ISSN 2079 0864, Biology Bulletin Reviews, 2011, Vol. 1, No. 4, pp. 390–394. Pleiades Publishing, Ltd., 2011.
Original Russian Text V.Kh. Khavinson, N.S. Lin’kova, A.V. Trofimov, V.O. Polyakova, N.N. Sevost’yanova, I.M. Kvetnoy, 2011, published in Uspekhi Sovremennoi Biologii,2011, Vol. 131, No. 2, pp. 115–121.
Morphofunctional Fundamentals for Peptide Regulation of Aging
V. Kh. Khavinson, N. S. Lin’kova, A. V. Trofimov, V. O. Polyakova, N. N. Sevost’yanova, and I. M. Kvetnoy
Institute of Bioregulation and Gerontology, Russian Academy of Medical Sciences, St. Petersburg, Russia Abstract⎯Processes of aging related to different morphological and functional changes due to pathological
or compensatory reactions are considered. Long term studies of the use of peptide bioregulators showed theirefficiency in the prophylaxis and treatment of pathologies characteristic for aged persons. The basis of thegeroprotective action of peptides is revealed to be their capacity for active protein synthesis at the molecularlevel, cytodifferentiation activation, and proliferation on the cell level. At the same time, they prevent thedevelopment of mitochondrial apoptosis and at tissue level restore morphofunctional interactions that areweakened in aging.
Keywords: peptides, protein synthesis, differentiation, proliferation, apoptosis, aging.
DOI: 10.1134/S2079086411040025
organisms of elderly people is due to the accumulationof DNA damage at reparation, telomere shortening, Study of the problem of aging is one of the most and an increase in the relative abundance of hetero challenging areas of contemporary biology and medi chromatin in the nucleus [22]. Therefore, the activa cine. Presently, the proportion of the elderly generation tion of apoptosis takes place in the organisms of eld in the world population is continuously growing [9].
erly people. At the intercellular and tissue levels, the The increase in life expectancy and, subsequently, pro decrease in abundance of regulatory proteins and pep gressive aging of the population [2, 17, 18] are expected tides involved in cell signaling processes leads to to lead in the near future to the necessity of solving a desynchronization of nervous, immune, and endo series of medical, social, and economic problems.
Therefore, the prophylaxis of age related pathologies isconsidered the main task of contemporary geriatrics Regulatory systems control the relative abundance and becomes the most important medical problem.
of different cell populations, their differentiation, pro Aging is a complex multilevel process that occurs not liferation, and apoptosis. The diversity of membrane only as hypoplastic alterations of cells and tissues but also receptors, neuromediators, cytokines, and other fac as the decrease in their functional activity. It is connected tors of intercellular regulation that integrate biosyn with a myriad of morphological and functional modifica thesis processes at the cell and organism level are char tions, which are due to pathological or compensatory acterized by the general term “bioregulation.” It reactions of an organism [1, 3, 7, 11].
unites all extracellular, intercellular, and intracellularmechanisms controlling biosynthesis, metabolism, The aging process is characterized by the involu and reproduction of genetic information in multicel tion of a variety organs and regulatory systems such as the liver, pancreas, intestine, thymus, pineal gland,and retina, as well as the nervous, immune, and endo The development and improvement of molecular crine systems [4, 5, 8, 10, 12, 24]. For all of these biological approaches in the second half of the twenti organs and systems, the general principles of aging and eth century, which provided the tools for subcellular some specific mechanisms that are due to their struc studies of regulatory systems, have led to the possibility tural and functional features are defined.
of verification of the myriad of low molecular weighthormone peptides, which were united into the group At the cell level, the aging process occurs as the dis of biologically active regulatory peptides [20].
order of synthesis and secretion of a variety of peptidesand proteins involved in cell signaling processes [15, Owing to the development of scientific methodol 25, 26]. It is suggested that the rate of aging of an ogy in recent decades, it has become possible to study organism depends on the ratio of proliferating cells intracellular processes, which allowed confirmation of and cells undergoing apoptosis. This ratio is, in turn, the fact that, in the diversity of information molecules, determined by the relative abundance of pro and regulatory peptides play the role of universal informa antiapoptotic proteins [6]. At the molecular level, the tion transporters at all levels of life organization, i.e., decrease in peptide and protein biosynthesis in the from the cell level to the organism level.
MORPHOFUNCTIONAL FUNDAMENTALS FOR PEPTIDE REGULATION Regulatory peptides occupy a special position The administration of T–34 peptide, which pos among vitally important bioregulators. Detailed study sesses an affinity to respiratory system tissues, did not of the role of peptides in the biological regulation sys affect the morphological and functional state of irradi tem of multicellular organisms is considered to be the ated organs. However, the administration of T–38 most challenging task of contemporary physiology. It peptide, which possesses an affinity to vascular tissue, appears that the transduction and effect of any incom led to a significant increase in proliferation of all stud ing information in an organism are regulated by pep ied tissue cells, though the irradiation induced tides, whose main function is aimed at the protection pathology of the vascular bed was not observed.
of functional stability of the genome [21].
Indeed, an increase in body weight and absence of At the same time, information about changes in the signs of anemia were observed in experiments with inner and outer environment appears to be the main irradiated animals treated with T–38. The T–38 pep factor initiating necessary modifications in the bioreg tide induced proliferation in the tissues of the intes ulation system that help sustain the required level of tine, spleen, and thymus. By the structural and func functional activity of cells. Some evidence suggests tional “intestinal crypt–villus” complex of the duode that these peptides normally fulfill their functions num, the mucosal tunic did not differ from the mostly at the cell level via induction of synthesis of a control, and the cellular composition of the lamina variety of regulatory proteins [16]. Peptide biosynthe propria was recovered. The effects of T–38 also led to sis disorders are observed during aging at the cellular normalization of microcirculation as well as recovery and subcellular levels [16, 19, 23]. Moreover, age of the submucous layer and neural ganglion structure.
related organism involution occurs due to the loss of In the spleen, treatment with T–38 after irradiation sensitivity to regulatory peptides by target cells in dif led to a relative increase in white pulp abundance and the occurrence of large hematopoietic islets. In lym At present, a series of synthetic peptides have been phatic follicles and the parafollicular zone, the abun obtained at the St. Petersburg Institute of Bioregulation dance of huge lymphoblasts increased. Many of them and Gerontology of the Russian Academy of Medical underwent mitotic division, which indirectly suggests Sciences. The most promising preparations with respect activation of reparation regeneration in the spleen. In to geroprotector efficiency are AT–0 (testagen, H–Lys– the thymus, treatment with T–38 peptide resulted in Glu–Asp–Gly–OH), AKS–P (pankragen, H–Lys–Glu– division into cortical and medulla zones, which com Asp–Trp–NH ), AB–9 (Nα–(γ–L–Glu)–L–Lys), AB– pletely disappeared after irradiation, suggesting gero 17 (normophthal, H–Lys(H–Glu–OH)–OH), T–31 protector effects of T–38 with respect to the thymus.
(katalacs, H–Ala–Glu–Asp–OH), T–33 (pinealon, H– At the same time, the proliferation potentials of all Glu–Asp–Arg–OH), T–34 (honluten, H–Glu–Asp– these tissues were higher than those in both the control Gly–OH), and T–38 (vesugen, H–Lys–Glu–Asp–OH).
Apparently, the synthetic peptide T–38 affects the Long term studies revealed that these peptides can vascular bed in a tissue specific manner, thus improv recover functions of tissues and organs undergoing ing the tissue trophism and activating proliferation.
age related involution. However, it has not been possi However, the T–34 peptide of the respiratory system ble thus far to follow the mechanisms of protein func was ineffective. The obtained results confirmed previ tions from the organ and tissue levels to the cellular ously obtained data about the tissue specific manner of peptide mediated effects [14], which occur not only Therefore, it appears interesting to study the mor at the tissue and organ levels but also at the cellular phological and functional characteristics of peptide level. Moreover, our study revealed that the geropro dependent regulation of aging at the organ, tissue, cel tector effects of the peptides are based on their capac ity to activate intracellular processes, the most signifi In order to reach this goal, we carried out a series of experiments allowing us to assess the regulatory effects The main goal of the second stage of our study was of the peptides and, based on the data obtained, con exploration of molecular mechanisms of the peptide sider the most important mechanisms of their action effects at the level of protein synthesis and regulation at the cellular and molecular levels.
At the first stage of the study, we conducted a compar Studies of mouse fibroblast cultures revealed that ative analysis of the influence of 20 ng/ml of T–34 and peptides fulfill their roles with respect to protein syn T–38 peptides on the duodenum, spleen, and thymus of thesis in a tissue specific manner. Indeed, T–31 pep rats undergoing radiation aging. It was shown that irradi tide, which possesses an affinity to connective tissue, ation leads to a series of pathological processes that occur up regulated cytoskeleton proteins (actin, vimentin, at the organ level as a decrease in organ mass; at the tissue and tubulin) and karyoskeleton proteins (lamin A and level as the destruction of the vascular bed, edema, and C) when taken in the concentration 10 mM. On the decrease in cell number; and at the cellular level as other hand, T–34 and T–38 peptides, which are spe changes in the nucleus structure that may possibly lead to cific to the respiratory and vascular systems, did not obtained data about the antiapoptotic effects of bioregulators [13].
Moreover, the stimulatory effects of the peptides on protein synthesis are known to be realized in a tissue specific manner. Indeed, the T–31 peptide, which possesses an affinity to connective tissue, up regulatedcytoskeleton proteins (actin, vimentin, and tubulin) and karyoskeleton (lamin A and C) in fibroblasts. Atthe same time, T–34 and T–38 peptides, which are specific to the respiratory and vascular systems, did The differentiation potential of cells was shown to decrease in both the model conditions of radiationinduced aging and the natural age related involution of organs. Therefore, the third stage of our research dealt with the study of the influence of AKS–P peptide on a pluripotential embryonic tissue, using the early gastrula ectoderm of Xenopus laevis.
In all control cultures of the embryonic pluripotential tissue, only atypical epidermis developed. Administra Tissues originating from the ectoderm of early stage gas tion of 2, 10, 20, 50, 100, and 200 ng/ml of AKS–P pep trula of Xenopus laevis treated with different concentra tide into the tissue culture induced the development of tions of the AKS–P peptide.
epidermis, somites, and mesenchyma in a dosedependent manner. In other words, it was shown that Peptide induced activation of cytoskeleton protein induction of one or the other pathway of pluripotential synthesis suggests that these peptides affect intracellu tissue differentiation in culture depended on the con lar signaling cascades, which are regulated via peptide mediated cytoskeleton protein remodeling. It also The maximal differentiation inducing activity of appears that the peptide dependent regulation of AKS–P peptide with respect to pluripotential cells was intranuclear protein synthesis may lead to alteration of observed when its concentration in the culture the heterochromatin and euchromatin ratio, which in medium was 2 ng/ml. It was observed that, under such turn facilitates changes in the gene expression pattern.
conditions, more than 35% of ectoderm differentiatedin the direction of the epidermis, mesenchyma, and Fibroblast apoptosis was induced by administration somites. A less obvious effect was observed when the of Helicobacter pylori into the cell culture, which led to concentration of AKS–P peptide in the culture mitochondria destruction, outer and inner mitochon drial membrane damage, and a decrease in mito GFPcomplex fluorescence in fibroblasts. Administration of The obtained data suggest that the pluripotential either T–31 or T–34 peptides into the fibroblast cell tissue differentiation induction effect of AKS–P pep culture prior to Helicobacter pylori resulted in increased tide is realized in a dose dependent manner. Appar mito GFP complex fluorescence and the absence of ently, the capacity of AKS–P peptide to stimulate mitochondrial membrane damage. The obtained data pluripotential cell differentiation is based on its ability suggest that both T–31 and T–34 peptides obviously to activate protein synthesis, in particular, the biosyn possess antiapoptotic activity with respect to fibroblasts, thesis of α actin, which is known to be one of the which occurs as the increase in mitochondria resistance to damaging factors and tolerance to the initiation of Therefore, at the first three stages of our study, we mitochondria dependent programmed cell death.
found that the geroprotector effects of the studied peptide were realized in the model system of accelerated Similar antiapoptotic effects of T–34 were shown aging in a tissue specific manner, and they are based in the culture of human stomach epithelial cells. Inter on the induction of cytoskeleton and karyoskeleton estingly, the revealed antiapoptotic activity of T–34 protein synthesis and inhibition of apoptosis. More was higher than that of clarithromycin, which is used over, it was shown that stem cells, which can differen as an antimicrobial agent for the treatment of Helico tiate to form a variety of tissues of an organism owing bacter pylori associated stomach diseases.
to peptide mediated regulation, can also be the targets At this stage of our research, we revealed that the geroprotector effects of the studied peptides are based At the final stage of our study, we summed up all the on protein synthesis stimulation and prevention of effects of the peptides studied, which were revealed in abnormal forms of mitochondrial dependent apopto former experiments on the immune system. The influ sis. This conclusion is consistent with the previously ence of AT–0, AB–9, AB–17, and T–31 peptides MORPHOFUNCTIONAL FUNDAMENTALS FOR PEPTIDE REGULATION Effects of the peptides on cells of human hematopoietic organs, the thymus, and lymphocytes Expression of HLA DR by T cells Expression of HLA DR by T cells Loss of CD4 or CD8 by DPLoss of CD3 by DP and SP cells Expression of HLA DR by T cells ↑ Quantity of CD4+3– and CD8+3+ ↑ Quantity of CD4+CD8– due to loss of Note: BM–bone marrow, EL–embryonic liver cells, ↓–decrease, ↑–increase, DN–double negative (CD4–CD8–) thymocytes, DP–double positive (CD4+CD8+) thymocytes, SP–single positive (CD4+CD8– and CD4–CD8+) thymocytes, TEC–thymus epithelium cells.
taken in concentrations of 2, 20, and 200 ng/ml on The majority of the peptides studied were shown to cultures of immune cells of bone marrow, thymus, and activate human immune cells, up regulate their prolif liver of human embryos, as well as immune cells of adult peripheral blood, was studied.
In the blood, AT–0 peptide in the concentrations It was revealed that the studied peptides produce 20 ng/ml and 200 ng/ml up regulated expression of multiple, mostly stimulatory, effects on differentia the HLA DR marker of late activation on the mem tion, activation, proliferation, and apoptosis of human branes of cytotoxic T lynphocytes. Moreover, this immune cells in the peripheral blood, bone marrow, peptide was shown to stimulate the mitotic potential liver, and thymus of embryos, as well as in the thymus and decrease the level of apoptosis in the population of of 1.5 year old children (table). It should be noted T lymphocytes in blood. The same concentrations of that the character of these effects depends on both AB–9 peptide provided similar effects on the activa type and concentration of the peptide, as well as on the tion, proliferation, and apoptosis of thymocytes.
type of tissue the peptide is targeted to.
The results obtained allow us to formulate some hypotheses about possible mechanisms of peptide For several peptides, a stimulatory effect on human mediated effects on the morphological and functional mature immune cell differentiation was shown.
characteristics of human immune cells, which may be Maximal effects on the differentiation capacity of proven by studies of other organs and systems.
CD34+ stem cell precursors of embryonic bone mar The stimulatory effects of the studied peptides on row and liver were provided by AT–0 and AB–17 pep differentiation and proliferation of immune cells are tides in the concentration 2 ng/ml and 20 ng/ml. Bone based on the capacity of these peptides to up regulate marrow stem cells treated with these peptides were gene expression and de novo protein biosynthesis.
shown to differentiate in the direction of myeloid This suggestion is based on data about the effects of CD14+ cells and immature CD3+ T lymphocytes, peptides on the phenotypes of T lymphocytes of blood whereas the liver stem cells tend to differentiate in the and thymocytes. T cells exhibited coexpression of two direction of mature T helpers and cytotoxic T cells.
receptors in both the thymus and peripheral blood. Initially, this effect could have been explained either by pep It was shown that AT–0 peptide in the concentra tide induced stimulation of the biosynthesis of this tion 20 ng/ml and 200 ng/ml provided the most pow receptor or by initiation of its biosynthesis due to up reg erful stimulatory effect on cell differentiation in the ulation of previously silent genes. Experiments with a direction of T lymphocytes and NK cells.
protein synthesis blocker revealed that the first suggestion Moreover, the studied peptides were shown to was false. Therefore, it was concluded that the mechanism modify the phenotype of differentiated human T cells.
of peptide induced modification of the mature T cell It was shown that mature T lymphocytes treated with phenotype in the thymus and blood is based on protein the studied peptides, especially AT–0, in the concen synthesis activation via up regulation of previously silent trations 20 ng/ml and 200 ng/ml changed their pheno genes rather than direct stimulation. Moreover, the stud types from CD4CD8+ and CD4+CD8– to CD4+CD8+.
ied peptides were shown to be tissue specific. Indeed, the In other words, the AT–0 peptide induced coexpres AT–0 and AB–17 peptides provided the most obvious sion of two receptors on the membrane of this subpop effects on stem cell differentiation in embryonic bone The studied properties of peptides (de novo protein 5. Polyakova, V.O., Knyaz’kin, I.V., Trofimov, A.V., and synthesis stimulation and tissue specificity) may be Kvetnoi, I.M., Al’manakh Gerontol. Geriatr., 2005, no. 4, considered not only in relation to immune cells but also in relation to other tissues, which will likely allow 6. Polyakova, V.O. and Benberin, V.V., Usp. Gerontol., 2006, fuller understanding of peptide dependent regulation mechanisms of the morphological and functional con 7. Polyakova, V.O., Usp. Gerontol, 2007, vol. 20, no. 1, It is known that age related organ and tissues invo 8. Polyakova, V.O. and Kvetnoi, I.M., Neiroimmunologiya, lution is based on the decreased capacity of cells for activation, differentiation, and proliferation, and, con 9. Safarova, G.L., Usp. Gerontol., 2009, vol. 22, no. 1, versely, on the activation of apoptosis. At the molecular level, these events are determined by the relative abun 10. Trofimov, A.V., Knyaz’kin, I.V., and Kvetnoi, I.M., dance of heterochromatin and inhibition of protein Neiroendokrinnye kletki zheludochno kishechnogo trakta synthesis. As tissue specific substances, peptides can v modelyakh prezhdevremennogo stareniya (Neuroen directionally activate cell proliferation and differentia docrine Cells of the Gastrointestinal Tract in Models of tion, as well as inhibit the abnormal initiation of mito Premature Aging), St. Petersburg: DEAN, 2005.
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molecular and cellular effects of the peptides occur at 14. Khavinson, V.Kh., Byull. Eksperim. Biol. Med., 2001, the tissue level, which manifests as tissue structure 15. Khavinson, V.Kh., Kvetnoi, I.M., Yuzhakov, V.V., Popu The first stage of our study revealed that, at the tissue chiev, V.V., and Konovalov, S.S., Peptidergicheskaya regu level, peptides can recover the structure and function of lyatsiya gomeostaza (Peptidergic Regulation of Homeosta organs that underwent accelerated aging. At the second stage of our research, we found that, at the cellular level, 16. Khavinson, V.Kh., Anisimov, S.V., Malinin, V.V., and the peptides stimulate cytoskeleton and karyoskeleton Anisimov, V.N., Peptidnaya regulyatsiya genoma i stare protein synthesis and, conversely, inhibit abnormal forms nie (Peptide Regulation of the Genome and Aging),Moscow: Izd. RAMN, 2005.
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