Overview

The optimal functioning of the human organism is directly connected with the state of cells. The scientific evidence shows that the health of the organism depends directly on the health of each individual cell. If cells work well, the organs and systems work well. In order for the cells to function well, their optimal supply with all necessary substances is required.

It has been already over 50 years ago, since medical scientists have discovered that for the normal functioning cells, among other substances, also need peptides.

Peptides - organic substances consisting of amino acids linked by peptide bonding. In living cells, the peptides are synthesized from amino acids or are the products of the protein metabolism - the degradation of proteins into small fractions.

Each cell of the human body forms / synthesizes proteins. This process is vital for the cell to develop and function properly. In a young body protein synthesis works very well. Accordingly, a sufficient amount of peptides is also formed. Therefore in a young body, usually, all the organs and systems work very well.
Unfortunately, the intensity of the protein synthesis decreases as a result of age, and in particular under the influence of a multitude of negative factors on the body (illness, stress, physical and mental stress, deficient nutrition, etc.). The older you get or the more intense the stress, the faster decreases the body's intensity of proteins synthesis. As a result, fewer proteins and eventually peptides are formed. The level of regulatory peptides decreases. This can lead to disorders of the cell functions, development of pathological conditions and accelerated 'wear' of the most important body systems. The more extreme the conditions in which the organism works, the greater the need for tissue-specific peptides.

The scientists found that deficiency of peptides in the body leads to the dysfunction of the cells, accelerated 'wear' of tissues, development of pathological conditions and accelerated aging of the organism. At the same time, they have shown in numerous studies that by using peptides and restoring the physiological peptide level in the organism, one can counteract these conditions. Accordingly, to more specifically and effectively support the body cells in certain situations, peptide preparations can play a very important role as an additional source of peptides.

Peptides are the same in all mammals. In numerous studies, the scientists have demonstrated that when peptides are produced from animal tissues, e.g. cattle, or pigs, and introduced to another animal or human being, these are assumed by the organism as endogenic substances.

Moreover, peptides have tissue-specific properties. They only work in the tissue from which they were originally isolated. By using peptides of animal origin, the enrichment of the pool of regulatory peptides takes place in the body of the tissue from which they were originally isolated. This leads to the normalization and maintenance of the physiological peptide level in the corresponding tissue, which is necessary for a physiologically normal functioning of the cells.

The modern technology ensures the recovery of peptides of biologically natural, unchanged form. This is very important for the safety of the peptides. In addition, thanks to elaborate filtration and concentration.

Peptides of animal origin have been carefully studied by scientists from many countries, such as the USA, Sweden, Germany and Russia for many years. The Russian scientists at the Saint Petersburg Institute of Bioregulation and Gerontology conducted the largest research work on peptides. This is by the way the only institution in the world that has more than 40 years of experience with the peptides. The results of numerous studies support as well as the safety of peptides, as well as their effectiveness.

Peptide Bioregulators and their role

Each cell produces/synthesizes proteins. This process is vital for the cells ability to develop and function properly. In the course of the protein metabolism protein molecules break down into smaller fractions = peptides. These peptides are in turn used by the cells to form new proteins. A sufficient amount of these peptides are required for optimal protein synthesis, and thus cell function. If the cells function well, then the organs and body systems work well. In young body protein synthesis works very well and it is sufficiently formed on peptides. With increasing age, unfortunately, the intensity of protein synthesis in cells decreases rapidly. That is also the reason why many body systems in the elderly may not function properly. Scientists have also discovered that even a young organism under the influence of extreme adverse conditions, such as permanent psycho emotional stress, increased physical stress, harmful environmental factors, poor diet etc. decreases the intensity of protein synthesis in the body cells. The result - wear of tissues and premature aging of the organism.

Peptide deficiency is one of the main factors of dysfunction of body systems and premature aging. Peptide deficiency can be influenced by diet. A series of such peptide preparations was first developed in Russia by Professor V.Khavinson and the team of the St. Petersburg Institute of bio-regulation and Gerontology.

Long-term investigations performed by the research team of the Institute resulted in creating a new class of geroprotectors – peptide bioregulators. The administration of peptide bioregulators enables effective prevention of premature ageing and therapy of age-related diseases.

Researchers of the Institute are the inventors of a number of medicinal and prophylactic pharmaceutical substances, which have been adopted by the Russian Ministry of Public Health and are presently under production.

According to the concept of peptide bioregulation, a theory of endogenous peptide bioregulators’ involvement in the maintenance of structural and functional homeostasis of cell populations, containing and producing these factors, was formulated.
These peptide bioregulators control gene expression and protein synthesis, thus preventing age-related accumulation of quantitative structural and functional alterations, which are the markers of transition of a biological system from the norm to the pathology. Disordered peptide bioregulation reduces organism resistance to external and internal destabilizing factors, serving a cause of premature ageing.
 
A long record of peptide bioregulators application in the health servicehas demonstrated their high effectiveness in combating various disease and pathologies, including those refractory to other medicines.

Biopeptide regulators exert a regulatory effect on the cellular level and are used for improving the organism resistance to the impact of adverse environmental, climatic, occupational and other factors, as well as during the rehabilitation period after surgeries, traumas, diseases; in case of malnutrition, high physical loads; for the purpose of maintaining the functions of the main organism systems in old and very old persons in order to reduce the risk of disease occurrence.

Here we review new data about the physiological role of short peptides and their use as biologically active food additives (parapharmaceutics). Some approaches to the development of peptide preparations for peroral administrations are considered and the mechanisms of non-specific and tissue-specific effects produced by peroral peptide parapharmaceutics are discussed. Particular attention is given to biological properties of short peptides synthesized at the St. Petersburg Institute of Bioregulation and Gerontology. These peptides hold much promise for the synthesis of parapharmaceutics increasing organism’s resistance to extreme factors and preventing accelerated aging and age-related diseases.

Endogenous peptides are involved in the compensatory and adaptive response of the organism to stress and disturbances in homeostasis. The peptide system plays a major role in neuroimmunoendocrine interactions [9].

Despite multilevel hierarchy, the main functions of homeostasis-regulating systems are coordination of biosynthesis and maintenance of stable genetic composition of cells in organs and tissues. Disturbances in the peptide-mediated regulation and transfer of informational molecules between cells lead to the development of pathological states associated with decreased organism’s resistance to destabilizing exogenous and endogenous factors.

Much progress was recently achieved in the synthesis of complex peptide-based preparations. Clinical efficiency of these drugs is extensively studied to substantiate their use in combination therapy of various diseases and disorders [11,13,20]. This approach is based on the fact that bioregulation in the organism is mediated by various oligopeptides selectively transferring information between the immune, nervous, and other cells. These oligopeptides are formed during partial proteolysis of precursor proteins (e.g., cytokines, growth and thymic factors, and immunoglobulins) in the immediate proximity to the corresponding receptors.

The general principle underlying organization of the protein molecule is that higher structures are determined by lower structures. Therefore, the primary sequence of amino acids includes information required for the formation of the protein molecule [1]. According to modern views, information can be transferred by molecules consisting of 2-4 amino acid residues with polar side radicals.

Homology of protein sequences of most peptide hormones of the gastrointestinal tract (GIT), insulin, calcitonin, and pituitary hormones attests to their common origin. For example, the study of the evolution of these hormones showed that insulin is synthesized in gastrointestinal mucosa in mollusks. Insulin and insulin-like growth factor have the same evolutionary origin. Moreover, insulin is evolutionarily similar to nerve growth factors. It was shown that the amino acid sequence of the peptide with insulin-like activity is similar to that of trypsin inhibitor, somatomedin, and relaxin. Comparative structural analysis of biologically active substances (BAS) secreted by cells of the diffuse neuroendocrine system showed common origin of peptide hormones [12,36].

Institute of Nutrition, Russian Academy of Medical Sciences, Moscow;

*St. Petersburg Institute of Bioregulation and Gerontology, Northwestern Division of the Russian Academy of Medical Sciences

Not only the whole molecule can affect physiological processes. Sometimes fragments of 3-4 amino acid residues are more effective than native compounds. Therefore, the regulation and coordination of functions can be realized via processing of polypeptides. During this process fragments with different activity, specificity, and effects on various physiological systems are cleaved from relatively long chains depending on the needs of organisms. Processing regulation is characterized by considerable plasticity. This process results in rapid and local formation of required regulators from preexistent precursors due to activation of specific peptidases. The mechanism of processing determines the sequence of activation of regulators. Processing regulation is most typical of peptide compounds with the linear structure. Their molecules can undergo considerable conformational changes even after cleavage of a single amino- or carboxyl-terminal amino acid residue. This cleavage is followed by changes in various properties of molecules, e.g., their hydrophobicity and the blood-tissue barriers [7].

A growing body of evidence indicates that regulatory oligopeptides are involved in the growth, development, and regeneration. Many oligopeptides are well-studied compounds regulating various physiological functions, coordination of homeostasis, and adaptation of functional systems to the environment was revised after studies of regulatory peptides performed over the past 2-3 decades.

Nutrition is the major environmental factor that affects the organism over the whole life. Nutrients are metabolized into structural elements of cells, provide physical and mental activity, and determine the health and lifetime. Inadequate nutrition is always followed by negative consequences. Nutrition adequate to the age, professional activity, and state of health is an important factor preventing various human diseases, including cardiovascular (atherosclerosis, myocardial infarction, insult, and hypertension) and gastrointestinal pathologies, metabolic disorders (obesity and osteochondrosis), and tumors.

In developed countries people consume considerable amounts of industrially manufactured food. Technological treatment markedly reduces the contents of vitamins, mineral elements, and other BAS that regulate metabolism and functional activity of various organs and systems in the organism. In modern urbanized society, people receiving traditional nutrient products are extremely predisposed to the development of nutrient deficiency. This determines inability of protective systems in the body to respond adequately to adverse environmental factors and increases the risk of various disorders. The experience of economically developed countries indicates that it is impossible to improve the structure and quality of nutrition by traditional methods. This problem can be solved via development of new alternative methods for the production of chemically pure BAS from natural sources [15].

A long search and use of BAS in practice showed that various chemical compounds with a completely or partially known structure possess biological activity. BAS were efficient during the therapy of diseases and correction of mental and physical disturbances. Recent lines of research involve the analysis of BAS effectiveness in traditional spheres and other fields that develop after the appearance of compounds with new action on living matter.

There is a good reason to introduce the term “systemic preparation”, whose components participate in the regulation of various stages of the same key process. They not only initiate certain stages of this process but also attenuate negative consequences of this activation.

Modern notions about nutrition and effects of nutrient substances on regulatory systems in the organism, studies of the mechanisms underlying the influence of short peptides, and synthesis of peroral medicinal preparations and parapharmaceutics indicate that the composition of therapeutic and preventive diets should be improved. Short peptides possess geroprotective properties and can be used as parapharmaceutics [18]. Probably, exogenous peptide preparations temporally substitute the impaired element of physiological regulation. This process allows the organism to restore the diminished or lost function and to maintain it for a long time. These data confirm the view that functional compensatory systems can be formed in old organisms [14]. We hypothesize that peptides normalize and maintain protein synthesis in the corresponding organ at a level typical of young individuals. The recovery of proteins in cell receptors normalizes their sensitivity to other humoral regulators.

Physiologically active short peptides should be used as biologically active food additives at any age for the maintenance of metabolic processes, prevention and therapy of various diseases, rehabilitation after severe disorders, traumas, and surgeries, and deceleration of aging.

The appropriate and substantiated use of biologically active food additives from short peptides opens up fresh opportunities for a new field of science, “integral medicine”. Pharmaconutrition in combination with modern diagnostic and procedures holds much promise as an effective and harmless method for the maintenance of health and increase in the lifetime.

REFERENCES

1. B. Alberts, D. Bray, J. Lewis, et al., Molecular Biology of the Cell [in Russian], Moscow (1986), Vol. 2.

2. P. K. Anokhin, Urgent Questions of Functional System [in Russian], Moscow (1960).

3. G. M. Barenboim and A. G. Malenkov, Biologically Active Substances. New Principles of the Search [in Russian], Moscow (1986).

4. A. A. Boldyrev, Carnosine. Biological Importance and Possible Use in Medicine [in Russian], Moscow (1998).

5. L. N. Valenkevich, Human Digestive System in Aging [in Russian], Leningrad (1982).

6. L. N. Valenkevich and A. M. Ugolev, Biology of Aging. Manual on Physiology [in Russian], Leningrad (1982), pp. 343-369.

7. T. M. Eroshenko, S. A. Titov, and L. L. Luk’yanova, Human and Animal Physiology [in Russian], Moscow (1991).

8. A. A. Zamyatnin, Fiziol. Zh., 78, No. 9, 39-51 (1992).

9. Immunophysiology, Ed. E. A. Korneva [in Russian], St. Petersburg (1993).

10. V. A. Konyshev, Nutrition and Regulatory Systems of the Organism [in Russian], Moscow (1985).

11. V. G. Morozov, V. Kh. Khavinson, and V. V. Malinin, Peptide Thymomimetics [in Russian], St. Petersburg (2000).

12. M. A. Osadchuk, V. F. Kirichuk, and I. M. Kvetnoi, Diffuse Neuroendocrine System: General Biological and Gastroenterologic Aspects [in Russian], Saratov (1996).

13. R. V. Petrov, A. A. Mikhailova, L. A. Fomina, and R. N. Stepanenko, Myelopeptides [in Russian], Moscow (2000).

14. K. V. Sudakov, General Theory of Functional Systems [in Russian], Moscow (1984).

15. V. A. Tutel’yan, B. P. Sukhanov, A. N. Avstrievskikh, and V. M. Poznyakovskii, Biologically Active Additives in Human Nutrition (Quality, Harmlessness, Effectiveness, Characteristics, and Use in Preventive and Clinical Medicine) [in Russian], Tomsk (1999).

16. A. M. Ugolev, V. V. Egorova, N. N. Iezuitova, et al., Fiziol. Zh. SSSR, 78, 29-37 (1992).

17. V. Kh. Khavinson, V. V. Egorova, N. M. Timofeeva, et al., Byull. Eksp. Biol. Med., 133, No. 5, 570-573 (2002).

18. V. Kh. Khavinson and V. V. Malinin, Ibid., 133, No. 1, 4-10 (2002).

19. V. Kh. Khavinson, V. V. Malinin, N. M. Timofeeva, et al., Ibid., 133, No. 3, 337-339 (2002).

20. V. Kh. Khavinson and V. G. Morozov, Epiphyseal and Thymic Peptides in the Regulation of Aging [in Russian], St. Petersburg (2001).

21. V. Kh. Khavinson, N. M. Timofeeva, and V. V. Malinin, Byull. Eksp. Biol. Med., 131, No. 6, 690-693 (2001).

22. J. P. Bai, L. L. Chang, and J. H. Guo, Crit. Rev. Ther. Drug Carrier Syst., 12, No. 4, 339-371 (1995).

23. R. Borchardt, J. Aube, T. J. Siahaan, et al., Adv. Drug Deliv. Rev., 27, Nos. 2-3, 235-256 (1997).

24. D. Cardona Pera, Nutr. Hosp., 13, No. 1, 8-20 (1998).

25. F. A. Dorkoosh, J. C. Verhoef, G. Borchard, et al., J. Control Release, 71, No. 3, 307-318 (2001).

26. G. M. Friedrichsen, C. U. Nielsen, B. Steffansen, and Begtrup M., Eur. J. Pharm. Sci., 14, No. 1, 13-19 (2001).

27. P. Furst, K, Pogan, and P. Stehle, Nutrition., 13, Nos. 7-8, 731-737 (1997).

28. T. Jung, W. Kamm, A. Breitenbach, et al., Eur. J. Pharm. Biopharm., 50, No, 1, 147-160 (2000).

29. M. K.ratzel, R. Hiessbock, and A. Bernkop-Schnurch, J. Med, Chem., 41, No. 13, 2339-2344 (1998).

30. J. Li, B. K. King, P. G. Janu, et al., J. Parenter. Enteral Nutr., 22, No. 1, 31-36 (1998).

31. M. K. Marschutz and A. Bernkop-Schnurch, Biomaterials, 21, No 14, 1499-1507 (2000).

32. D. M. Matthews, Peptide transport in protein nutrition, Eds. D. M. Matthews and J. W. Payne, Amsterdam (1975) pp. 61-146.

33. D. M. Matthews, Physiol, Rev., 55, No. 4, 537-608 (1975).

34. B. J. Morlion, P. Stehle, P. Wachtler, et al., Ann. Surg., 227, No, 2, 302-308 (1998).

35. C. U. Nielsen, R. Andersen, B. Brodin, et al., J. Control Release., 73, No. 1, 21-30 (2001).

36. A. G. Pearse, Med. Biol., 55, No. 3, 115-125 (1977).

37. M. Rothstein and M. Coppens, Comp. Biochem. Physiol., 61, No. 1, 99-104 (1978).

38. H. Shen, D. E. Smith, and F. C. Brosius, Pediatr. Res., 49, No. 6, 789-795 (2001).

39. S. Stauch, G. Kircheis, G. Adler, et al., J. Hepatol., 28, No. 5, 856-864 (1998).

40. M. Thamotharan, S. Z. Bawani, X. Zhou, and S. A. Adibi, Proc. Ass. Am. Physicians., 110, No. 4, 361-368 (1998).

41. W. Wang, G. Camenisch, D. C. Sane, et al., J. Control Release., 65, Nos. 1-2, 245-251 (2000).

42. C. Winckler, G. Breves, M. Boll, and H. Daniel, J. Comp. Physical., 169, No. 7, 495-500 (1999).

43. A. W. Zhou, J. Guo and Y. C. Du, Biomed. Pept. Proteins Nucleic Acids., 1, No. 1, 57-58 (1994-1995).