Short Peptides Regulate Gene Expression, Protein Synthesis and Enhance Life Span

There is accumulated evidence that many of the so-called “diseases of ageing”, including cancer, are caused by dysregulated immune functions and decreased organism resistance to infections.

Peptide extracts of thymus and peptides isolated from thymus were the first preparations proposed for correction of immunodeficiency.
The origin of short regulatory peptides in the organism became obvious after the discovery of protein degradation in proteasomes.
The same high-molecular proteins can be differentially hydrolyzed resulting in various short peptides. The peptides produced show different biological functions as compared to the original macromolecules. Karlin and Altschul demonstrated in their work that protein macromolecules contain several types of recurrent blocks of amino-acid residues with charged side chains. Such blocks are mostly observed in nucleoproteins. Among them, there are transcription factors, centromere proteins and high mobility group.

Proteasome hydrolysis of these nucleoproteins can provide a sufficient amount of peptides with charged side chains. These and some other investigations gave rise to the development of the peptide bioregulation concept. This concept suggests that low-molecular peptides are involved in an intercellular transfer of information encoded in the amino acid sequence and conformation modifications, thus facilitating regulation of proliferation, differentiation and intercellular interaction. Peptide bioregulators were isolated from different tissues. Their major function consists of normalizing the functions of the organs from which they have been isolated. They can also substitute and/or complement biologically active compounds secreted in this morphological structure.8 Apart from immunity dysregulation, aging causes other alterations on the cellular level, for example, accumulation of mutations in somatic cells.

Although the rate of accumulation of age-specific changes is determined genetically, there are a number of exogenous factors that accelerate this process. Oxidative stress is considered to induce both cell and body aging. Proteins and DNA are known to be damaged by reactive oxygen species (ROS). There is substantial evidence of the role of DNA oxidative damage in organismal senescence. Aging-associated accumulation of somatic mutations is accompanied by the decreasing of DNA repair level, which leads to growing incidence of pathologies including cancer.

Higher concentration of damages in heterochromatin regions as compared to active (euchromatic) regions of the DNA can be explained by the fact that reparation can occur only in the DNA regions that are involved in active transcription and are accessible for reparation enzymes. This corresponds to intensive DNA reparative synthesis in the G2 cycle with more active chromosome heterochromatinization, as compared to in the G1 cycle.17 The frequency of sister chromatid exchanges (SCE) confirms age-related reduction of reparation level. The SCE level in fibroblasts and lymphocytes of the elderly (60–70 y.o.) was found to be lower than that of the younger donors (30–40 y.o.), regardless of their gender.

Thus chromosome heterochromatinization and related decrease in the DNA reparation intensity is considered to be a key factor in organismal aging. Various experimental models have been used for studying preparations with a protective effect against aging and carcinogenesis. In several animal studies, short peptides were demonstrated to be promising in anti-aging medicine. Their neuroprotective and anticarcinogenic effects are believed to be mediated by their immunomodulatory and antioxidative properties.

The peptides were shown to lead to the reduction of the level of age-related chromosome aberrations (ChA) and to affect the chromosome heterochromatinization,19 thus retarding the ageing process. They can influence the expression of various genes, which is determined by specific short peptides–DNA binding. Safety of long-term administration is one of the main advantages of peptide therapy. These properties make them promising candidates for clinical application in old and senile patients. Further investigation of peptide bioregulators appears to be very perspective in modern gerontology, bearing in mind their capacity to inhibit senescence and restore functions of the aging organism.

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