October 27, 2002
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Neuroendocrinology Letters incl. Psychoneuroimmunology & Chronobiology

NEUROENDOCRINOLOGY LETTERS


PEPTIDES AND AGEING
Book by Vladimir Kh. Khavinson

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Hard cover,
144 pages, with 30 Tables and 14 Figures.

 


ABSTRACT

Keywords
Ageing; Animal; Human; Peptides; Pharmacology; Physiology; Therapeutic use; Immunity; Pineal Body; Retina; Retinal degeneration

A technology has been developed for manufacturing of biologically active complex peptide preparations from extracts of different tissues. In particular, the pineal preparation (Epithalamin) augments the in vitro outgrowth of explants from the pineal gland but not from other tissues, the latter being stimulated by peptide preparations from respective tissues. Epithalamin increases melatonin production by the pineal gland of rats, improves immunological parameters in rats and mice, produces anticarcinogenic effects in different experimental models, stimulates antioxidant defenses, and restores the reproductive function in old rats. These effects are combined in the ability of Epithalamin to increase the lifespan in rats, mice, and fruit flies. Many of these effects are reproduced in clinical trials, which have demonstrated the geroprotector activity of Epithalamin in humans. Among the effects of the thymic preparation Thymalin, those related to its ability to stimulate immunity are the most prominent. This ability is associated with anticarcinogenic and geroprotector activities. Clinical trials of the peptide preparations obtained from other organs including the prostate, the cerebral cortex, and the eye retina, have demonstrated beneficial effects reflected by the improvement of the conditions of respective organs. Based on the data about the amino acid compositions of the peptide preparations, novel principles of the design of biologically active short peptides possessing tissue-specific activities has been developed. Dipeptides specific for the thymus and tetrapeptides specific for the heart, liver, brain cortex, and pineal glands stimulate the in vitro outgrowth of explants of respective organs. Interestingly, for eye retina and the pineal gland, a common tetrapeptide Ala-Glu-Asp-Gly (Epitalon) has been designed, probably reflecting the common embryonal origin of these two organs. Epitalon reproduces the effects of Epithalamin including those related to its geroprotector activity. In particular, Epitalon increases the lifespan of mice and fruit flies and restores the circadian rhythms of melatonin and cortisol production in old rhesus monkeys. At the same time, Epitalon prolongs the functional integrity of the eye retina in Campbell rats with hereditary Retinitis Pigmentosa and improves the visual functions in patients with pigmental retinal degeneration. Changes in gene expression were observed to be produced by the short peptide preparations. Therefore, the effects of Epitalon are suggested to be mediated by transcriptional machinery common for the pineal gland and the retina and, probably, for regulation of melatonin production in fruit flies. Based on three decades of studies of the peptide preparations, the peptide theory of ageing has been put forward. According this theory, ageing is an evolutionary determined biological process of changes in gene expression resulting in impaired synthesis of regulatory and tissue-specific peptides in organs and tissues, which provokes their structural and functional changes and the development of diseases. Correspondingly, correction of such disorders by means of stimulation of peptide production in the organism or through their delivery can promote the normalisation of disturbed body functions.

 

TABLE OF CONTENTS 'PEPTIDES AND AGEING'
Vladimir Kh. Khavinson

FOREWORD . 5
ABSTRACT . 11
INTRODUCTION . 13


CHAPTER 1.
Aspects of peptide biology

1.1. General considerations. 19
1.2. Regulatory peptides . 21
1.3. Ageing and peptides . 32

CHAPTER 2.
Experimental studies of the anti-ageing effects of " peptide preparations

2.1. General characteristic of peptide preparations
2.1.1. Complex peptide preparations (Cytomedins) 41
2.1.2. Synthetic small peptides (Cytogens) 44
2.2. Effects of peptide preparations on ageing, longevity,
and spontaneous carcinogenesis
2.2.1. Epithalamin, ageing rate, and lifespan 47
2.2.2. Effects of Epithalamin and Thymalin on lifespan and
spontaneous carcinogenesis in rodents 47
2.2.3. Epitalon, ageing rate, and lifespan 50
2.2.4. Effects of Epitalon, Thymogen, and Vilon on lifespan and
spontaneous carcinogenesis in rodents 52
2.3. Effects of peptide preparations on the factors and
correlates of ageing
2.3.1. Antioxidant defences 55
2.3.1.1. Effects of Epithalamin and melatonin on free radical processes 55
2.3.1.2. Effects of Vilon and Epitalon on free radical processes 58
2.3.2. Immunity 59
2.3.2.1. Effects of Thymalin 59
2.3.2.2. Effects of Thymogen and Vilon 60
2.3.2.3. Comparative studies of immunomodulating activities of
Thymalin, Thymogen, and Vilon 62
2.3.3. Carcinogenesis
2.3.3.1. Effects of Epithalamin and Thymalin on induced
carcinogenesis in rodents 63
2.3.3.2. Effects of Epitalon, Thymogen, and Vilon on induced
carcinogenesis in rodents 65
2.3.4. Tissue regeneration and degeneration
2.3.4.1. Tissue-specific effects of peptide preparations in tissue
and cell cultures 67
2.3.4.2. Effects of peptide preparations on tissue regeneration in vivo 75
2.3.4.3. Effects of Epitalon on visual functions in Campbell rats
with hereditary pigmented retinal degeneration 77
2.3.5. Neuroendocrine system
2.3.5.1. Neuroendocrine effects of Thymalin, Thymogen, and Vilon 80
2.3.5.2. Effects of Epithalamin on the reproductive system 80
2.3.5.3. Effects of Epithalamin and Epitalon on the pineal gland 82
2.3.6. Gene expression . 85
2.3.7. Mitochondrial functions . 88
2.4. Summary and conclusions . 90


CHAPTER 3.
Clinical studies of peptide preparations


3.1. Epithalamin
3.1.1. Hereditary predisposition to age-associated diseases 93
3.1.2. Age-associated diseases 96
3.1.3. Non-insulin-dependent diabetes mellitus (NIDDM) 98
3.1.4. Premature senescence 98
3.1.5. Climacteric cardiomyopathy 99
3.1.6. Cancer after radio- or chemotherapy 100
3.1.7. Aspirin-induced asthma 102
3.1.8. Asthenic syndrome 104
3.2. Thymalin
3.2.1. Conditions after thymectomy 105
3.2.2. Age-associated diseases 105
3.3.3. Cancer after radio- or chemotherapy 106
3.3. Thymogen
3.3.1. Infectious diseases 109
3.3.2. Immune impairments 110
3.3.3. Other conditions 113
3.4. Vilon
3.4.1. Chronic inflammations and infections 115
3.4.2. Cancer after radiation therapy 116
3.5. Cortexin
.5.1. Circulatory encephalopathies 117
3.6. Retinalamin
3.6.1. Retinalamin in treating eye diseases 119
3.6.2. Retinalamin in combination with other Cytomedin
preparations in treating eye diseases 120
3.7. Prostatilen
3.7.1. Prostate adenoma 121
3.7.2. Prostatitis 122
3.7.3. Male sexual dysfunctions 124
3.8. Summary and conclusions. 125


GENERAL DISCUSSION. 127
ACKNOWLEDGEMENT. 130
REFERENCES. 131

Foreword

Scanning of the latest issues of periodicals specialised in ageing research may draw a gerontologist’s attention to a number of publications that describe the effects of peptide preparations developed in Russia at the St. Petersburg Institute of Bioregulation and Gerontology. The authors claim that their products are able to render a whole range of effects generally believed to be beneficial for the inhibition of ageing and age-associated diseases. It is noteworthy that some of the preparations are included into the State Russian Pharmacopoeia and used in clinics for good as it comes out. Moreover, the authors report that some of the preparations increase the lifespan and slow down ageing rate in a bewilderingly broad range of experimental settings: from mature Drosophila flies whose larvae have been treated with an unprecedentedly low dose of the preparations to rats and mice treated lifelong. Among other outcomes it has been reported that a synthetic tetrapeptide designed based on amino acid composition of a mixture of peptides extracted from the pineal gland could restore melatonin production in old monkeys, reduce spontaneous and induced tumour incidence in rats and mice, enhance antioxidant defence in flies, rats, and humans, and slow down retinal degeneration in rats with Retinitis Pigmentosa. All this is a result of more than thirty years of research effort, which mostly remained concealed being reported in obscure Russian journals unavailable to the Western audience. Now, thanks to this book, for which this foreword has been written, the entire range of evidences that substantiate the advances achieved by the developers of the preparations in question is open to anyone. So, it is up to readers to decide whether they believe what they read or not. Of course, although the book fills many gaps evident from the first glance at scattered publications, it exposes other gaps not filled by research. It is only quite recently that the most advanced methods of modern biology including DNA-microarray have been used to get a better insight into mechanisms of action of the peptides described in this book. Hopefully, it will stimulate efforts to control the data expose, confirm the results obtained, regarding the biological and clinical activity of the peptide developed in St.Petersburg as well as to understand the mechanisms of action of these preparations.

Professor Mario Passeri
President
European Region
International Association of Gerontology

 

Introduction

Evolutionary processes in very different systems ranging from the populations of living organisms to scientific disciplines are based on a random search for novelties and subsequent selection and saving of the most beneficial findings. Mathematical modeling demonstrates that in situation where evolutionary changes in relatively isolated subsystems are accumulating independently and this alternates with periods of removed barriers and free information flow, the entire system develops faster than without temporal restrictions for such flow. This is what occurs in present day science. Russian researchers have long been working in a relative isolation from the world scientific community and developed their own original approaches in some research areas. The time has come to exchange ideas. Russian science has gained a unique experience in several fields of biology and, in particular, in studying and practical usage of biologically active peptides.
Intensive investigation of biologically active peptides started all over the world some thirty years ago after the discovery of endogenous opioids and in connection with searching for thymic regulators of immunity. Methods for obtaining biologically active peptide extracts from the thymus were developed almost simultaneously by several research teams in the USA, Western Europe, and Russia, in particular, by the author of this book in collaboration with V. G. Morozov. Then the ways of scientists on different sides of the iron curtain diverged. Western researchers followed the trodden paths of isolation of specific substances, their molecular identification, determination of their target cells, receptors, intracellular signal transmission pathways, etc. Russian scientists also isolated several defined biologically active thymic peptides, which were partially identical to those isolated by foreign researchers. However, Russian peptide research was guided not only by technologies, which lagged increasingly behind, but also by concepts, which emerged soon after obtaining the first data about biological effects of peptide extracts from the thymus and other organs and tissues.
V. Kh. Khavinson and V. G. Morozov suggested that the extracts they obtained could contain peptides involved in information exchange between cells. Such extracts were named “cytomedins” (from Greek cytos – ‘cell’ and Latin mediator) [1, 2]. At first, these products were extracted from the thymus, hypothalamus, and epiphysis and, later, from virtually all organs and tissues. The method of obtaining cytomedins is described in Chapter 2 of this book. These preparations are named according to tissues and organs of their origin. For example, Epithalamin is the name for a cytomedin preparation from the epithalamic area of the brain including the pineal gland, Thymalin is for a thymic Cytomedin preparation, Cordialin is for heart peptides, and so on. All cytomedins are complexes of alkaline polypeptides with molecular weight usually within 10 kDa.
The very first studies of Cytomedins have revealed that Epithalamin, a complex of pineal peptides, contains components that can reduce one of important manifestations of ageing in mammals, i. e., the decreased sensitivity of the hypothalamo-pituitary system to estrogens. Administration of Epithalamin to old animals promoted the restoration of their reproductive functions (section 2.3.5.2 of the book). Cytomedins from the pineal gland and thymus were shown to have an antitumour activity (sections 2.2. and 2.3.3). Thymic cytomedins (Thymalin) were shown to take a part in regulation of immunity (section 2.3.2).
Another essential property of cytomedins is their ability to activate antioxidant defences of the organism (section 2.3.1), which is important for protection against cancer and ageing. Ageing and the development of complications of irradiation have much in common: in both cases lipid peroxidation is activated, immunity is depressed, the risk of tumour development increases, and the resistance of the organism to unfavourable factors declines. Consequently, cytomedins can be regarded as natural immuno-, gero-, and radioprotectors.
Many years of research confirm the suggestion that cytomedins exert their maximal effect upon the organ they have been isolated from (section 2.1). A model of development of pathological conditions has been suggested assigning a key role in their pathogenesis to disorders in cytomedin-mediated regulation. This refers to the complex of pathologic processes associated with ageing. According to the cytomedin concept, ageing is an evolutionary determined biological process of age-related changes in gene expression resulting in impaired synthesis of regulatory and tissue-specific peptides in organs and tissues, which provokes their structural and functional changes and the development of diseases [3]. Correspondingly, correction of such disorders by means of stimulation of Cytomedin production in the organism or through their delivery from outside is expected to promote the normalisation of disturbed body functions [4].
The Cytomedin concept emerged at the time when biology lacked grounds it stands on now as a result of technological developments. Nevertheless, this concept proved to be an efficient guide to action, as is evidenced by results obtained.
Experiments with rats, mice, and fruit flies Drosophila melanogaster have revealed the potential of Epithalamin and Thymalin to significantly increase longevity and inhibit the development of age-related disorders (section 2.2).
Much experience has been gained in using Epithalamin and Thymalin in geriatrics (Chapter 3). Based on many years of clinical trials carried out at the Institute of Gerontology of the Ukrainian Academy of Sciences, these two preparations are rated among the few that satisfy human geroprotector criteria [5]. Epithalamin has been shown to promote the normalisation of estradiol, follicle stimulating hormone, and cortisol levels in climacteric women. Patients with non-insulin dependent diabetes mellitus show a decrease in blood glucose after the administration of Epithalamin. In oncology, Epithalamin is useful in treating patients having hormone-dependent tumours. Administration of this drug simultaneously with radio- and chemotherapy increases blood lymphocyte counts, improves the general conditions of patients, and mitigates intoxication symptoms. Administration of Epithalamin to elderly patients is accompanied by an increase in the total antioxidation activity of blood serum, decrease in lipid peroxidation products, and increases in superoxide dismutase and glutathione peroxidase activities.
Thymalin has been successfully used to treat patients after thymectomy and elderly patients with thymus involution (section 3.2).
Trials on the effectiveness of Cortexin (a complex peptide preparation from the cerebral cortex) in neurological practice have demonstrated its positive effects in elderly patients with brain dysfunctions caused by organic lesions of the brain and disturbed cerebral circulation (section 3.5).
Eyesight disorders are usual in ageing. The problem of a therapy for retinal degeneration is of an even greater general medical and social significance. The use of Retinalamin (a peptide preparation from the retina) in such cases has been shown to stimulate functions of photoreceptors and other cellular elements of the retina and promote the restoration of retinal photosensitivity. The drug normalises blood vessel permeability, diminishes manifestations of inflammation, and stimulates reparative processes in injured eye retina (section 3.3).
Treatment of patients with chronic prostatitis and benign hyperplasia (adenoma) of the prostate is among the most burning problems of present day geriatric urology and andrology. The use of Prostatilen, a polypeptide preparation from animal prostate, has been shown to reduce a number of symptoms of these diseases and improve male sexual performance (section 3.7).
Based on studies of cytomedins, a principally new approach to searching for physiologically active peptides and for their synthesis has been worked out. The approach implies the analysis of amino acid composition of complex polypeptide preparations, determination of the most prevalent amino acids in each preparation, and the design of primary structures of small peptides consisting of these amino acids (section 2.1.2). A technology for manufacturing of peptide regulators of thymus, brain, pineal gland, retina, and liver cells has been developed based on this approach.
Comparative studies of the biological activities of complex polypeptide preparations and respective synthetic peptides revealed parallelisms between their effects on various organs and tissues (Chapter 2). For example, Epitalon (Ala-Glu-Asp-Gly) as well as Epithalamin stimulates the pineal gland (section 2.3.5.3). It is remarkable that peptides designed on the basis of Epithalamin and Retinalamin compositions appear to be identical, which is consistent with the histogenetic kinship of respective organs and points at common mechanisms of their peptidergic regulation. Administration of Epitalon to rats with hereditary pigmental degeneration of the retina prolongs the integrity of its structure and functions (section 2.3.4.4). Another synthetic peptide, Vilon (Lys-Glu), designed on the basis of Thymalin, a thymic peptide extract, stimulates the expression of IL-2 gene in lymphocytes, which usually decreases with age (section 2.3.6). Intramuscular administration of Cortagen (Ala-Glu-Asp-Pro) designed on the basis of Cortexin amino acid composition stimulates the structural and functional restoration of damaged peripheral nerves (section 2.3.4.3).
During thirty years of studying the role of peptides in ageing and of developing peptide geroprotectors, 23 bioregulatory preparations have been invented. Six of them are included in the State Pharmacopeia of the Russian Federation and 17 are licensed in Russia as biologically active food supplements.
The major part of this book is dedicated to the description and analysis of the results obtained in studies of Cytomedins and synthetic peptides designed on their basis. In the most recent experiments, the latest technological developments of molecular biology were employed, such as DNA-microarray technique for studying the effects of synthetic peptides on gene expression (section 2.3.6). However, it is obvious that the more convincing proof of the heuristic potency of cytomedin concept is provided through generally recognised achievements of molecular biology, the greater is the necessity to find correlations between Cytomedin concept and established facts and concepts of regulatory peptide biology. Issues relevant to that problem will be considered in Chapter 1 of this book within a minimal scope consistent with the format of this publication.


Approval of Ethic Committee

Following standard pre-clinical and clinical studies, peptide bioregulators were approved for medical application by the USSR Ministry of Health (later on Russian Ministry of Health), whose competence covered observation of ethic norms in studying new medicine:
1. Thymalin – USSR Ministry of Health Instruction # 1008 of 10.11.1982 (Reg. # 82.1008.8)
2. Thymogen – USSR Ministry of Health Instruction # 250 of 19.06.1990 (Reg. # 90.250.1)
3. Epithalamin – USSR Ministry of Health Instruction # 250 of 19.06.1990 (Reg. # 90.250.6)
4. Prostatilen – Russian Ministry of Health Instruction # 329 of 17.12.1992 (Reg. # 92.329.7)
5. Cortexin – Russian Ministry of Health Instruction # 136 of 19.04.1999 (Reg. # 99.136.14)
6. Retinalamin – Russian Ministry of Health Instruction # 212 of 01.06.1999 (Reg. # 99.212.7)
Ethic committee at the Federal department of the drug quality, efficacy and safety control was established in Russia in 1998. Peptide Vilon was covered by the Ethic committee approval in 2001 (Protocol # 20 of 28.11.2001).

Prof. F.I. Komarov, M.D., Ph.D.
Chairman of the Ethic committee
Active member of the Russian Academy of
Medical Sciences


Vol. 23 Supplement 3 - Special Issue, 2002
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