Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
The circadian and circannual rhythms play the main role in the adaptation of human immune and pituitary-adrenal systems functioning to the changing photoperiod. The rhythmicity of thymus endocrine function is an important part of the chronobiological organization of immune system. The pineal hormone melatonin is the central regulator of rhythms of healthy human organism functions and involves thymus hormones (namely FTS/thymulin) in synchronizing influence on the immune system functioning. Age-related changes of thymus hormone and melatonin rhythms in healthy people are linked and precede the aging desynchronosis of immune and pituitary-adrenal system functions. In healthy male versus female the above changes occur at earlier life periods and are more pronounced. The thymus endocrine function does not completely disappear in the elderly/old people and is able to respond to the synchronizing influence of melatonin with part of the adrenal gland. Age-related changes in the circadian and circannual rhythms of the thymus hormone, melatonin, immune system, and adrenal gland functions become more pronounced at the development of age-associated diseases (neurodegenerative, cardiovascular, oncological). Melatonin can be perspective medicine for restoration of disturbed rhythmicity of thymus, immune system, and adrenal glands in accelerated human aging and in patients with age-dependent diseases.
Experimental Modeling Laboratory, Cell and Tissue Technologies Department, Institute of Genetic and Regenerative Medicine, National Scientific Center “M.D. Strazhesko Institute of Cardiology, Clinical and Regenerative Medicine of the National Academy of Medical Sciences of Ukraine”, Kyiv, Ukraine
Laboratory of Pathophysiology and Immunology, D. F. Chebotarev State Institute of Gerontology of the National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
*Address all correspondence to: irina_labunets@ukr.net
1. Introduction
Time-dependent rhythmicity in the organization of physiological processes is an important property of living organisms [1]. Circadian (daily) and circannual (seasonal) rhythms play the main role in human organism adaptation to such changing environmental factors as light, temperature, geomagnetic field, and humidity [1, 2]. Among the above factors, the photoperiod has the most stable synchronizing properties for circadian and circannual rhythms of different human organs and system functions. The circadian rhythms provide fast adaptation of organism functions to the day-night shifts, whereas the circannual rhythms control potential possibilities of functions and differentiation processes.
The control system of these rhythms includes the next components: (a) generator (pacemaker) of endogenous rhythms of functions (suprachiasmatic nucleus (SCN) of the hypothalamus), (b) afferent way to the pacemaker and (c) efferent pathway from the pacemaker to peripheral organs [1, 3]. The pineal gland hormone melatonin plays a key role in the regulation of human circadian and circannual rhythms of organism functions through the coordination of endogenous rhythms that are generated in SCN [4, 5]. In adult organisms melatonin production during the dark period and with the shortening season photoperiod increases.
The circadian and circannual rhythms of immune system indices in healthy young/adult human subjects are found [6, 7, 8, 9]. Human immune system functions are under the influence of thymus hormones [10]. The thymus endocrine function is characterized by circadian rhythm and melatonin is responsible for its nocturnal increase [11].
In aging there occurs dyscoordination of rhythms and disturbance of adaptive capacity of the immune and neuroendocrine systems which are associated with the development of age-related diseases [12]. Age-dependent changes in the thymus and pineal gland functioning precede the aging disturbances of the above systems and influence lifespan [4, 10]. At the same time, the administration of melatonin and thymus hormones to aging people leads to a decrease not only in age changes in immune and neuroendocrine system functions but also in the incidence of age-related diseases [13, 14].
This chapter of the monograph reviews the published and our own data about circadian and circannual rhythms of the thymus hormonal function and the pineal melatonin-producing function in young/adult healthy human, their changes in aging, and link with disturbances in rhythmicity of immune and neuroendocrine systems. A connection was shown between age desynchronosis of the thymus and pineal gland functioning, on the one hand, and the development of some age-related diseases, on the other hand. The significance of the maintenance of rhythmicity of immune-neuroendocrine interactions involving thymus and pineal gland in the activation of adaptive features of the human organism is substantiated.
2. Thymus as a regulator of immune system functions in healthy human organism
2.1 Young/adult people
2.1.1 Cytocrine and endocrine thymus functions
2.1.1.1 T cells differentiation
Different subpopulations of T lymphocytes with certain functional properties (T effectors/suppressors, T helpers) are formed in the thymus [15, 16, 17, 18, 19]. “Maturation” of T cells in thymus begins from the migration of their progenitors (prothymocytes) from bone marrow. After “maturation” T cell subpopulations (CD4+ and CD8+ T cells) migrate from thymus to T-dependent zones of spleen and lymphoid nodes and bone marrow [18, 19]. Small amounts of immature T cells also migrate from thymus to peripheral lymphoid organs where they can differentiate into mature cells. A more detailed description of thymus cytocrine function is presented in the book review [20].
Along with cytocrine function, the thymus acts as an endocrine organ. It is known that true hormones, including the thymus hormones, must meet the following criteria:
formation by specialized glandular cells mainly or exclusively in the endocrine gland (for the thymus by epithelial cells);
secretion into the circulating fluids, determination in the bloodstream, and disappearance from it after gland removal (thymectomy for the thymus);
specific and high biological activity (biologically active concentration in the circulation);
the effects mainly outside gland (for thymus—influence on bone marrow, peripheral lymphoid organs, and circulating T-lymphocytes);
loss of gland function after its removal and recovery after administration of its factors (change in T lymphocyte functions after thymus removal and their restoration by thymus factors).
Only a few of the numerous peptides of the thymus meet the criteria for true hormones. It was shown that the thymus produces the next hormones: thymosin-α1, thymopoetin II, and thymulin/thymic serum factor (FTS) [15, 21, 22, 23, 24].
2.1.1.2 Thymosin-α1
Thymosin-α1 was found in medullary epithelial cells and Hassal's bodies of the human thymus just like in blood [21, 25]. Besides, thymosin-α1 is formed in other lymphoid and non-lymphoid tissues of humans [26]. Hormone blood content decreases after thymus removal and with age [27]. Thymosin-α1 influence on T lymphocytes differentiation in the thymus and the activity of mature peripheral immune cells (antibodies production, change in lymphocytes proliferation) increases interleukin (IL)-10 production and decreases the content of blood tumor necrosis factor α (TNF-α) and IL-6 [21]. Thymosin-α1 due to its immunomodulatory properties is already used in the clinical treatment of infectious diseases, immunodeficiency, and cancer [28].
2.1.1.3 Thymopoietins
The discovery of thymopoietins was associated with the study of neuromuscular transmission in severe myasthenia gravis and significant therapeutic effect after thymectomy [22]. Along with its influence on neuromuscular transmission, thymopoietins modulate the expression of membrane molecules on immature T cells (induction differentiation of prothymocytes to thymocytes) and enhance manifestations of T-immune defense [22, 29]. Thymopoietins are ubiquitously produced, mainly by immune system organs (including thymus) and are determined in the blood [27]. Its serum content begins to decrease around 10 years of age [27].
So, thymosins and thymopoietins can be attributed to the true thymus hormones, since they are secreted by the epithelial cells of the thymus, are found in the blood, and influence differentiation of T-lymphocytes and their activity. A more detailed description of these hormones' properties is presented in a number of reviews [21, 22, 30].
2.1.1.4 Thymulin/FTS
Among the thymus hormones, of particular interest is the highly biologically active FTS/thymulin with a Zn2+-dependent activity. It is formed exclusively in the thymic epithelial cells of humans and animals, circulates in the blood, disappears from circulation after thymectomy and shows biological properties of all known thymus hormones [23, 31, 32]. FTS influences all stages of differentiation of T lymphocytes (bone marrow, thymus, peripheral lymphoid organs). Thus, in the bone marrow suboptimal doses of FTS act on the expression of CD90 (Thy-1 antigens), CD2, CD5, and CD7 markers on the progenitors of T lymphocytes [15]. Expression of these markers on T cells progenitors characterizes an increase in their ability to migration and adhesion [16]. FTS also acts as a chemotactic signal that plays a role in the migration of bone marrow T-cell progenitors into thymus.
In the thymus FTS affects thymocyte antigen-1 (Thy-1) and cluster of differentiation 3 protein (СD3) expression and influences the balance of regulatory T lymphocytes, cytokine production by CD4+ thymocytes, and transformation of cortisol-sensitive thymocytes into cortisol-resistant ones [15]. Besides, under the FTS influence, there appear markers of mature T lymphocytes on immature cells in the lymph nodes.
FTS affects the functional activity of “mature” T-lymphocytes in peripheral lymphoid organs. Thus, it enhances the proliferative response of T cells to mitogen (phytohemagglutinin) and keeps the regulatory T cells balance, namely helper T cells type 1 and type 2, and increases the number of cytotoxic T cells [33]. FTS enhances the production of interferon γ (ІFN-γ) and ІL-2 by T helpers type 1 [34]. FTS effects on immune cells can be mediated via high-affinity specific membrane receptors [23, 31]. Besides, FTS stimulates the activity of natural killer cells and the response of peritoneal macrophages to activating effect of IFN-γ [33].
2.1.2 Thymus and bone marrow functioning
Bone marrow is the central organ of the immune and hematopoietic systems. Bone marrow lymphoid and myeloid lineages of hematopoiesis are derived from the common progenitor—hematopoietic stem cells (HSCs) [35, 36]. Progenitor cells of hematopoiesis in bone marrow differentiate into granulocytes, monocytes/macrophages, thrombocytes, and erythrocytes. Bone marrow cells of the microenvironment, namely stromal fibroblasts, macrophages, T helpers, and B cells play an important role in directed differentiation of HSCs [37, 38]. In particular, T lymphocytes (CD4+) of thymus origin can function as regulatory elements of hematopoiesis producing such cytokines as IL-3,4,5,6,13,17 and granulocyte macrophage colony-stimulating factor (GM-CSF) [18, 37]. In human patients with combined immunodeficiency, recovery of impaired differentiation of bone marrow stem cells in the granulocyte-macrophage direction was observed after injections of bioactive thymus factors [24].
As shown, the thymus is involved in the differentiation of multipotent mesenchymal stromal cells (MMSCs) in the bone marrow. These cells differentiate into osteoblasts, adipocytes, chondrocytes and have immunosuppressive action [39]. Reduced proliferative and osteogenic potentials of MSCs after thymus removal coincides with the decreased amount of bone marrow CD4+ T-cells and lack of thymulin in the blood [40]. At the same time, the above properties of bone marrow MSCs were restored after in vitro addition of synthetic FTS [40]. The immunosuppressive effect of bone marrow MSCs was enhanced after thymus removal or after a decrease in its endocrine function [40].
So, the thymus functions are important for the normal functioning of the peripheral immune system and the realization of biological properties of bone marrow HSCs and MSCs in adult organisms. Thymus acts on the bone marrow functions through its hormones and T-lymphocytes. Therefore, thymus dysfunction affects immune defense of the organism against damaging factors of different origins and efficiency of cell therapy using these stem cells.
2.2 Elderly/old people
2.2.1 Cytocrine and endocrine thymus functions
Age-related processes in the thymus play a crucial role in changes of immune system functioning in aging [41, 42]. Thymus involution depends on the intra- and extrathymus influences. Intrathymus changes include the degenerative alterations of the epithelial thymus cells, decreased proliferation and enhanced apoptosis of the thymocytes, imbalance in the production of intrathymus cytokines (leukemia inhibitory factor, IL-6, IL-7), blockade of the rearrangement of T cell receptor genes and attenuation of the keratinocyte growth factor production, etc. Age-related deterioration of the thymus epithelial cells structure leads to a decrease in its endocrine function. Age-dependent decrease of the blood serum thymulin level is the most pronounced compared to other thymus hormones [23, 27]. Extrathymus factors of thymus involution may be associated with age-related changes in the neuroendocrine system [41].
The pathways of intrathymus differentiation of thymocytes change with age [43]. Diminished expression of CD3 receptors on the thymocyte membrane may result in age-related changes in T cell selection in the thymus [41]. The peripheral T cell functions (proliferation, cytotoxicity, lymphokine production, etc.) in old humans are worsening [41]. There occurs an imbalance not only between helper and suppressor T cells but also between helper T cells type 1 and type 2 [44]. The range of cytokines being synthesized by these cells is altered thereby stimulating humoral immune response. Besides, the functional activity of neutrophils and mononuclear phagocytes is reduced.
2.2.2 Bone marrow functioning
The proliferative and differentiation potential of HSCs and lymphoid progenitor cells in the bone marrow decreases with age [35, 45]. Alterations of the hematopoiesis are explained by the deterioration of the regulatory mechanisms, accumulation of mutations in cell genome, deoxyribonucleic acid damage and oxidative stress. The shift in the hematopoiesis, namely from lymphopoiesis to myelopoiesis affects blood system functioning and leads to the higher frequency of myeloproliferative disorders.
The proliferative capability of stromal elements in the old bone marrow is changed and an imbalance in their differentiation towards active adipocyte generation can be observed [46]. Aging human MMSCs secrete other cytokines and trophic factors displaying a reduced differentiation potential.
2.2.3 Administration of thymus active factors in aging organism
The positive effect of thymosin-α1 on immune system is most pronounced in immunodeficiency states (aging, cancer, use of immunosuppressants) [21, 28]. In old patients, following injections of thymus factor thymalin (its structure has sequences that are homologous to thymulin) was observed the increase of diminished blood thymulin level and number of peripheral T cells and neutrophil phagocytic activity [14]. There is evidence that the development of osteoporosis may be linked to an imbalance of regulatory T cells in bone marrow and thymus dysfunction [47]. After thymus factor thymalin administration the reduced spongy bone mineral density increased and bone structure improved in old human subjects [14]. In the old human subjects with thymus endocrine hypofunction, thymus factor administration enhances the differentiation of bone marrow stem cells into macrophages and activates liver macrophages [24], which is associated with a decrease in blood content of small circulating immune complexes [14]. As a result of the long-term circulation of these complexes, the vascular walls are damaged promoting the development of vascular diseases.
In summing up, the thymus biologically active factors produce geroprotective effects in elderly people thereby influencing positively age-related changes in immunological indices and bone marrow functioning.
3. Biorhythms of thymus and immune system functions and their age-related changes in healthy people
3.1 Circadian rhythms
3.1.1 Thymus
Studies on the circadian rhythm of thymus endocrine function revealed higher nocturnal thymulin/FTS and thymosin-α1 levels in the blood of healthy young human subjects compared to daytime content [11, 21]. According to our data, the thymus endocrine function in young healthy humans (20–29 years old) is characterized by increased blood FTS content at 21.00 and its highest value at 1.00 am [6, 7, 48, 49]. In elderly healthy people (after 60 years), the nocturnal rise FTS level is less compared to young subjects or the hormone rhythm is monotonous [48, 49, 50].
3.1.2 Bone marrow
The human bone marrow hematopoietic and microenvironment cells have a circadian rhythm [51, 52]. Human HSCs taken for transplantation at evening hours (during thymus function activation) have shown better positive effects compared to morning hours [52].
3.1.3 Peripheral immune system
In healthy young human subjects, the circadian rhythms in the peripheral blood contents of CD4+ and CD8+ T cells, granulocytes, imunoglobulins (Ig), and some cytokines were observed [6, 53, 54]. Age-related changes in circadian rhythms of immune cells show themselves both in their number and functional activity. Thus, in elderly humans, the nocturnal amplitude of the number of blood T cells and its T helper subpopulation is decreased and daily acrophase of neutrophils content is shifted [12, 54]. At the same time, the nocturnal amount of activated T cells and cell production of ІL-1, TNF-α, and IFN-γ are increased. So, the response of certain immunological indices to changed light regimens in old organisms can be linked with thymus dysfunction and is not only diminished but also enhanced.
3.2 Circannual rhythms
3.2.1 Thymus
There are no literature data on age-related changes in the thymus endocrine function in healthy people in different seasons of the year. According to our results, the FTS production by thymus in young healthy men and women is characterized by circannual rhythms [6, 55]. We found that the FTS level in healthy humans at age 20–29 years in summer and autumn is higher compared to other seasons (Table 1). FTS levels in women higher compared to men (Table 1).
In 30–39 old men the FTS blood content in summer decreases and at the age of over 40 its fluctuations become monotonous. In men, after 60 years the highest FTS level is observed in spring. The season changes in FTS level in elderly women mostly look like those in young women although its values decreased in summer and autumn.
So, age-associated changes in the circannual rhythm of FTS level have sex differences. Thus, the first signs of thymus dysfunction are found in men over 30 years old and become more pronounced with age. Age-related changes in thymus hormonal rhythmicity in healthy women are less significant compared to men. It is important that in elderly people the thymus endocrine function does not completely disappear.
3.2.2 Bone marrow
In the human bone marrow, season-dependent fluctuations of proliferative activity in hematopoietic progenitor and stromal cells have been established [51, 56]. In healthy young individuals, the highest number of colony-forming unit granulocyte-macrophage (CFU-GM) was at the end of summer, and the least MSCs possibility for colony formation in the spring and autumn [56]. According to the authors, the annual changes in the number of bone marrow colony-forming unit fibroblasts (CFU-F) should be considered in cell therapy of patients with bone tissue disturbances. After thymus removal in adult organisms, the number of CFU-GM and CFU-F decrease in seasons of their maximum content in bone marrow [57].
3.2.3 Peripheral immune system
According to the below authors and our data, in healthy young human subjects the amount of blood CD3+, CD4+, and CD8+ T cells; B cells; and content of Ig have maximal values in autumn [6, 53, 54]. In old healthy human subjects, age-related changes of annual fluctuations of immune indices coincide with seasonal desynchronosis of thymus endocrine function and they are characterized by shifting seasonal peaks of the number of blood CD3+, CD4+T cells, and Ig level from autumn to spring [6, 55].
So, age-related immune system response to photoperiod changes is largely associated with age-dependent desynchronosis of thymus functions and can be explained by the disturbance of interactions with the pineal gland which coordinates such reaction [5, 12].
4. Role of the pineal gland in the regulation of thymus and immune system biorhythms in healthy people
4.1 The pineal gland biorhythms and their changes in aging
The pineal gland and its hormone melatonin is the main regulator of circadian and circannual rhythms not only in mammals but also in the human organism [5, 58]. Production of melatonin during light period is suppressed whereas in the dark hours is increased. Besides, with shortening of the seasonal photoperiod melatonin production is enhanced [59]. Melatonin regulates endogenic rhythms of organisms that are generated in the SCN of the hypothalamus [5, 58]. Melatonin acts on the activity of the hypothalamus-pituitary system and peripheral endocrine glands through its binding with nucleus and membrane receptors which are identified in various brain and endocrine structures. There is a link between pineal gland functioning, organism adaptation, and lifespan [60].
The circadian rhythm of pineal gland function and its changes in aging were found in humans [4, 61]. In the majority of elderly and old human subjects, the nocturnal peak of blood melatonin level is diminished compared to young people [4, 13]. Elderly human subjects with saved pineal gland melatonin-produced function have higher physical and psychomotor activity as well as expressed circadian rhythms of some functions and lifespan [13, 62]. We also observed a nocturnal peak of blood melatonin concentration in young people and its decrease in aging [48, 63, 64]. Age-related decrease of the nocturnal peak of melatonin content in the pineal gland and blood is explained by the diminished activity of the key enzymes of its synthesis (N- acetyltransferase, hydroxyindol-O-methyltransferase), decrease both in the density of β-adrenergic receptors on the pinealocyte membrane and in the capability of postganglionic sympathetic fibers for synthesis and noradrenaline release [4, 61].
The circannual rhythm of blood and pineal gland melatonin content in old humans is characterized by the decrease of the winter peak of hormone level or the shift of its seasonal acrophase to the spring compared to young people [4]. We also found that melatonin level in the blood of young (20–29 years old) healthy men and women was maximal in winter [55]. According to our data, age-related changes in melatonin blood level rhythmicity have sex differences. Thus, in healthy men aged 30-49 years the seasonal peak of blood melatonin content was in summer and in men after 60 years it was in spring. In men, after 30 years melatonin blood level decreases in winter. In elderly women, the spring increases and the winter decrease of blood melatonin was less than in men.
So, the circannual rhythm of melatonin level changes in the blood of healthy men after 30 years. Desynchronosis of this hormone increases with age. Age-related dysfunction of the pineal gland is less pronounced in women compared to men.
4.2 Age-related changes of pituitary-adrenal system biorhythms and its link with pineal gland disfunction in healthy people
The rhythmicity of pituitary-adrenal system functioning undergoes changes due to the modulation of the pineal melatonin-producing function [4, 62, 65, 66]. Thus, in young people, the highest blood contents of such adaptive hormones as adrenocorticotrophic hormone (ACTH) and cortisol are observed in the light period of the day compared to evening and night. According to our data, the blood cortisol level in the elderly healthy people does not differ in the morning and evening [48]. At the same time, the altered circadian rhythms of endocrine glands (in particular, adrenal gland) in old human subjects were improved after melatonin injections [4, 48].
The authors found the seasonal fluctuations of cortisol in the blood of healthy people and its age-related changes [4]. We studied annual fluctuations of blood ACTH and cortisol levels in healthy men and women of different ages [55]. We found that in young healthy men and women (20–29 years old), the highest ACTH level was in spring-summer periods of the year and cortisol in autumn. In 30–39 old men, ACTH level increases in winter and such changes in hormone level were also observed in 40–59 old men. In healthy women (30–59 years old) age-related increase in ACTH level is less intensive and forms later compared to men.
In young healthy men (20–39 years old), the blood cortisol level increases in autumn and winter. After 40 cortisol level significantly increases in spring and its annual rhythm becomes monotonous. The seasonal increase of cortisol content in autumn observed in 20–29-year-old healthy women remains unchanged up to the age of 50. The blood cortisol content in spring and summer is lower in women after 40 than in men of the same age.
So, changes in circannual rhythms of blood melatonin and ACTH levels are seen in men as early as the age of 30–39 years. These changes are ahead of age-related activation of the glucocorticoid function of the adrenal cortex and the formation of its seasonal desynchronosis in elderly people. In healthy men changes in the pituitary-adrenal system are more intense compared to women and are formed earlier [55]. Sex differences in age-related changes of the above system functioning can be explained not only by higher blood melatonin levels in women but also by the neuroprotective and neurotrophic effects of estrogens. Melatonin stimulates neurotransmitters exchanged in the hypothalamus and promotes brain sensitivity to peripheral regulatory signals [5].
Thus, the age pineal gland dysfunction is the pathogenetic link of age-related desynchronosis of the pituitary-adrenal system. Gender and age-related changes in the pineal gland and pituitary-adrenal system functions may be explained by certain sex-related differences in the development of some age-associated diseases (cardiovascular diseases, cancer, osteoporosis, diabetes, etc.) as well as in the medicine pharmacodynamics during treatment.
4.3 Melatonin, other hormones, and the immune system functions in healthy people
Immune system functioning is in close interaction with the neuroendocrine system [30, 67]. Melatonin effects on the immune system functions include not only direct ways via own receptors in immune cells but also indirect ways via changing endocrine glands functions [67].
4.3.1 Thymus
Thymus is the first target for melatonin [67]. Melatonin is capable to influence directly on the synthesis and secretion of thymus hormones [67, 68]. Melatonin action on the thymus endocrine function can pass through changes in hypothalamus-pituitary-adrenal axis functioning [69, 70]. High concentrations of glucocorticoids suppress thymus endocrine function [70]. The efficiency of thymus hormone administration is increased under the condition of short-term hypocorticism. Fluctuations of the expression and/or sensitivity of glucocorticoid receptors on the thymus epithelial cells are controlled by melatonin [71]. The lymphocytes and epithelial cells of the thymus have receptors for glucocorticoids and androgens [68]. Corticosteroids influence the differentiation of thymus epithelial cells and sex hormones act on the differentiation of thymocytes via FTS synthesis [72, 73]. Besides, glucocorticoids influence the distribution of mature T-lymphocytes in the organism and their accumulation in bone marrow [18].
The authors' data and our own findings have shown that in young human subjects, the nocturnal peaks of blood thymus hormones level (thymulin/FTS, thymosin-α1) and melatonin are similar [6, 11, 48]. We found that in young healthy men aged 20–29 years, the increase of blood melatonin and FTS levels was at 21.0 p.m. with a peak at about 1.0 a.m. (Figure 1), whereas the level of cortisol was lowest at 21.0 p.m. and highest at about 5.0 a.m. and 9.0 a.m. [6, 48].
Figure 1.
FTS and melatonin blood levels in healthy young people (aged 20–29 years) during 24 hours (our data [48]). * p < 0.05–9.00; **p < 0.05–17.00, #p < 0.05–21.00; ##p < 0.05–1.00; &p < 0.05–5.00.
In young organisms, pineal gland hypofunction (removal, prolonged lighting) is accompanied by the disappearance of nocturnal peaks of blood thymulin content. On the contrary, melatonin treatment enhances the expression of prothymosin-α1 in the thymus epithelium and restores circadian changes of T cell composition in the thymus after its damage by constant lighting [74].
The daily fluctuations of thymulin and melatonin blood levels coincide and are characterized by increased values in the evening and highest values at 1.00 a.m. In the morning, the content of these hormone decreases compared to the night period.
In aging organisms, following melatonin injections the nocturnal peak of thymulin blood level, the blood zinc and IL-2 contents were increased and the number of thymus apoptotic cells and the glucocorticoid blood levels were decreased [75, 76]. According to our data, in the elderly subjects, the circadian rhythm of blood FTS was ambiguous and correlated with the patterns of melatonin blood rhythmicity [48, 49, 63]. Thus, an increase in FTS level during dark hours (21.0 p.m. or 3.0 a.m.) coincides with a more pronounced nocturnal increase of blood melatonin content compared to elderly people without thymus activation in dark hours. Besides, our own finding of two-week melatonin injections to elderly human healthy subjects demonstrates an increase in FTS levels in the evening and at night and a decrease in blood cortisol and testosterone levels in the evening [48, 49, 50]. In the comparison with our younger patients, this effect was registered with lesser melatonin doses [50]. A melatonin-like synchronizing effect on blood FTS and cortisol levels in elderly people was shown by us for pineal gland peptides [77]. The melatonin level after administration of pineal gland peptides (epithalamin, epithalon) increases in the body [14].
4.3.2 Bone marrow
Melatonin influence on hematopoiesis is realized directly via the receptors in monocytes/macrophages cells and owing to an increased response of these cells to activating hematopoiesis cytokines, namely ІL-3, 4, 6 or GM-CSF [74]. Bone marrow T cells progenitors and T helpers type 1 are the main targets for melatonin [67]. Melatonin synthesized by human bone marrow cells protects in situ cells against oxidative stress and enhances the functional activity of the lymphocytes [74]. Pineal gland hypofunction is accompanied by diurnal desynchronosis in the bone marrow functioning.
Our studies have established thymus involvement in melatonin influence on circannual changes of the number of MMSC, CFU-GM as well as CD3+, CD4+, and CD8+ T cells in the bone marrow of young and old organisms [78]. In adult organisms, exogenous melatonin acts on bone marrow cells of the microenvironment and this action is realized via thymus hormone. In old organisms, the participant of thymus hormone in action of melatonin is mainly linked with bone marrow CFU-GM changes.
4.3.3 Peripheral immune system
Under the influence of exogenous melatonin (evening injections) the number of СD3+ and СD4+ T lymphocytes increased and that of СD8+ T cells decreased in the blood and lymphoid organs; balance not only of СD3+ and СD4+ T cells but also of T helpers type 1 and type 2 was changed and the number of mature B cells in the lymphoid organs and functional activity of the macrophages increased [67, 74]. Melatonin also influences circannual rhythms of the immune system. We have shown that in elderly human subjects after melatonin injections FTS blood level, the amount of blood CD3+ and CD4+ cells, and the phagocytic activity of neutrophils are increased in autumn, being similar to those being seen in the younger subjects [48]. Adrenal and sex hormones also influence cellular and humoral immune responses and phagocytosis.
So, the above data show the pathogenic significance of pineal melatonin-producing dysfunction for age-related changes of thymus and immune system rhythmicity and involvement of adrenal glands and gonads in the synchronizing effect of melatonin.
It is important that along with produced hormones, a number of cytokines are formed in the thymus, for example, TNF-α, IL-1,3,6,7,8,15, ІFN-γ, and GM-CSF [79]. All types of thymus cells are able to produce cytokines both spontaneously and after stimulation. But the main producers of cytokines in the thymus are epithelial cells and thymocytes [80]. Intrathymic cytokines are important at various stages of activation, proliferation, and differentiation of thymocytes [80].
Some intrathymic cytokines are involved in the interactions between the thymus and pineal gland. Among such intrathymic cytokines, TNF- α is of particular interest. This cytokine has pronounced pro-inflammatory properties and is considered as a key factor in the pineal-immune axis [30]. TNF-α is secreted by cultured mouse thymocytes, indicating its importance for the development and/or regulation of the immune response [81]. The ability of TNF-α to influence melatonin secretion by the pineal gland has been shown in Ref. [82]. Thus inhibitory effects of this cytokine in vitro are realized at the level of transcription factors and manifest themselves in a decrease of N-acetylserotonin and N-acetyltransferase synthesis. The disappearance of the inhibitory effect of TNF-α after its prolonged incubation with the pineal gland suggests the involvement of melatonin in the different phases of the inflammatory process.
In addition, there are data on the stimulating effect of ІFN-γ and CSF-GM in vitro on the secretion of melatonin by the pineal gland [83].
Therefore, the interaction of melatonin and thymus can be realized not only through thymus hormones but also intrathymic cytokines.
4.4 Reverse effects of thymus hormones on neuroendocrine system
Regarding the immune-endocrine interactions, the lymphokines and monokines act as afferent signals for the hypothalamus-pituitary-adrenal axis. Besides, thymulin, thymopoetin, thymosin, and thymic humoral factors are believed to link the immune and central nervous systems [69, 84]. Thus, after injections of thymulin and thymosin fraction 5, the blood ACTH and corticosterone levels increase in adult organisms [68]. In conditions of thymus hypofunction, thymulin gene therapy restores the decreased blood follicle-stimulating hormone and luteinizing hormone (LH) levels, whereas thymosin-β4 stimulates the production of LH in the pituitary gland [85, 86]. Thymulin is believed to be the pituitary trophic peptide [86]. Thymus factors can directly change corticosteroid secretion by adrenal glands in organisms of different ages.
We found the reverse influence of the thymus hormone on the pineal functioning in young organisms [87]. The in vivo and in vitro studies showed that this influence depends on season and age. Thus, the seasonal dependence of blood melatonin level on thymus factor administration is absent in old versus adult organisms. The in vitro studies show that the activating effect of synthetic FTS on melatonin production by the pineal gland is also absent in old organisms [87]. Age-related decrease in the pineal gland response to thymus hormone can be associated with the development of structural disturbances in the gland [61]. Moreover, the endocrine balance of aging organisms may play a role in the appearance of changes in the seasonal reaction of pineal melatonin-producing function to thymus factor injections. In aging the excess of glucocorticoids diminishes the melatonin-producing function of the pineal gland and the activating influence of thymus factors on this gland.
So, thymus hormones are an important component in immune-neuroendocrine interactions in adult organisms. In aging the reverse effects of thymus hormones on the neuroendocrine system are disturbed.
5. Age-related changes in the thymulin/FTS and melatonin biorhythms in human age-associated pathologies
As was shown in previous sections, circadian and circannual rhythms play an important role in the adaptive reactions of human neuroendocrine and immune systems to changing photoperiods. The rhythms of these systems are disturbed in human aging and are linked with altered rhythmicity of melatonin and thymus hormone production. The development of age-dependent diseases may be associated with the intensification or acceleration of age-related changes in the immune and neuroendocrine systems functions.
5.1 Neurodegenerative diseases
The frequency of age-related neurodegenerative pathology, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), brain ischemia, and multiple sclerosis (MS) increases worldwide and has great socio-economic implications. Progressive neurons loss was shown in neurodegenerative diseases. Their development includes enhancement of oxidative stress, neuroinflammation along with microglia activation, mitochondrial dysfunction, disturbances of brain neurogenesis, sleep-wake cycle, and immune system functions. It is important that along with its influence on the neuroendocrine system functions, thymus hormone thymulin has anti-inflammatory effects on the central nervous system, reducing the synthesis of pro-inflammatory cytokines [88].
5.1.1 Alzheimer’s disease
A more pronounced age-related decrease of the nocturnal blood melatonin content in AD elderly patients compared to the control group are coincided with the development of daily desynchronosis of blood ACTH and cortisol levels and cognitive disturbances [66, 89]. Circadian changes in organism functions often occur at early stages of AD and may precede the appearance of cognitive symptoms. Infiltration of active T lymphocytes and mononuclear phagocytes into the injured brain was shown in AD [90]. Melatonin treatment improves disturbed sleep rhythm and produces synchronizing, antioxidant anti-inflammatory and immunomodulatory effects in this pathology [89].
5.1.2 Parkinson’s disease
PD is characterized by circadian disturbances in blood melatonin and cortisol levels compared to the elderly healthy control group as well as the disturbed sleep rhythm [91]. PD development is slowed after melatonin administration which may be linked with its chronobiological, antioxidant and anti-inflammatory effects [92]. Active peripheral T cells, macrophages, and neutrophils infiltrate the brain and damage dopaminergic neurons [93]. In our study, the immune disturbances in parkinsonism were connected with the decrease of blood thymulin level which is restored after melatonin administration [94]. The gender differences in the frequency and clinical symptoms were found in neurodegenerative diseases. Thus, more men than women suffer from PD. These sex differences may be linked with estrogen neurotrophic influence on brain, in particular neurons in SCN. In our data, the women had less intensive and slower age-related development of circannual rhythms disorders in blood FTS, melatonin, ACTH, and cortisol levels compared to men [55].
5.1.3 Brain ischemia
In the elderly ischemic stroke patients the nocturnal melatonin content is decreased compared to the age control group and is associated with elevated blood cortisol levels and altered sleep-wake rhythm [95]. Peripheral T cells may migrate into the injured brain, release pro-inflammatory cytokines and chemokine and cause further injury to the ischemic brain [96]. In cerebral ischemia, exogenous melatonin reveals antioxidant, anti-apoptotic, and anti-inflammatory properties [95]. In our experimental brain ischemia, the decreasing blood FTS and melatonin levels coincided [97].
5.1.4 Multiple sclerosis
In MS patients, the decrease in melatonin level at night is associated with circadian rhythm sleep disturbances and daily blood cortisol level rhythmicity [98, 99]. The higher frequency of MS relapses in the spring/summer period against the winter season is linked with a more marked decrease in nocturnal melatonin levels in these seasons [99]. Melatonin treatment improves the life quality of MS patients. Activation of immune cells leads to damage of myelin and neurons in MS. At the same time melatonin decreases the formation of pathogenic T helper 17 and stimulates the formation of protective Tr1 regulatory cells and anti-inflammatory cytokine IL-10 [99]. We have shown that exogenous melatonin has neuroprotective, anti-inflammatory, antioxidant, and immunomodulatory effects in demyelinating pathology [100]. It is important that melatonin activates the thymus endocrine function in adult and old organisms with demyelinating pathology and restores thymulin blood levels in autumn.
5.2 Cardiovascular diseases
Cardiovascular diseases (ischemic heart disease (IHD), essential hypertension, and myocardial infarction) are the most common causes of disability and mortality worldwide. Risk factors of these diseases (metabolic and alimentary disturbances, hypodynamia, unhealthy habits, psycho-emotional tensions, and inheritance) occur preferably in elderly humans and coincide with changes in the neuro-endocrine and immune systems functions [14]. Thus, in elderly patients with IHD and essential hypertension, the nocturnal blood melatonin content is lower compared to the healthy control group [13]. The degree of pineal gland dysfunction correlates with disturbances in rhythmicity of cardiovascular system indices.
Clinical data indicate an acceleration of age-related changes in peripheral immune system functioning and their role in the development of cardiovascular diseases [13, 14]. The cytokines, activated leucocytes, circulating immune complexes, and macrophages are able to damage artery walls, alter endothelium and change vessel permeability that, in turn, can cause plaque formation in the damaged areas. Positive effects of biologically active thymus factors on some of the above immunological indices were shown [14]. According to our data, in elderly patients with cardiovascular diseases, the types of FTS circadian rhythms were similar to those recorded in the healthy control group [48, 50, 77]. However, the number of patients with monotonous and inverted FTS blood level rhythms was significantly greater than in the age control group in which the people with reduced nighttime hormone levels predominated. Taking melatonin in the evening led to thymus activation and appearance of daily differences in the FTS blood levels due to its increase in the evening. In these patients, the circadian rhythm of blood cortisol levels also improved. So, melatonin administration in the evening delays the onset of aging changes in the rhythmicity of thymus, immune system, and adrenal glands functioning in elderly patients with IHD. Besides, in cardiovascular pathology melatonin produces antioxidant and anti-inflammatory effects [13].
5.3 Oncological diseases
The frequency of tumors increases every 5 years in people after 40 years of age. According to the below authors, circadian rhythms the number of blood lymphocytes and their T-populations are destroyed in tumor organisms and seasonal changes in tumor growth are linked with the seasonal fluctuations of immune system functions [101]. In oncological patients, the nocturnal peak of melatonin blood level is decreased and the circadian rhythm of blood cortisol content is monotonous [102].
We have shown that in oncological patients over 50 years of age, the features of the circadian rhythm of blood FTS and cortisol levels are associated with the character of blood melatonin rhythmicity and point to an increase in their age-related changes [6, 7]. In particular, under conditions of increased melatonin blood level at 21.00 compared to 9.00, the FTS level and the amount of T cells also increased in the evening. When melatonin blood rhythm was inverted, the rhythmicity of FTS blood level and T-lymphocyte content was monotonous. In such patients, the scope of daily changes in blood cortisol content exceeded that observed in patients with activation of pineal gland function in the evening.
In the oncological patients aged 20–40 years, the seasonal peak of blood melatonin level was observed in spring but not in winter as in age-matched controls [6, 7, 103]. The rhythm of blood FTS content becomes monotonous compared to the age control subjects and rhythmicity of the number of blood T-lymphocytes inverted with the highest values in the spring. It is important that the features of rhythmicity of pineal gland and thymus functions in cancer patients till 40 years old are similar to those of healthy older people. These results suggest a possible acceleration of age-related changes in the circannual rhythms of the pineal gland and thymus functioning in oncological patients [104].
The interaction of the thymus and pineal gland may appear during the rhythmical activity of the ovaries (menstrual cycle). The authors showed the link between ovarian dysfunction, on the one hand, and reduced longevity and increased tumor incidence in aging organisms, on the other hand [60]. At the same time, administration of melatonin improves ovarian cyclicity, increases immune system functions, and decreases tumor development. We found that in healthy women under 40, the melatonin blood levels were increased during the follicular and luteal phases of the menstrual cycle and those of FTS during the luteal phase [103]. Unchanged blood levels of melatonin and decreased FTS content in the luteal phase of the cycle were typical for women over 40 [103]. So, the thymus is involved in the ovarian cyclicity regulation by melatonin which can be changed in aging.
Thus, age-related changes in the rhythmicity of immune and neuroendocrine systems functions in patients suffering from neurodegenerative, cardiovascular, and oncological diseases are linked with dysfunction of their central regulators, thymus hormones, and melatonin.
The biorhythms play the main role in the adaptation of the human immune system functioning to the changing environmental factors in particular photoperiod. The circadian (daily) and circannual (season) rhythms of immune system indices (blood T cells, granulocytes and cytokines, bone marrow T cells, hematopoietic and microenvironment cells) are found in healthy young/adult human organisms.
Thymus hormones regulate immune system functions in healthy people. The rhythmicity (circadian, circannual) of thymus endocrine function (in particular, thymulin/FTS production) is an important part of the chronobiological organization of the immune system.
The pineal hormone melatonin is the central regulator of rhythms of healthy human organism functions and involves thymus hormone (namely thymulin) in synchronizing influence on the immune system functioning. Besides, melatonin effects on the thymus and peripheral immune system rhythmicity include not only direct ways via own receptors in immune cells but also indirect ways via changing endocrine glands functions (pituitary-adrenal system). In thymus-pineal gland interactions, the reverse influence of thymus hormone on the rhythm of melatonin production was found.
Age-related changes in the circadian and circannual rhythms of immune system functions (peripheral immune system, bone marrow) in healthy people are linked with age-dependent desynchronosis of thymus endocrine function. Age-dependent changes in the rhythm of blood thymulin level have sex differences. Thus, the first signs of thymus dysfunction are found in men over 30 years and become more pronounced with age. Age-related changes in thymus hormonal rhythmicity in healthy women are less significant compared to men. It is important that in elderly/old people the thymus endocrine function does not completely disappear.
Melatonin production decreases in healthy people in aging and is coincided with desynchronosis in thymus, bone marrow, and peripheral immune system functioning. Age changes in rhythmicity of pineal gland and thymus endocrine functions are interrelated and precede aging desynchronosis of immune and pituitary-adrenal system functioning. In healthy males versus females the above changes occur at earlier life periods and are more pronounced. The synchronizing effect of melatonin on thymus hormones is also manifested in elderly/old people, but the reverse effects of thymus hormones on the neuroendocrine system are disturbed.
Age-related changes in the circadian and circannual rhythms of the thymus hormone, melatonin, immune system, and pituitary-adrenal system functions become more pronounced at the development of age-associated diseases (neurodegenerative, cardiovascular, oncological). Age-related changes in rhythmicity of immune and neuroendocrine system function in patients suffering from the above diseases are linked with dysfunction of their central regulators, thymus hormones, and melatonin. Besides, the development of age-dependent diseases may be associated with the intensification or acceleration of age-related changes in rhythms of the immune and neuroendocrine systems functions in adverse conditions (in particular, night shift work, permanent lighting, insomnia).
New chronobiological approaches to the prevention and treatment of age-dependent diseases (neurodegenerative, cardiovascular, oncological) may be linked with restoration of the aging disturbances in rhythmicity of immune-neuroendocrine interactions involving the thymus and pineal gland. Melatonin can be useful in the treatment of risk groups with accelerated human aging and in patients with age-dependent diseases to restore circadian and circannual rhythms of thymus hormone (thymulin/FTS) production. Besides, exogenous melatonin has neuroprotective, anti-inflammatory, antioxidant effects, and normalizes fat metabolism in pathological conditions.
In conclusion, we hope that this review has shown pathogenic significance of pineal melatonin-producing dysfunction for age-related changes in the thymus and immune and endocrine systems rhythms and pointed to the importance of supporting immune-neuroendocrine interactions rhythmicity in aging and pathology development.
1.Reinberg A, Ashkenazi I. Concepts in human biological rhythms. Dialogues in Clinical Neuroscience. 2003;5(4):327-342. DOI: 10.31887/DCNS.2003.5.4/areinberg
2.Duffy JF, Wright KP. Entrainment of the human circadian system by light. Journal of Biological Rhythms. 2005;20(4):326-338. DOI: 10.1177/0748730405277983
4.Touitou Y. Human aging and melatonin. Clinical relevance. Experimental Gerontology. 2001;36(7):1083-1100. DOI: 10.1016/s0531-5565(01)00120-6
5.Reiter RJ, Rosales-Corral S, Coto-Montes A, Boga JA, Tan DX, Davis JM, et al. The photoperiod, circadian regulation and chronodisruption: Requisite interplay between the suprachiasmatic nuclei and the pineal and gut melatonin. Journal of Physiology and Pharmacology. 2011;62(3):269-274
6.Labunets IF, Grinevich YA. Biological rhythms of immune system functions and possibilities of their regulation in patients with malignant tumours (review of published and authors’ own research data). Clinical Oncology. 2014;2(14):46-52. Available from: https://www.clinicaloncology.com.ua/archive
7.Labunets IF. Changes in melatonin biorhythms and immune-neuroendocrine interactions in oncological patients of different ages. Gerontology & Geriatrics Studies. 2018;3(2):GGS.000557.2018. DOI: 10.31031/GGS.2018.03.00057
8.Scheirmann C, Kunisaki Y, Frenette PS. Circadian control of the immune system. Nature Reviews Immunology. 2013;13(3):190-198. DOI: 1038/nri3386
9.Geiger SS, Fagundes CT, Siegel RM. Chrono-immunology: Progress and challenges in understanding links between the circadian and immune systems. Immunology. 2015;146(3):349-358. DOI: 10.1111/imm.12525. Epub: 2015 Sep 28
10.Csaba G. The immunoendocrine thymus as a pacemaker of lifespan. Acta Microbiologica et Immunologica Hungarica. 2016;63(2):139-158. DOI: 10.1556/030.63.2016.2.1
11.Molinero P, Soutto M, Benot S, Hmadcha A, Guerrero JM. Melatonin is responsible for nocturnal increase observed in serum and thymus of thymosin alpha1 and thymulin concentrations: Observations in rats and humans. Journal of Neuroimmunology. 2000;103(2):180-188. DOI: 10.1016/s0165-5728(99)00237-4
12.Mate I, Madrid JA, De la Fuerite M. Chronobiology of the neuroimmunoendocrine system and aging. Current Pharmaceutical Design. 2014;20(29):4642-4655
13.Korkushko OV, Khavinson VK, Shatilo VB. Handbook of Pineal Gland: Ways for Correction in Aging. St. Petersburg: Nauka; 2006. 204 p. ISBN 5-02-026268-4
14.Korkushko OV, Khavinson VK, Butenko GM, Shatilo VB. Handbook of Peptide Preparations of Thymus and Pineal Gland in Prevention of Accelerated Aging. St.-Petersburg: Nauka; 2002. 202 p. ISBN 5-02-026176-9
15.Yarilin AA, Pinchuk VG, Grinevich YA. Handbook of Structure of Thymus and Differentiation of T Lymphocytes. Kiev: Naukova Dumka; 1991. 248 p. ISBN 5-12-001942-0
16.Boehm T, Bleul CC. Thymus-homing precursors and the thymic microenvironment. Trends Immunology. 2006;27(10):477-484. DOI: 10,1016/j.it.2006.08.004
17.Alves NL, Huntingto ND, Rodewald HR, Di Santo JP. Thymic epithelial cells: The multitasking framework of the T cell “cradle”. Trends Immunology. 2009;30(10):468-471. DOI: 10.1016/j.it.2009.07.010
18.Di Rosa F. T-lymphocyte interaction with stromal, bone and hematopoietic cells in the bone marrow. Immunology and Cell Biology. Cell Biol. 2009;87(1):20-29. DOI: 10.1038/icb.2008.84 Epub2008Nov25
19.Zou L, Barnett B, Safah H, Larussa VF, Evdemon-Hogan M, Mottram P, et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cell that traffic through CXCL12/CXCR4 signals. Cancer Research. 2004;64:8451-8455. DOI: 10.1158/0008-5472.CAN-04-1987
20.Rezali N, editor. Handbook of Thymus. London; IntechOpen, 2020.144 p. DOI: 10,5772/intechopen.73777
21.Goldstein AL, Badamchian M. Thymosins: Chemistry and biological properties in health and disease. Expert Opinion in Biological Therapy. 2004;4(4):559-573. DOI: 10.1517/14712598.4.4.559
22.Hadden JW. Thymic endocrinology. Annals of The New York Academy Sciences. 1998;840:352-358. DOI: 10.1111/j.1749-6632.1998.tb09574.x
23.Bach JF, Dardenne M. Studies on thymus products. II. Demonstration and characterization of a circulating thymic hormone Immunology. 1973 Sep;25(3):353-366
24.Trainin N, Pecht M, Handzel ZT. Thymic hormones – inducers and regulators of the T-cell system. Immunology Today. 1983;4(1):16-21. DOI: 10.1016/0167-5699(83)90097-X
25.McClure JE, Lameris N, Wara DW, Goldstein AL. Immunochemical studies on thymosin: Radioimmunoassay of thymosin alpha 1. The Journal of Immunology. 1982;128:368-375
26.Chen C, Li M, Yang H, Chai H, Fisher W, Yao Q. Roles of thymosins in cancers and other organ systems. World Journal of Surgery. 2005;29(3):204-270. DOI: 10.1007/s00268-004-7817-2
27.Bodey B, Bodey B Jr, Siegel SE, Kaiser HE. Involution of the mammalian thymus, one of the leading regulatory of aging. In vivo. 1997;11(5):421-440
28.King R, Tuthill C. Immune modulation with thymosin alpha1 treatment. Vitamins and Hormones. 2016;102:151-178. DOI: 10.1016/bs.vh.2016.04.003
29.Harris CA, Andryuk PJ, Cline S, Chan HK, Natarajan A, Siekierka JJ, et al. Three distinct human thymopoietins are derived from alternatively spliced mRNAs. Proceedings of the National Academy of Sciences of the United States of America. 1994;91:6283-6287. DOI: 10.1073/pnas.91.14.6283
30.Rezzani R, Franco C, Hardeland R, Fabrio LF. Thymus-pineal gland axis: Revisiting its role in human life and ageing. International Journal of Molecular Sciences. 2020;21:806. DOI: 10.3390/ijms21228806
31.Bach JF, Dardenne M. Thymulin, a zinc-dependent hormone. Medical Oncology and Tumor Pharmacotherapy. 1989;6:25-29. DOI: 10.1007/BF02985220
32.Reggiani PC, Schwerdt JI, Console GM, Roggero EA, Dardenne N, Goya RG. Physiology and therapeutic potential of the thymic peptide thymulin. Current Pharmaceutical Design. 2014;20:4690-4696. DOI: 10.2174/1381612820 666140130211157
33.Prasad AS. Effects of zinc deficiency on Th1 and Th2 cytokine shifts. The Journal of Infectious Diseases. 2000;182(Suppl 1):62-68. DOI: 10.1086/315916
34.Haddad JJ, Saade NE, Safieh-Garabedian B. Thymulin: An emerging anti-inflammatory molecule. Current Medicinal Chemistry. 2005;4(3):333-338. DOI: 10.2174/1568014054065195
35.Geiger H, Rudolf KL. Aging in the lympho-hematopoietic stem cell compartment. Trends Immunology. 2009;30(7):360-365. DOI: 10.1016/j.it.2009.03.010
36.Klein F, Feldhahn N, Lee S, Wang H, Ciuffi F, von Elstermann M, et al. T lymphoid differentiation in human bone marrow. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(11):6747-6752. DOI: 10.1073/pnas.1031503100
37.Monteiro JP, Benjamin A, Costa ES, Barcinski MA, Bonomo A. Normal hematopoiesis is maintained by activated bone marrow CD4+ T cells. Blood. 2005;105(4):1484-1491. DOI: 10.1182/blood-2004-07-2856
38.Ogawa T, Kitagawa M, Hirokawa K. Age-related changes of human bone marrow: A histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mechanism of Ageing and Development. 2000;117:57-68. DOI: 10.1016/s0047-6374(00)00137-8
39.Li X, Bal J, Ji X, Li R, Xuan Y, Wang Y. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immunoproperties, proliferation and differentiation. International Journal of Molecular Medicine. 2014;34(3):695-704. DOI: 10.3892/ijmm.2014.1821
40.Labunets IF, Rodnichenko AE. The effects of different doses thymulin in vivo and in vitro on some biological properties of bone marrow-derived multipotent mesenchymal stromal cells in mice of different strains. Cell and Organ Transplantology. 2018;6(1):68-73. DOI: 10.22494/cot.v6i1.82
41.Hirokawa K, Utsuyama M, Makinodan T. Immunity and aging. In: Pathy MS, editor. Principles and Practice of Geriatric Medicine. 4nd ed. Vol. Vol. 2. New York: J. - Wiley; 2006. pp. 19-36. DOI: 10.1002/9780470090572.ch3
42.Lynch HE, Goldberg GL, Chidgey A, Van den Brink MR, Boyd R, Sempowski GD. Thymic involution and immune reconstitution. Trends Immunology. 2009;30(7):366-373. DOI: 10.1016/j.it.2009.04.003
43.Thoman LM. The pattern of T lymphocyte differentiation is altered during thymic involution. Mechanism of Ageing and Development. 1995;82(2-3):155-170. DOI: 10.1016/0047-6374(95)01597-S
44.Kidd P. Th1/Th2 balance: The hypothesis, its limitations and implications for health and disease. Alternative Medicine Review. 2003;8(3):223-246
45.Gross L. Mechanisms of aging in bone marrow stem cells. PLoS Biology. 2007;5(8):215-216. DOI: 10.1371/journal.pbio.0050215
47.Zhao R. Immune regulation of osteoclast function in postmenopausal osteoporosis: A critical interdisciplinary perspective. International Journal of Medical Sciences. 2012;9:825-832. DOI: 10.7150/ijms.5180
48.Labunets IF. Influence of melatonin on biorhythms of functional status of thymus, immune system and adrenal glands cortex in elderly people. Probl Stareniya i Dolgoletiya. 2005;14(4):313-322. ISSN 0869-1703. Available from:. http://geront.kiev.ua/psid
49.Labunets IF. Age-related circadian disturbances in melatonin causing changes in thymus hormones and glucocorticoids rhythmicity in healthy animals and humans. International Journal of Aging Research. 2018;1:25. Available from: http://escipub.com/international-journal-of-aging-research/
50.Antoniuk-Shcheglova IA, Labunets IF, Shatylo VB. Correction of disorders of endocrine function of the thymus by melatonin in the apparently healthy elderly people. Probl Stareniya i Dolgoletiya. 2010;19(4):382-387. ISSN 0869-1703. Available from: http://geront.kiev.ua/psid
51.Smaaland R, Sothern RB, Laerum OD, Abrahamsen JF. Rhythms in human bone marrow and blood cells. Chronobiology International. 2002;19(1):101-127. DOI: 10.1081/cbi-120002594
52.Lucas D, Battista M, Shi PA, Isola L, Frenette PC. Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Blood. 2008;112(11):3494. DOI: 10.1182/blood.v.112.11.3494.3494
53.Suzuki S, Toyabe S, Moroda T, Tada T, Tsukahara A, Iiai T, et al. Circadian rhythm of leucocytes and lymphocyte subsets and its possible correlation with the function of the autonomic nervous system. Clinical and Experimental Immunology. 1997;110:500-508
54.Born J, Uthgenannt D, Dodt C, Nünninghoff D, Ringvolt E, Wagner T, et al. Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mechanism of Ageing and Development. 1995;84(2):113-126. DOI: 10.1016/0047-6374(95)016384
55.Labunets IF. Sex peculiarities of age-related changes in circannual rhythms of pineal gland, hypothalamo-pituitary-adrenal axis and thymus in healthy subjects. Advances in Gerontology. 2013;3(4):290-296. DOI: 10.1134/s207905701304005X
56.Astakhova VS, Panchenko LM. Using of cloning methods for discovering the influence of endogermetics action on stroma cells (in vitro). Annals of Mechnicov Institute. 2006;4:38-44. ISSN 1993-4327 (online). Available from:. http://nbuv.gov.ua/UJRN/ami_2006_4_9
57.Labunets IF, Rodnichenko AE, Magdich LV, Butenko GM. The thymus and adaptive changes in the cellular composition of bone marrow in animals of different ages. Advances in Gerontology. 2012;2(1):27-34. DOI: 10.1134/s2079057012010079
58.Arendt J. Melatonin: Characteristics, concerns, and prospects. Journal of Biological Rhythms. 2005;20:291-303. DOI: 10.1177/0748730405277492
60.Anisimov VN. Pineal gland, biorhythms and aging of an organism. Uspekhi Fiziologicheskikh Nauk. 2008;39(4):40-64
61.Reiter RJ. Pineal function during aging: Attenuation of the melatonin rhythm and its neurobiological consequences. Acta Neurobiological Experimentalis. 1994;54(Suppl):31-39
62.Ferrari E, Cravello L, Falvo F, Barili L, Solerte SB, Fioravanti M, et al. Neuroendocrine features in extreme longevity. Experimental Gerontolology. 2008;43(2):88-94. DOI: 10.1016/j.exger.2007.06.010
63.Labunets IF. Age-related changes in the melatonin and thymulin biorhythms as risk factors for human neurodegenerative diseases. Gerontollogy & Geriatrics Studies. 2017;1(2). DOI: 10.31031/GGS.2017.01.000506
64.Korkushko OV, Khavinson VK, Shatilo VB, Magdich LV, Labunets IF. Circadian rhythms of pineal gland melatonin forming function in healthy elderly people. Advances in gerontology=Uspekhi gerontologii. 2004;15:70-75
65.Hermann M, Berger P. Hormonal changes in aging men: A therapeutic indication. Experimental Gerontology. 2001;36(7):1075-1082. DOI: 10.1016/s0531-5565(00)00160
66.Ferrari E, Arcaini A, Gornati R, Pelanconi L, Cravello L, Fioravanti M, et al. Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia. Experimental Gerontology. 2000;35(9-10):1239-1250. DOI: 10.1016/s05531-5565(00)00160-1
67.Cardinali DP, Esquifino AJ, Srinivasan V, Pandi-Perumal SR. Melatonin and the immune system in aging. Neuroimmunomodulation. 2008;15(4-6):272-278. DOI: 10.1159/000156470
68.Savino W, Dardenne M. Neuroendocrine control of thymus physiology. Endocrine Reviews. 2000;21(4):412-443. DOI: 10.1210/edrv.21.4.0402
69.Reggiani C, Morel GR, Console GM, Barbeito CG, Rodriguez SS, Brown OA. Thymus–neuroendocrine axis. Physiology, molecular biology, and therapeutic potential of the thymic peptide thymulin. Annals of the New York Academy of Sciences. 2009;1153(1):98-106
70.Savino W, Mendes-da-Cruz DA, Lepletier A, Dardenne M. Hormonal control of T-cell development in health and disease. Nature Reviews Endocrinology. 2016;12(2):77-89. DOI: 10.1038/nrendo.2015.168
71.Saintz RM, Mayo JC, Reiter RJ, Antolin I, Esteban MM, Rodriguez C. Melatonin regulates glucocorticoid receptor: An answer to its antiapoptotic action in thymus. FASEB Journal. 1999;13(12):1547-1556. DOI: 10.1096/fasebj.13.12.1547
72.Hale LP, Markert ML. Corticosteroids regulate epithelial cells differentiation and hasal body formation in the human thymus. The Journal of Immunology. 2004;172:617-624. DOI: 10.4049/jimmunol.172.1.617
73.Seiki K, Sakabe K. Sex hormones and the thymus in relation to thymocyte proliferation and maturation. Archives of Histology and Cytology. 1997;60(1):29-38. DOI: 10.1679/aohc.60.29
74.Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opinion Investigational Drugs. 2001;10(3):467-476. DOI: 10.1517/13543784.10.3.467
75.Mocchegiani E, Santarelli L, Tibaldi A, Muzzioli M, Bulian D, Cipriano K, et al. Presence of links between zinc and melatonin during the circadian cycle in old mice: Effects on thymic endocrine activity and on the survival. Journal of Neuroimmunology. 1998;86(2):111-122. DOI: 10.1016/s0165-5728(97)00253-1
76.Tian YM, Zhang GY, Dai YR. Melatonin rejuvenates degenerated thymus and redresses peripheral immune functions in aged mice. Immunology Letters. 2003;88(2):101-104. DOI: 10.1016/S0165-2478(03)00068-3
77.Labunets IF, Butenko GM, Magdich LV, Korkushko OV, Khavinson VK, Shatilo VB. Effect of epithalamin on circadian relationship between the endocrine function of the thymus and melatonin-producing function of the pineal gland in elderly people. Bulletin of Experimental Biology and Medicine. 2004;137(5):507-509. DOI: 10.1023/b:bebm.0000038165.09563.b5
78.Labunets IF, Rodnichenko AE, Butenko GM. Influence of the pineal gland’s factors on the cell composition of the bone marrow in animals of different ages in conditions of changed thymus functional state. Advances in Gerontolology= Uspekhi gerontologii. 2011;24(1):54-60
79.Yarilin AA, Belyakov JM. Cytokines in the thymus: Production and biological effects. Current Medicinal Chemistry. 2004;11(4):447-464. DOI: 10.2174/0929867043455972
80.Bodey B, Bodey B Jr, Siegel SE, Kaiser HE. The role of the reticulo-epithelial (RE) cell network in the immuno-neuroendocrine regulation of intrathymic lymphopoiesis. Anticancer Research. 2000;20(3A):1871-1888
81.Giroir BP, Brown T, Beutler B. Consitutive synthesis of tumor necrosis factor in the thymus. The Proceedings of the National Academy of Sciences (PNAS). 1992;89(11):4864-4868
82.Fernandes PACM, Cecon E, Markus RP, Ferreira ZS. Effect of TNF-alpha on the melatonin synthetic pathway in the rat pineal gland: Basis for ’feedback’ of the immune response on circadian time. Journal of Pineal Research. 2006;41(4):344-350. DOI: 10.1111/j.1600-079X2006.00373.x
83.Withyachumnarnkul B, Nonaka KO, Santana C, Attia AM, Reiter RJ. Interferon-gamma production in rat modulates melatonin pineal glands in organ culture. Journal of Interferon Research. 1990;10(4):403-411. DOI: 10.1089/jir.1990.10.403
84.Hall NR, McGillis JP, Spangelo BL, Goldstein AL. Evidence that thymosin and other biologic response modifiers can function as neuroactive immunotransmitters. The Journal of Immunology. 1985;135:806-811
85.Goya RG, Reggiani PC, Vesenbeckh SM, Pléau JM, Sosa YE, Cónsole GM, et al. Thymulin gene therapy prevents the reduction in circulating gonadotropins induced by thymulin deficiency in mice. American Journal of Physiology Endocrinology and Metabolism. 2007;293(1):E182-E187. DOI: 10.1152/ajpendo.00085.2007
86.Goya RJ, Brown OA, Pleau JM, Dardenne M. Thymulin and the neuroendocrine system. Peptides. 2004;25(1):139-142. DOI: 10.1016/j.peptides.2003.11.002
87.Labunets IF. Thymic factors influence on melatonin-producing pineal function in mice of different age: The possible mechanisms. Advances in gerontology=Uspekhi gerontologii. 2007;20(1):86-91
88.Haddad JJ, Hanbali LH. The anti-inflammatory and immunomodulatory activity of thymulin peptide is NF-kB dependent and involves the downregulation of I kB-α. American Journal of Medical and Biological Research. 2013;1(2):41-49. DOI: 10.12691/ajmbr-1-2-2
89.Hardeland R. Melatonin in aging and disease-multiple consequences of reduced secretion, options and limits of treatment. Aging and Disease. 2012;3(2):194-225
90.Town T. Inflammation, immunity and Alzheimer’s disease. CNS & Neurological Disorders—Drug Targets. 2010;9(2):129-131. DOI: 10.2174/187152710791012008
91.Lin L, Du Y, Yuan S, Shen J, Lin X, Zheng Z. Serum melatonin is an alternative index of Parkinson’s disease severity. Brain Research. 2014;1547:43-48. DOI: 10.1016/j.brainres.2013.12.021. Epub 2013 Dec 30
92.Srinivasan V. Therapeutic potential of melatonin and its analogs in Parkinson’s disease: Focus on sleep and neuroprotection. Therapeutic Advances in Neurological Disorders. 2011;4(5):297-317. DOI: 10.1177/1756285611406166
93.Maguire-Zeiss KA, Federoff HJ. Future directions for immune modulation in neurodegenerative disorders: Focus on Parkinson’s disease. Journal of Neural Transmission. 2010;117(8):1019-1025. DOI: 10.1007/s00702-010-0431-6
94.Labunets IF. Neuroprotective еffects of the pineal hormone melatonin in animals with experimental model of neurodegenerative pathology. In: Handbook of Conceptual Options for the Development of Medical Science and Education: Collective monograph. Riga: Izdevnieciba “Baltija Bublishing”; 2020. pp. 355-370. DOI: 10.30525/978-9934-588-44-0/18
95.Andrabi SS, Parvez S, Tabassum H. Melatonin and ischemic stroke: Mechanistic roles and action. Advances in Pharmacological Sciences. 2015:384750. DOI: 10.1155/2015/384750
96.Chengrui A, Yejie S, Peiying L, Xiaoming H, Yu G, Steler RA. Molecular dialogs between the ischemic brain and the peripheral immune system: Dualistic roles in injury and repair. Progress in Neurobiology. 2014;115:6-24. DOI: 10.1016/j.pneurobio.2013.12002
97.Labunets I. Immune-neuroendocrine interactions involving thymus and pineal gland in stem cell therapy of age-related diseases. Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (IEMAMC). 2015;15(2):101-120. DOI: 10.2174/1871522215666150831203443
98.Damasceno A, Moraes AS, Farias A, Damasceno BP, dos Santos LM, Cendes F. Disruption of melatonin circadian rhythm production is related to multiple sclerosis severity: A preliminary study. Journal of the Neurological Sciences. 2015;353(1-2):166-168. DOI: 10.1016/j.jns.2015.03.040
99.Wurtman R. Multiple sclerosis, melatonin and neurobehavioral diseases. Frontiers in Endocrinology. 2017. DOI: 10.3389/fendo.2017.00280
100.Labunets IF, Rodnichenko AE. Melatonin effects in young and aging mice with the toxic cuprizone-induced demyelination. Advances in Gerontology. 2020;10(1):41-49. DOI: 10.1134/S2079057020010105
101.Nelson RJ, Blom JMC. Photoperiodic effects on tumor development and immune function. Journal of Biological Rhythms. 1994;9(3-4):233-249. DOI: 10.1177/074873049400900305
102.Bartsch C, Bartsch H, Peschke E. Light, melatonin and cancer: Current results and future perspectives. Biological Rhythm Research. 2009;40(1):17-35. DOI: 10.1080/09291010802066983
103.Labunets IF. Age-related biorhythmical disfunction of the pineal gland, thymus and hypophysial-adrenal system in healthy subjects. Aging: Immunology and Infectious Disease. 1996;6(3&4):167-176. ISSN: 08928762
104.Grinevich YA, Labunets IF. Melatonin, thymic serum factor, and cortisol levels in healthy subjects of different age and patients with skin melanoma. Journal of Pineal Research. 1986;3(3):263-275. DOI: 10.1111/j.1600-079x.1986.tb00749.x
Open access peer-reviewed chapter
