A profound analysis of the 45-year long research in peptides used in different species brought us to a conclusion about a common mechanism of peptide regulation of gene expression and protein biosynthesis. Short peptides are able to penetrate into cell and its nucleus. Complementary interaction of short peptides with gene promoter regions seems to be a transcription regulatory signal. These peptide-DNA interactions stimulate functioning of various organs and increase organism resource up to species limit. Investigated short peptides caused similar specific changes in gene transcription in bacteria, plants, insects, amphibians, birds, rodents, mammals, monkeys and humans. It was accompanied by a decreased tumor incidence and increased lifespan.
Director of the St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences, Vice President of the Gerontological Society of the Russian Academy of Sciences, Associate Member of the Russian Academy of Medical Sciences, Distinguished Inventor of the Russian Federation, Winner of the USSR Council of Ministers Award and K.M. Bykov Award of the USSR Academy of Sciences, professor, Doctor of Medical Sciences. Graduated from the S.M. Kirov Military Medical Academy. Colonel of the Military Medical Service in reserve. His main interests in the field of science are related to the development of the concept of peptide regulation of ageing, as well as to the design, experimental and clinical study of peptide bioregulators – geroprotectors, and to the elaboration of theoretical and practical grounds of bioregulation therapy and gerontology.
Vladimir Khavinson [from Wikipedia, the free encyclopedia]
Vladimir Khavinson - (Russian: Владимир Хавинсон; born 27 November 1946, Cottbus, Germany) is a Professor, Treasurer of the European region of the International Association of Gerontology and Geriatrics; Main gerontologist of the Health Committee of the Government of Saint Petersburg, Russia; Director of the Saint Petersburg Institute of Bioregulation and Gerontology; Vice-president of Gerontological Society of the Russian Academy of Sciences; Head of the Chair of Gerontology and Geriatrics of the North-Western State Medical University, St-Petersburg; Colonel of medical service (USSR, Russia), retired.
Vladimir Khavinson is known for the discovery, experimental and clinical studies of new classes of peptide bioregulators as well as for the development of bioregulating peptide therapy. He is engaged in studying of the role of peptides in regulation of the mechanisms of ageing. His main field of actions is design, pre-clinical and clinical studies of new peptide geroprotectors. A 40-year-long investigation resulted in a multitude of methods of application of peptide bioregulators to slow down the process of ageing and increase human life span. Six peptide-based pharmaceuticals and 64 peptide food supplements have been introduced into clinical practice by V. Khavinson. Patenting peptides is not a common practice as peptides are considered a "natural product". He is an author of 196 patents (Russian and international) as well as of 775 scientific publications.
His major achievements are presented in two books: “Peptides and Ageing” (NEL, 2002) and “Gerontological aspects of genome peptide regulation” (Karger AG, 2005).
Vladimir Khavinson introduced scientific specialty "Gerontology and Geriatrics" in the Russian Federation on the governmental level. Academic Council headed by V. Khavinson has oversighted over 200 Ph.D. and Doctorate theses from many different countries.
History Research Peptide Bioregulation [Peptides, genome, aging. V.Khavinson, 2020]
Aging is the most difficult problem in biology and medicine. The aging process is a gradual involution of organs and tissues and, as a result, a violation of the body's functions. Symptoms of old age appear at the end of the reproductive period and become more intense with aging.
At the end of the 19th century I.I. Mechnikov showed that an increase in cellular immunity contributes to an increase in life expectancy. He developed the phagocytic theory of immunity and believed that in the body itself a person has opportunities that allow him to successfully fight pathological old age. In 1908 I.I. Mechnikov was awarded the Nobel Prize in Physiology or Medicine together with P. Ehrlich. A century later, P. Dougherty and R. Zinkernagel carried out detailed studies specificity of cellular immunity in viral infection (Nobel Prize in Physiology or Medicine in 1996).
D. Watson and F. Crick, together with M. Wilkinson, received the Nobel Prize in Physiology or Medicine in 1962 "for the discovery of the molecular structure of nucleic acids and its importance in the transmission of information in living matter."
In 1961, F. Jacob and J. Monod proposed a model for the genetic regulation of protein synthesis with the participation of a low molecular weight ligand, which displaces the repressor and causes an allosteric conformational transition in the DNA structure in a bacterial cell. They received the Nobel Prize in Physiology or Medicine in 1965 together with A. Lvov.
As a result of many years of work, M. Nirenberg and G. Korana deciphered the genetic code and were able to determine the codons (triplets of nucleotides) for each of the twenty amino acids (the Nobel Prize in Physiology or Medicine in 1968 together with R. Holly). Fundamental studies of the biochemistry of nucleic acids and determination of the sequence of bases in RNA and DNA were carried out in the 60-70s of the XX century by P. Berg, W. Hilbert and F. Sanger (Nobel Prize in Chemistry in 1980).
Experimental and clinical studies in gerontology have shown that the body's immune defense is the first systemic function that is impaired with aging. B. Bötler, J. Hoffman and R. Steinman also pointed out the key role of innate immunity activation in the therapy of immunopathology and oncological diseases.
(Nobel Prize in Physiology or Medicine in 2011). Peptide extracts isolated from the thymus were the first drugs proposed for the correction of an immunodeficiency state.
It should be noted that immunotherapy has a number of advantages, including in the treatment of infectious diseases. For example, muramylpeptides act on the innate links of the immune response, which are able to prevent excessive inflammatory reactions.
The origin of the pool of short regulatory peptides in the body became apparent after the discovery by A. Chikhanover, A. Gershko, and I. Rose of ubiquitin-mediated degradation of proteins in proteosomes (Nobel Prize in Chemistry in 2004). In their work, it was shown that short peptides play an important role in the transmission of biological information, such as autocrine hormones and neuropeptides. One a high molecular weight protein can be hydrolyzed in various ways, resulting in several short peptides. This mechanism leads to the appearance of peptides with different biological functions in comparison with the original macromolecule.
In the works of American mathematicians S. Karlin and S. Altshul it was shown that in protein macromolecules there are several types of repeating blocks of amino acid residues with charged side groups. The largest number of such blocks is contained in nuclear proteins: transcription factors, centromere proteins and a group of proteins high mobility. Proteosomal hydrolysis of these proteins in the nucleus can ensure the presence of a sufficient set of peptides with charged side groups. F. Arnold, J. Smith and G. Winter developed a method for obtaining proteins and peptides with high biological activity based on imitating the natural path of biological evolution (Nobel Prize in Chemistry in 2018), which indicates the important physiological role of peptides and the prospect of creating drugs based on them.
With aging, in addition to suppressing immunity, there is a decrease in the melatonin-forming function of the pineal gland - a regulator of circadian rhythms.
These and other age-related changes are also observed at the taphole level. Thus, J. Hall, M. Rosebash and M. Young discovered the molecular mechanism of regulation of circadian rhythms (Nobel Prize in Physiology or Medicine in 2017). It is known that the internal structure of the cell nucleus also changes during aging. The DNA-protein complex of the cell nucleus (chromatin) self-organizes into chromosomes only during cell division.
In a steady state, chromatin exists in two varieties: euchromatin and heterochromatin. Heterochromatin is usually localized at the periphery of the nucleus and contains a generally inactive part of the genome: genes blocked by repressors. The euchromatin / heterochromatin ratio changes with aging due to a decrease in the content of active euchromatina, which determines a decrease in protein synthesis in the cell. E. Blackburn, K. Grader and J. Shostak established that telomeres and the telomerase enzyme protect chromosomes from damage, which is the most important factor determining the rate of aging at the cellular level. (Nobel Prize in Physiology or Medicine in 2009).
Thus, aging has many levels of dysfunction and can be classified as a systemic syndrome. The results of the correction of immunodeficiencies using endogenous regulatory peptides indicated the need for further expansion of research and search for a possible single mechanism for the regulation of gene expression and protein synthesis in living nature.
For the first time ever in the world medical practice a new medical technology (bioregulation therapy) has been designed and put into practice for restoring and maintaining main functions of the organs and tissues throughout the genetically determined span of human life (110-120 years)
The complex of measures aimed at preventing agerelated pathology, holding back ageing and thus extending the life span up to the specific limit is based on the administration of peptide bioregulators.
The 30-year experience of clinical study of peptide bioregulators has pointed out three main aspects of their application in gerontology. The first one is geroprotective. The ultimate goal of gerontological research is to slow down the rate of ageing and to increase human life span and, in particular, the working years.
The efficacy of peptide bioregulators was confirmed experimentally. Their long-term administration to mice, rats and drosophila melanogaster entailed a 30-40% expansion of average life span.
Geroprotective effects of Thymalin and Epithalamin were dynamically tested for 14-20 years and proved highly effective in clinical application. The indices of the two major homeostatic systems – neuroendocrine and immune – were restored to their normal values in middle-aged and elderly patients.
The second one is preventive. Peptide bioregulators may be administered to healthy subjects for the prevention of age-related involution changes, which serve a prerequisite for pathology development.
The third one is therapeutic. It consists in the administration of peptide bioregulators to elderly patients with various diseases and pathologies for treatment or rehabilitation.
The use of peptide bioregulator-based pharmaceuticals and their synthesized analogues opens up new vistas in prevention and therapy of age-related diseases.
Background And Activities Of The Institute
ST. PETERSBURG INSTITUTE OF BIOREGULATION AND GERONTOLOGY was established in 1992 and has been engaged in research in bioregulation and gerontology.
Its basic task is to introduce into the medical practice the results of 20-year experimental and clinical studies of a new class of medicinal substances – peptide bioregulators, which were created in the Research Laboratory of Bioregulators of the S.M. Kirov Military Medical Academy.
In 2001 the Institute was integrated into the North-Western Branch of the Russian Academy of Medical Sciences.
Research activities of the St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences are related to:
- fundamental studies, improvement of methods for diagnosis and prognosis of various diseases, development of research and production programmes in bioregulation and gerontology;
- design, clinical study, manufacture and introduction into the clinical practice of medications, stateof-the-art technologies of diagnostics and therapy for the purpose of early diagnostics, prevention and treatment of age-related pathologies;
- propagation of research findings in the field of bioregulation and gerontology (by organizing scientific conferences, publishing research papers etc.)
Presently St. Petersburg Institute of Bioregulation and Gerontology of the North-Western Branch of the Russian Academy of Medical Sciences is the only research institution in the North-Western region
of Russia, which is engaged in research on ageing, and at the same time is an active clinical diagnostic center in gerontology and geriatrics.
Staff of the Institute constitutes 150 persons, with 80 researchers among them. The research team of the Institute consists of highly qualified specialists, including 1 Associate Member of the Russian Academy of Medical Sciences, 27 professors and doctors of sciences, 27 candidates of sciences, 9 doctors bearing higher category.
The Institute comprises 15 laboratories, which are united in three major departments: the Department of Biogerontology, the Department of Cell Biology and Pathology, and the Department of Clinical Gerontology and Geriatrics. All laboratories are equipped with modern research facilities, providing for high-quality experimental and clinical studies in genetics, chemistry, biochemistry, immunology, physiology, molecular and cell biology, morphology.
Research efforts of the Institute team are concentrated on the following priority directions: studying the mechanisms of ageing; studying the properties and mechanisms of peptide bioregulators effects; design and introduction into clinical practice of new medicinal substances based on peptide bioregulators; studying the markers for in vivo diagnostics of age-related diseases; exploration of demographic aspects of population ageing.
Main research efforts of the Department are concentrated on the study of mechanisms of peptidergic regulation of homeostasis in the course of organism ageing. Laboratories within the Department are engaged in the study of molecular mechanisms underlying interaction between peptides and nucleic acids, as well as of geroprotective activities of peptides, of genetic mechanisms of peptide bioregulators neuroprotective effect; mechanisms of peptides involvement in the enhancement of adaptive capacities in ageing. The research team of the Department performs the comparative analysis of the effects of certain amino acids and small peptides on organotrophic cell cultures, of the effects of peptide bioregulators on psychoemotional status of old and very old persons. The role of peptides and melatonin in the mechanisms of ageing and carcinogenesis is continuously under study. There are performed computer modeling and synthesis of physiologically active peptides with subsequent comprehensive study of their biological properties and ongoing optimization of requirements for the studies of new peptide pharmaceuticals. The search for new biomarkers for in vivo diagnostics of age-related diseases, as well as the assessment of their diagnostic and prognostic value constitute a special issue in the research activities of the Department.
Department Of Cell Biology And Pathology
Major research performed at the Department relates to the study of neuroimmunoendocrine mechanisms of ageing. The laboratories of this Department are engaged in molecular-biologic studies of structural and functional organization of diffusal neuroimmunoendocrine system in ageing, as well as of molecular and cellular mechanisms of ageing of the human thymus; functional morphology and biochemistry of human reproductive system in ageing; mechanisms of alteration in organism antioxidation status in ageing; genetic mechanisms of neuroprotective effect of peptide bioregulators; regulatory effects of small synthesized peptides on the differentiation of hemopoietic stem cells. Methods of molecular-genetic diagnostics for the prognosis, optimized prophylaxis and treatment of the most frequently occurring multifactorial diseases in different age groups are designed. Genetic predisposition to certain multifactorial diseases may be identified using the methods developed in this Department.
Priority Indications For Peptide Bioregulators
PREVENTION OF PREMATURE AGEING
Correction of pathologic alterations.
Improvement of intellectual and physical working capacity.
PREVENTION AND TREATMENT OF AGERELATED PATHOLOGY
Cardio-vascular function disorders.
Metabolic and hormonal disorders.
TREATMENT OF EYE DISEASES
Hereditary tapetoretinal degeneration.
Central and peripheral tapetoretinal abiotrophies
with prevalent changes in pigmented epithelium.
Secondary posttraumatic and post-inflammatory central retinal degeneration.
Pigmented retinal degeneration of various etiologies.
Initial stage of cataract of various etiologies.
NEUROLOGICAL DISEASES TREATMENT
Craniocerebral trauma at the stage of rehabilitation and residual period.
Cerebral blood circulation disorders at the stage of rehabilitation and residual period.
Degeneration of vertebral column.
CORRECTION OF HORMONAL SHIFTS
Dysfunctional climacteric uterine hemorrhages caused by anovulatory process involving endometrial hyperplasia.
PREVENTION AND TREATMENT OF UROGENITAL DISEASE
Benign hyperplasia of the prostate.
Traumas of the urinary bladder, urethra and prostate.
PREVENTION AND TREATMENT OF AGERELATED SKIN ALTERATIONS (GERONTOCOSMETOLOGY)
Dry and thin skin.
Teleangiectasia, spider angioma.