ISSN 20790570, Advances in Gerontology, 2011, Vol. 1, No. 4, pp. 295–298. © Pleiades Publishing, Ltd., 2011. Original Russian Text © N.S. Lin’kova, V.O. Polyakova, I.M. Kvetnoi, A.V. Trofimov, N.N. Sevost’yanova, 2011, published in Uspekhi Gerontologii, 2011, Vol. 24, No. 1, pp. 38–42.
Specific Features in the Pineal Gland–Thymus Relationships during Aging N. S. Lin’kova, V. O. Polyakova, I. M. Kvetnoi, A. V. Trofimov, and N. N. Sevost’yanova St. Petersburg Institute of Bioregulation and Gerontology, Northwestern Branch, Russian Academy of Medical Sciences, pr. Dinamo 3, St. Petersburg, 197110 Russia email:
[email protected] Received September 28, 2010
Abstract—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 (epi thalamin 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 res toration of the thymus function in its agerelated involution by epithalamin and epithalon are the immunoen docrine mechanisms implemented at the level of transcription activation of various proteins. Keywords: epithalon, epithalamin, thymus, pineal gland, aging DOI: 10.1134/S2079057011040096
The current demographic situation in Russia is changing towards an increase in the rate of elderly peo ple. In particular, the number of elderly people (over 60 years old) in the second half of the 20th century dou bled and will account for over 25% of the population by 2025 [10, 12]. Correspondingly, the problem of pro longing life and improving the quality of life of elderly and senile people is undoubtedly a topical issue. Despite the abundant experimental data on aging mechanisms, a unified concept of an agerelated invo lution of an organism has still not been found. How ever, there are no doubts that the majority of aging related changes in the body are associated with a decrease in the functions of the immune and endo crine systems. Correspondingly, the data on the invo lution processes taking place in the thymus and pineal gland during life are of special importance. The age related changes in the thymus play a key role in the weakening of the cellmediated and humoral immuni ties in elderly and senile persons, and the thymus invo lution is accompanied by pronounced morphological changes in the cells of the microenvironment and insufficient synthesis of the signaling molecules involved in controlling the functional activities of the immune organs and Tlymphocyte maturation [11]. Morphological and pronounced functional changes in the pineal gland are also observed during aging; a noc turnal decrease in the secretion of the main pineal hor mone, melatonin, is of special importance among them. Numerous studies on the functions of melato nin have demonstrated that this hormone synchro nizes the biological rhythms of the body, which is
inseparable from the duration of life, and that a decrease in the melatoninproducing function of the pineal gland leads to an increase in the rate of cancer, neurodegenerative, cardiovascular, immune, and endocrine diseases [4, 5, 9]. Within the theory of united neuroimmunoendo crine interactions in the body while maintaining bal ance control, it has been shown that the thymus and pineal gland are functionally interconnected. It has been found that the pinealectomized mice display a decrease in the pineal gland weight, cellular depletion, and impairment in its secretory function [21, 22]. A pharmacological blockade of the pineal gland causes a decrease in the thymus hormone thymulin in the blood of mice [7]. There are certain data showing that the thymus influences the pineal gland. It has been shown that the rhythmic pattern of several immune characteristics associated with the glucocorticoid syn theses in the adrenal cortex, a structure tightly associ ated with the pineal gland, is changed in thymecto mized mice [6, 22]. The neuroimmunoendocrine interactions between the thymus and pineal gland, as well as the key role of the involution of these organs in aging, have allowed Kvetnoi and Polyakova (2009) to postulate that the functional interactions between the thymus and pineal gland change during aging and that it is possible to pre serve a high level of functional activity of both organs at minimal involutive changes in one of them [11]. As early as the beginning of the 1970s, it was found that the involutive changes in the central organ of the immune system, the thymus, and an endocrine organ,
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the pineal gland, could be successfully restored with the extracts of these organs or the corresponding syn thesized peptides [13–16, 18, 19]. Morozov and Khavinson (1981) assumed that the thymus and pineal extracts that they isolated contained biologically active substances, cytomedines, displaying a geroprotective effect predominantly on the organ from which they were isolated [8]. The cytomedine extracted from the epithalamic region of the brain, containing the pineal gland, was named epithalamin and the complex of peptides extracted from the thymus, thymalin. Long term research has demonstrated that the drugs epith alamin and thymalin increase the average lifespan of animals by up to 25–30% as compared with the con trol groups [13–16, 18, 19]. The observed effect is ascribed to the oncostatic, immunomodulatory, and antioxidant actions of the thymus and pineal gland. Further studies of the biologically active substances involving epithalamin and thymalin have been associ ated with the development of the concept of process ing the regulation of peptides. This theory is based on the fact that the short polypeptide fragments cleaved by peptidases according to the demand of an organism are involved in the regulation of body functions rather than whole polypeptides [1, 14, 18]. Based on the amino acid analysis of the thymus and pineal cytomedines, the short peptides thymogen (Glu– Trp), vilon (Lys–Glu), and epithalon (Ala–Glu– Asp–Gly) were synthesized. A comparative study of the geroprotective, oncostatic, antiinflammatory, and antioxidant effects of the synthetic peptides and the cytomedines used for their synthesis has demonstrated that the lowmolecularweight peptides display a higher biological activity at lower doses and more pro nounced tissue specificity, as well as a lack of species specificity and immunogenicity [13, 15]. As has been shown by numerous studies, the thy mus and pineal cytomedines, as well as the corre sponding synthesized short peptides, are most effec tive in an homonymous organ [13, 15, 17]. However, the hypothesis on a tight functional interaction between the thymus and pineal gland, which can be impaired during aging, suggests that the geroprotective effect of thymalin and synthetic thymus peptides can manifest itself when acting on the pineal gland and, vice versa, epithalamin and epithalon are able to influ ence the thymus. Although the mutual influence of the thymus and pineal synthetic peptides and cytomedines is still insufficiently studied, there are certain data confirming the mentioned hypothesis. In particular, Labunets (2007) demonstrated that thymalin administration to adult mice enhanced an increase in the melatoninforming function in their pineal gland [7]. The melatonin concentration in ani mal blood 20 min after thymalin administration decreased, increased during the period from 3 to 24 h, and then again decreased. The author explains the decrease in the melatoninforming function of the pineal gland 24 h after thymalin administration by the
limitation of an excess synthesis of the pineal melato nin, since it has been earlier demonstrated that the action of this hormone present at an increased con centration in the blood can change and have the oppo site effects, and enhance carcinogenesis [2]. Thymalin administration to old animals had no statistically sig nificant effect on the melatoninforming function of the pineal gland; presumably, this suggests develop ment of agerelated involutive changes in the pineal gland and a partial loss of its ability to implement neu roimmunoendocrine interactions with the thymus. However, melatonin administration to old animals or transplantation of the pineal gland led to a restoration of the thymus structure and function [3]. For example, old rats with decreased melatonin secretion displayed an inhibited proliferative activity of the thymus lym phocytes and decreased rate of DNA synthesis. How ever, these characteristics approached the normal val ues after melatonin administration [20]. The humoral immune response increased after melatonin adminis tration, the thymus structure was restored, and inter leukin2 and γinterferon production increased [26]. These data demonstrate that the biologically active substances of the pineal gland during aging are to a greater degree able to restore the thymus functions than vice versa. (1) The following results have been obtained when estimating the regulation of thymus aging in cell cul ture by epithalon. It has been shown that epithalon inhibits the expression of the activation marker thy mus epithelial cells (TECs) CD54, CD69, and HLA DR. However, epithalon stimulated TEC production of interleukin1β and interleukin7. Epithalon, at a concentrations of 20 and 200 ng/ml, stimulated prolif eration of the TECs of the seventh passage. Epithalon also enhanced a decrease in the expression of nucle olar organizer proteins in TECs by 10% on the average [3]. These results suggest that epithalon inhibits the TECs’ functional activity; however, further studies have demonstrated that this tetrapeptide enhances thymocyte activation. In particular, epithalon increased the expression of the activation molecules CD54 and HLADR on the thymocytes; moreover, this effect was even more pronounced as compared with vilon added to the thymocyte culture. The binary action of epithalon on the TECs and thymocytes may be explained as follows. Presumably, epithalon decreases the TECs’ ability to induce thymocyte apo ptosis upon their contact, while the apoptosis is one of the mechanisms of the negative selection of thy mocyte. In addition, at doses of 20 and 200 ng/ml, epitha lon displays a more pronounced antiapoptotic effect on thymocytes as compared with vilon [3]. These data suggest that the synthetic pineal peptide epithalon enhances a more pronounced activation and prolifer ation of thymocytes as compared with the thymus peptide vilon, thereby demonstrating the ability of the ADVANCES IN GERONTOLOGY
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pineal gland to partially restore the immune function of the thymus, which decreased with age. A comparative study of the dynamics of the immune and endocrine statuses in women of 66– 94 years old treated with thymalin in combination with epithalamin has demonstrated that these two preparations together have a less pronounced effect on the studied characteristics as compared with adminis tration of epithalamin alone [14, 18, 23, 25]. Presum ably, this is explainable by the fact that the pineal cytomedine influences not only the endocrine system, but also activates the production of thymus biological active substances, which, in turn, have an immuno modulatory effect in the case of a decrease in the immune response of elderly people. This assumption is confirmed by the data on epith alamin and thymalin administration, aimed at restor ing the immune status in patients with cancer [17]. The daily administration of epithalamin at a dose of 10–20 mg for 10–15 days to cancer patients with leu kopenia and lymphopenia while preparing them for chemotherapy caused a statistically significant increase in the leukocyte and Tlymphocyte counts (especially of Thelpers). An analogous effect was observed in this group of patients when administering thymalin according to the same scheme but at a higher dose (20 mg). Epithalamin and thymalin at a dose of 10–20 mg administered for 5–10 days were also effec tive in restoring the immune status after chemo and radiation therapies in cancer patients. Epithalamin enhanced a complete restoration of the immunogram 1 month after chemo and radiation therapies, while thymalin considerably elevated the leukocyte, Tlym phocyte, and Blymphocyte counts, although these characteristics did not reach the normal level. These data demonstrate that the pineal gland preparation epi thalamin has even more pronounced immunomodula tory action as compared with the preparation thymalin, extracted from the thymus. Presumably, epithalamin not only directly influences characteristics of the immune status, but also activates thymocytes, thereby additionally stimulating proliferation of various sub populations of the immune cells. The described data confirming the effect of pineal peptides on the immune system, in particular, its cen tral organ, the thymus, suggest an activation of both the synthesis of biologically active substances and the proliferative ability of Tlymphocytes. There are data that explain the molecular mechanism underlying the epithaloninduced increase in the synthesis of the sub stances secreted by lymphocytes [13, 15, 17]. The in vitro experiments on the effect of epithalon at doses of 50 pg/ml, 5, 50, and 100 ng/ml on the expression of the interleukin2 gene in mouse spleen lymphocytes have demonstrated that epithalon stimulates the syn thesis of interleukin2 mRNA in these cells and that the degree of this effect depends on both the concen tration and duration of exposure. The maximal inter leukin2 gene expression was observed for 5 h after ADVANCES IN GERONTOLOGY
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exposure to epithalon at the two lowest concentra tions, whereas an increase in the concentration and exposure time to 20 h caused a decrease in the effect. Presumably, the mechanism of epithaloncaused induction of the interleukin2 synthesis is associated with the ability of this tetrapeptide to enter the cyto plasm of the lymphocyte and interact with it nuclear structures. This assumption is based on the data obtained using DNA microarray technology that sev eral peptides, including epithalon, enter the cell and regulate gene expression via the interaction with nuclear structures [24]. A review of the published data suggests that the functional connection between the thymus and pineal gland, which weakens in elderly persons, can be restored by the action of pineal and thymus peptides. The following main patterns in the action of the con sidered biologically active molecules on the pineal gland and thymus can be considered. (2) During aging, the biologically active substances of the pineal gland (epithalamin, epithalon, and mela tonin) are to a greater degree able to restore the func tions of the thymus, while the thymus peptides (thy malin and thymogen) have a less pronounced geropro tective effect on the involutive changes in the pineal gland; however, this can result from an insufficient number of corresponding studies. (3) Epithalamin enhances restoration of the char acteristics of the immune and endocrine statuses in elderly and senile people, longliving persons, and cancer patients. Presumably, the immunomodulatory effect of epithalamin is connected with its ability to activate thymocytes and produce biologically active substances of thymus, which, in turn, have an immu nomodulatory effect in the case of a decreased immune response associated with aging. (4) The synthetic pineal peptide epithalon inhibits the thymus epithelial cells and activates thymocytes: on the one hand, it decreases expression of the TEC activation markers (CD54, CD69, and HLADR) and, on the other, increases expression of the thy mocyte activation markers (CD54 and HLADR). Presumably, epithalon decreases the ability of TECs to induce the apoptosis of thymocytes when contacting them, which enhances the transition of the thy mocytes to the next differentiation stages, as is indi cated by their activation. (5) The epithaloninduced activation of the syn thesis of interleukins in thymus epithelial cells and lymphocytes suggests that this tetrapeptide can be involved in intracellular signaling cascades of thymus cells and can also enter their nuclear structures and regulate the transcription of the genes responsible for the synthesis of interleukins. REFERENCES 1. Anisimov, V.N., Khavinson, V.Kh., and Morozov, V.G., Role of Epiphyseal Peptides in regulation of Homeo
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