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
Neuroendocrinology Letters www.nel.edu
More
information available: publisher@nel.edu
