October 25, 2002
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Neuroendocrinology Letters incl. Psychoneuroimmunology & Chronobiology

NEUROENDOCRINOLOGY LETTERS
including Psychoneuroimmunology, Neuro
psychopharmacology,
Reproductive Medicine, Chronobiology
and Human Ethology
ISSN 0172–780X

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Hard Cover Book
'Peptides and Ageing'
144 pages, with 30 Tables and 14 Figures

PEPTIDES AND AGEING
(Vladimir Kh. Khavinson)


The functions of cells, tissues, organs and the whole body are tuned by many means among which biologically active peptides occupy a special position. Peptides are protein-like molecules composed of a relatively small number of amino acids, usually within a dozen. However this is enough to provide for a great number of different amino acid combinations forming individual peptide species. Hundreds of biologically active peptides have been identified in human body and many still await identification. Each cell can produce several different peptides and respond to a whole array of peptide species. Altogether, this forms a tight regulatory network responding to subtle variations in body conditions and contributing to optimisation of body functions. Of course, biological regulation is performed not only by peptides but also by other signal molecules including low molecular weight neurotransmitters and hormones along with contacts of cells with other cells, in particular with neurons and their endings. However, these kinds of signals mediate commands for performing different body functions rather than their tuning, adjustment and maintenance. On the other hand, many pathological conditions are characterised by off-tuned functions. In particular, body tuning deteriorates in the course of ageing. So it is plausible that impairments in peptide production and action significantly contribute to what occurs in ageing.

The above is an approximate presentation of the line of reasoning that has lead to the development a number of clinically useful peptide preparations by a research team headed by Prof. V. Kh. Khavinson at the Saint-Petersburg Institute of Bioregulation and Gerontology in Russia. This work started more than thirty years ago when Dr. Khavinson asked whether is it possible to restore the functions of important body organs by peptide preparations obtained from these organs? He chose to work with the pineal gland and the thymus. This proved to be a happy choice since the pineal gland is currently believed to be the main organ adjusting neuroendocrine body functions to the diurnal rhythm, and the thymus is known to be the central organ of the immune system. A somewhat straightforward, as it may seem, this approach proved to be highly productive.

It soon has been found that Epithalamin, a peptide preparation from bovine epithalamus, the brain structure that comprises the pineal gland, improves impaired neuroendocrine functions in old female rats, in particular restores their reproductive functions, and also enhances immunity, and reduces the number of tumours, which can be explained by the known immunostimulating and anticancer activities of the pineal gland. Importantly, the lifespans of mice, rats, and even fruit flies treated with Epithalamin have been shown to significantly increase. Thymalin, a peptide preparation from the thymus, has also been found to stimulate immunity and inhibit carcinogenesis and to increase longevity in experimental animals. Both preparations have passed clinical tests and are now used to treat a number of age-associated diseases. In fact, trials carried out at the Institute of Gerontology of the Ukrainian Academy of Medical Sciences, which for decades has been engaged in testing putative geroprotectors, have shown that, apart from vitamin and micronutrient complexes, Thymalin and Epithalamin are among quite a few preparations satisfying the criteria of geroprotector means appropriate for human use.

The range of tissue-specific peptide preparations developed by V. Kh. Khavinson is not limited by the two above said ones and includes also Retinalamine, Prostatilen, and others designated after respective source organs and active in treating diseases of these organs. This series of complex peptide preparations is named Cytomedins. Further research has resulted in the development of an approach to designing of biologically active small peptides with defined structures basing on studies of the amino acid compositions of Cytomedins. The series of synthetic peptides is called Cytogens and includes tetrapeptides Epitalon, Cortagen, Livagen, and Prostamax, which are specific for the pineal gland, brain cortex, liver, and prostate, respectively, and dipeptides Thymogen and Vilon, which are specific for the thymus. Cytogens can reproduce many effects of respective Cytomedins. In particular, the tissue specificity of Cytogens has been demonstrated by their ability to stimulate the growth of the explants of respective tissues. A striking finding is that the structure of Epitalon is identical to that of the tetrapeptide constructed basing on the amino acid composition of Retinalamine. This probably reflects the common embryonic origin of the pineal gland and the eye retina. Correspondingly, Epitalon has been shown not only to restore diurnal rhythms of the activity of the pineal gland in aged rhesus monkeys and to reproduce the anti-ageing effects of Epithalamin but, also, to prolong the integrity of the visual functions in Campbell rats with a hereditary pigmental degeneration of the eye retina.

The whole story of Cytomedins and Cytogens is told in a book by Prof. V. Kh. Khavinson "Peptides and Ageing". The book presents many experimental and clinical data accumulated over three decades of studies of the peptide preparations. These results have been mostly published in Russian journals, and the book for the first time makes the whole body of the data available to an English-speaking reader. In the recent years, the work of V. Kh. Khavinson has focussed on studies of the mechanisms of action of Cytomedins and Cytogens using the latest methodological achievements including DNA-arrays for assessment of gene expression, a putative target of Cytomedins and Cytogens.
As follows from other published DNA-microarray studies of gene expression, genes involved in inflammation are upregulated in ageing, while those involved in energy production, cell proliferation control, and differentiated tissue functions show decreased expression. Noteworthy is that inflammation contributes to the two most significant age-related pathologies in humans, i.e., atherosclerosis and Alzheimer's disease. The predisposition to inflammatory disorders results, to a significant extent, from immune imbalances involving decreased specific T-mediated immune reactions. Such decrease also compromises body resistance to infections and cancer. Indeed, their prevalence is known to increase with advancing age. Another factor of cancer development in ageing is a compromised stringency of control over cell proliferation and differentiation, which not only promotes tumour growth but, also, impairs cell homeostasis, regeneration, and functions of normal tissues. The latter are contributed to by impaired energy production by mitochondria. Impaired mitochondrial functions are also fraught with increased reactive oxygen species generation, which cause tissue damage, cancer, atherosclerosis, and age-related neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. Among changes in differentiated tissue function, the most important for ageing are those involving endocrine glands as far as they affect many body systems controlled by respective hormones.

The comparison of the effects observed in experiments with and clinical use of Cytomedins and Cytogens with the known age-related changes in humans and animals makes it clear that many of the effects counteract many of the changes.
With regard to inflammation, noteworthy is that clinical effects of Cytomedins consistently include manifestations of their anti-inflammatory activity. Cytomedins appear to be efficient in pathological conditions in which inflammation is important. This activity is featured not only by peptide preparations that are derived from tissues referred to the immune system and thus are the first to be anticipated to normalise immune functions including those involved in control of inflammation. It is shared by virtually all Cytomedins irrespective of the tissues of their origin. One reason of such nonspecific effects of Cytomedins may be that they contain components derived from the blood, vasculature, and resident immunocompetent cells present in body tissues.
At the same time, Cytomedins contain constituents that are responsible for tissue-specific effects. Such tissue specificity is most clearly demonstrated by the ability of Cytomedins to specifically affect respective tissue explants. However, these effects, while being specific with regard to the relationships between tissues and peptide preparations are non-specific with regard to their manifestations, which relate only to the growth characteristics of tissue explants. The functional specificity of influences of Cytomedins on the tissues of their origin is seen from experiments performed in vivo and from clinical observations.

Thymalin is most active toward immune functions. Epithalamin stimulates pineal gland functions. Cortexin is active in stimulating CNS functions. Retinalamin is efficient in treating eye diseases. In all these cases, the final effects, especially the clinical ones, are likely to be produced by concerted non-specific and specific activities of Cytomedins. The latter activities underlie many systemic consequences of using Cytomedins in vivo. For example, many in vivo effects of Epithalamin are most likely mediated by its ability to stimulate the secretion of melatonin and, possibly, other products by the pineal gland. Melatonin is known to enhance antioxidant defences, to be an antioxidant per se, to be involved in regulation of reproductive functions, to suppress some tumours, especially hormone-dependent ones, and to affect mitochondrial functions. All these effects have been demonstrated in experiments with Epithalamin and Epitalon. Effects of Thymalin include suppression of tumour growth, which is most likely mediated by the stimulation of anticancer immune reactions. However, the direct effects of Thymalin on tumours are also possible because a dipeptide Glu-Trp (Thymogen) isolated from Thymalin has been demonstrated to be antiangiogenic.

Many questions concerning the mechanisms, by which Cytomedins and Cytogens render their effects, remain unanswered. However, it is essential for the progress of science to put right questions. Hopefully, the questions that follow form the results described in the book "Peptides and Ageing" are the right ones.

On the whole, the book may be useful for both, clinicians and biomedical researchers. For the former, it may suggest novel approaches to widespread clinical problems. For the latter, it provides challenges that can drive further research in the fields of biologically active peptides and the biology of ageing.

Table of Contents HERE

Released in October
Vol. 23 Supplement 3 - Special Issue, 2002
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