Article by Dr. Rosario Perona. Biomedical Researcher at the Institute of Biomedical Research (CSIC).
The GSE4 peptide increases the ability of cells to divide, as well as the elongation of telomeres, preventing their natural shortening as we age.
Telomeres, the protective ends of our chromosomes, represent a biological clock. At birth we have about 12,000 base pairs in these structures and they are progressively lost and shortened with age as we grow older. This process is common to all tissues in the body, but is especially relevant in tissues that are renewed more frequently, such as the skin.
There is an enzyme complex responsible for telomere repair, called the telomerase complex, in which the TERT, dyskerin and TR RNA proteins play a fundamental role. However, the vast majority of cells in our body lose telomerase activity, with the exception of germ cells and stem cells, which maintain the functionality of the complex and therefore the length of their telomeres.
In many tissues, stem cells also progressively lose telomerase activity and thus the ability to maintain tissue renewal, which is one of the main causes of ageing.
Dyskerin is one of the 3 subunits of the telomerase complex. The GSE4 peptide corresponds to an internal sequence of dyskerin and has the ability to partially reverse the inactivation of the telomerase complex. The activity of this peptide has been studied using different models of healthy cells and cells derived from various patients who have an altered cellular process, with accelerated ageing. The diseases that afflict them are due to the presence of mutations in genes encoding proteins of the telomerase complex or involved in other processes of telomere repair and maintenance.
The peptide GSE4 increases telomerase activity in cells with decreased telomerase activity by increasing the expression of the TERT gene, which is the subunit that cells lose in the ageing process.
In addition to telomere shortening, during ageing the cells of the organism acquire certain alterations such as an increase in genetic damage or an increase in the presence of reactive oxygen species, i.e. increased oxidation. In organisms, there is also an increase in inflammatory processes during ageing, a decrease in the capacity for tissue repair and cell growth, and a deficit in the production of connective tissue.
We have found that administration of the GSE4 peptide decreases genetic damage by increasing the ability of cells to repair such damage. In particular, we have observed that GSE4 stimulates the signalling pathways for genetic damage, which constitute the initial phase of DNA repair processes. In terms of oxidative damage, GSE4 increases the levels of cellular antioxidant enzymes such as superoxide dismutases 1 and 2 and catalase. As a result, it decreases the amount of reactive oxygen species, which contribute to the oxidation of DNA and other molecules in cells that accelerate tissue ageing. In addition, when faced with stimuli that increase cellular oxidation, GSE4 increases the cells’ capacity to neutralise them.
The GSE4 peptide increases the ability of cells to divide, as well as the elongation of telomeres, preventing their natural shortening as we age.
During ageing, as a consequence of increased oxidative damage, cells increase the secretion of cytokines that cause inflammation and activate the process of cellular senescence. As a consequence of this stress and inflammation, the ability of cells to divide and thus to repair tissues decreases.
We have observed that GSE4, due to its inhibitory effect on the oxidative process, in turn reduces the secretion of pro-inflammatory cytokines, thus attenuating the inflammation associated with oxidative damage. As a consequence, a decrease in cellular senescence and an increase in DNA synthesis is observed, which is reflected in an increase in the ability of cells to divide, as well as an elongation of telomeres. CAP peptide 5 shares sequence homology with the GSE4 peptide and acts on the same physiological targets, offering the benefits described above on ageing.
As a conclusion of all these trials, it could be said that GSE4 has an anti-ageing effect because it is capable of modifying various cellular parameters at different levels.
The different studies we have carried out indicate that the activity of GSE4 acts on these pathways in a synergistic way and the net result is an increase in cell viability in the face of different external insults and, therefore, a delay in tissue ageing. These beneficial effects may have an impact on improving the health of patients with the accelerated ageing mentioned above. In these patients, some organs such as the lungs or bone marrow are seriously affected, but there are also important symptoms in epidermal tissues such as the skin or the mucous membranes of the digestive system. In addition, this peptide can help to slow down some of the physiological effects derived from the natural ageing of the different tissues and organs that make up our organism.
References
GSE4, a Small Dyskerin- and GSE24.2-Related Peptide, Induces Telomerase Activity, Cell Proliferation and Reduces DNA Damage, Oxidative Stress and Cell Senescence in Dyskerin Mutant Cells.
Iarriccio L, Manguán-García C, Pintado-Berninches L, Mancheño JM, Molina A, Perona R, Sastre L. PLoS One. 2015 Nov 16;10(11):e0142980. doi: 10.1371/journal.pone.0142980. eCollection 2015.
Perona R., Iarriccio L., Pintado-Berninches L., Rodriguez-Centeno J., Manguan-Garcia C., Garcia E., Lopez-Ayllón B., Sastre L. Molecular Diagnosis and Precision Therapeutic Approaches for Telomere Biology Disorders. In Telomeres a complex end of the chromosome. Ed. M. Larramendy and S. Soloneski. INTECH, ISBN 978-953-51-4609-4. P 77-117.
