, those related to its ability to stimulate immunity are the most prominent. This ability is associated with anticarcinogenic and geroprotector activities. Clinical trials of the peptide preparations obtained from other organs including the prostate, the cerebral cortex, and the eye retina, have demonstrated beneficial effects reflected by the improvement of the conditions of respective organs. Based on the data about the amino acid compositions of the peptide preparations, novel principles of the design of biologically active short peptides possessing tissue-specific activities has been developed. Dipeptides specific for the thymus and tetrapeptides specific for the heart, liver, brain cortex, and pineal glands stimulate the in vitro outgrowth of explants of respective organs. Interestingly, for eye retina and the pineal gland, a common tetrapeptide Ala-Glu-Asp-Gly (Epitalon) has been designed, probably reflecting the common embryonal origin of these two organs. Epitalon reproduces the effects of Epithalamin including those related to its geroprotector activity. In particular, Epitalon increases the lifespan of mice and fruit flies and restores the circadian rhythms of melatonin and cortisol production in old rhesus monkeys. At the same time, Epitalon prolongs the functional integrity of the eye retina in Campbell rats with hereditary Retinitis Pigmentosa and improves the visual functions in patients with pigmental retinal degeneration. Changes in gene expression were observed to be produced by the short peptide preparations. Therefore, the effects of Epitalon are suggested to be mediated by transcriptional machinery common for the pineal gland and the retina and, probably, for regulation of melatonin production in fruit flies. Based on three decades of studies of the peptide preparations, the peptide theory of ageing has been put forward. According this theory, ageing is an evolutionary determined biological process of changes in gene expression resulting in impaired synthesis of regulatory and tissue-specific peptides in organs and tissues, which provokes their structural and functional changes and the development of diseases. Correspondingly, correction of such disorders by means of stimulation of peptide production in the organism or through their delivery can promote the normalisation of disturbed body functions.