Epitalon (Epithalon, Epitalon, AGAG, AE-0 peptide, AEDG, CAS 307297-39-8) is a synthetic pineal tetrapeptide, a telomerase activator and a potential anti-aging drug developed at the St. Petersburg Institute of Bioregulation and Gerontology by the research team led by prof. V. H. Havinson, a corresponding member of the RAS [1, 2]. The peptide was synthesized by directed engineering based on the amino acid analysis of epithalamin (a pineal gland preparation, a bioregulator of the neuroendocrine system, which is the sum of peptides isolated from the epithalamus-epiphysis region of the bovine brain) and has the following sequence: Ala-Glu-Asp-Gly.
According to the study of human fibroblast cell cultures in vitro, the biological activity of epitalon is based on the induction of telomere elongation by increasing the telomerase activity in human somatic cells [3]. The elongation of telomeres by epitalon is sufficient to exceed the Hayflick limit (the number of somatic cell divisions in a cell culture is limited to 50 divisions as telomeres of the DNA molecule shorten with each cell division). In a cell culture of human fetal fibroblast cells, their proliferative potential extended from 34 passages in the control cell population to more than 44 passages in the treated cell population with the length of telomeres increased to levels comparable to those in the original cell culture [4]. In the aging skin fibroblasts in vitro, epitalon inhibits the synthesis of MMP-9 protein associated with numerous pathological processes, including cancer, placental malaria, immunological and cardiovascular diseases [4]. In cultured lymphocytes extracted from samples collected from elderly people aged 76 to 80 years, epitalon induces decondensation of heterochromatin by activation thereof and prompts the activation of ribosomal genes and the release of genes repressed due to the age-related condensation of euchromatic chromosome regions [5]. Epitalon is supposed to be involved in regulation of the CCL11 and HMGB1 genes as an activator of their expression, and this probably underlies its geroprotective effect. It should be noted that since epitalon has affinity to the binding sites in the promoter regions of the CCL11 and HMGB1 genes, it can epigenetically slow the aging processes, significantly delay manifestation of atherosclerosis and associated cardiovascular diseases, and considerably improve cognitive functions in individuals of all ages [6].
Animal studies showed the effect of epitalon on lifespan and development of spontaneous tumors in female rats exposed to standard and constant lighting, typical for the North-West of Russia. In control group of animals exposed to constant or natural lighting, the average and the maximum lifespans decreased by 13.5 and 25.5 % and by 9 and 7 months, respectively, and spontaneous tumors developed much faster than in animals under a standard lighting regime. Epitalon (0.1 μg daily 5 times a week starting from 4 months of age) did not alter the lifespan of rats under a standard day/night regimen, while in rats exposed to natural and constant lighting, it prolonged the maximum lifespan by 95 and 24 days, respectively. The average lifespan of these rats increased by 10 %, i. e., 137 and 43 days, respectively. The tetrapeptide significantly inhibited the development of spontaneous tumors in rats exposed to natural light [7]. An in vivo study in aging mice demonstrated that epitalon treatment significantly reduces the incidence of chromosome aberrations which may be associated with carcinogenesis in both wild-type mice and those with an accelerated aging phenotype, which is consistent with elongation of telomeres [8]. In clinical studies in humans, epitalon and epithalamin both significantly increased telomere lengths in the blood cells of patients aged 60–65 and 75–80 years, and their efficacy was comparable to one another. Moreover, it was found that the addition of epitalon to the culture medium of human lung fibroblasts induces the expression of the telomerase gene and elongates telomeres by a factor of 2.4 [9]. Activation of gene expression was accompanied by an increase in the number of cell divisions of 42.5 %. This fully correlates with a previously reported maximum increase in lifespan of animals of 42.3 % following the administration of this peptide [9]. Epitalon reduced the number of spontaneous tumors and the number of metastases in mice in an experiment with one-year-old female C3/He mice, suggesting that this peptide has oncostatic and anti-metastatic activities [10]. Epitalon and pineal gland peptides were found to be potential inhibitors of carcinogenesis in breast cancer [11].
Another study in aging rats showed that epitalon enhanced the activity of the antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase [12]. In an experiment in hypophysectomized chickens, epitalon demonstrated regenerative effects and, in subsequent maturation of birds, it contributed to the restoration of morphological structures of the thymus gland [13], as well as the structure and function of the thyroid gland [14]. Also, epitalon increases the proliferation of lymphocytes in the thymus, presumably increasing the production of interferon gamma by T-cells [14].
Epitalon and epithalamin restore the melatonin secretion by the pineal gland in both aged monkeys and humans [12, 15]. Two groups of 15 young (20–34 years old) and 49 elderly (60–79 years old) patients received intramuscular injections of epitalon at a dose of 10 mg in 2 mL of saline once every 3 days in a course of five or ten injections. At a course dose of 0.1 mg, epitalon affects the nocturnal production of melatonin, and its effect is comparable to the administration of epithalamin at a course dose of 50 mg, which, based on their dosage ratio of 1:500, indicates a significantly greater biological activity of epitalon [15]. It should be noted that the study of the effect of epitalon on circadian rhythms, model-disrupted upon a single injection of 1,2-dimethylhydrazine, showed the restoration of typical circadian rhythms in the hypothalamic content of dopamine and norepinephrine [16].
A clinical study in humans (162 patients, 18–72 years old, parabulbar injections of 5 μg/eye/day for 10 days) conducted in selected patients with retinitis pigmentosa, demonstrated the clinical benefit of epitalon in 90 % of cases in treated patients [17].
In a clinical trial in patients with pulmonary tuberculosis, epitalon did not correct pre-existing structural chromosome aberrations associated with telomere degradation, but exerted a protective effect against the future development of additional chromosome aberrations that may be associated with a high incidence of recurrent TB [18]. In another study, epigenetic genome variations were studied using lymphocyte cultures from patients with primary drug-susceptible pulmonary tuberculosis before and after exposure to 0.01 μg/mL of epithalon, which corresponds to a single therapeutic dose. The level of heterochromatin decreased in the telomeric regions of chromosomes (high in the control) and increased in the middle regions of chromosomes (reduced in the control). As a result, the ability of epitalon to normalize altered genome parameters in patients with TB was revealed. The bioregulator can be used both to determine the effectiveness of treatment and to develop new treatments for TB [19].
Therefore, based on the known data, it is clear that epitalon is a very promising drug for the treatment of a number of serious diseases, including pulmonary tuberculosis and some types of cancer. Also, epitalon exhibits pronounced anti-aging properties and can significantly improve the quality of life of elderly patients. This effective bioregulator with a wide spectrum of biological activity and low toxicity can become more widely used and requires further clinical studies.
- Khavinson, V. K., Izmaylov, D. M., Obukhova, L. K., Malinin, V. V., Effect of epitalon on the lifespan increase in Drosophila melanogaster. Mechanisms of Ageing and Development, 2000. 120(1): p. 141-149. doi: https://doi.org/10.1016/S0047-6374(00)00217-7
- Анисимов, В. Н., Средства профилактики преждевременного старения (геропротекторы). Успехи геронтологии, 2000. 4: p. 275-7.
- Khavinson, V. K., Bondarev, I. E., Butyugov, A. A., Epithalon Peptide Induces Telomerase Activity and Telomere Elongation in Human Somatic Cells.Bulletin of Experimental Biology and Medicine, 2003. 135(6): p. 590-592. doi: 10.1023/A:1025493705728
- Lin’kova, N. S., Drobintseva, A. O., Orlova, O. A., Kuznetsova, E. P., Polyakova, V. O., Kvetnoy, I. M., Khavinson, V. K., Peptide Regulation of Skin Fibroblast Functions during Their Aging In Vitro. Bulletin of Experimental Biology and Medicine, 2016. 161(1): p. 175-178. doi: 10.1007/s10517-016-3370-x
- Khavinson, V. K., Lezhava, T. A., Monaselidze, J. R., Jokhadze, T. A., Dvalishvili, N. A., Bablishvili, N. K., Trofimova, S. V., Peptide Epitalon activates chromatin at the old age. Neuro endocrinology letters, 2003. 24(5): p. 329-333.
- Khavinson, V. K., Kuznik, B. I., Tarnovskaya, S. I., Linkova, N. S., Peptides and CCL11 and HMGB1 as molecular markers of aging: Literature review and own data. Advances in Gerontology, 2015. 5(3): p. 133-140. doi: 10.1134/S2079057015030078
- Vinogradova, I. A., Bukalev, A. V., Zabezhinski, M. A., Semenchenko, A. V., Khavinson, V. K., Anisimov, V. N., Effect of Ala-Glu-Asp-Gly peptide on life span and development of spontaneous tumors in female rats exposed to different illumination regimes. Bulletin of Experimental Biology and Medicine, 2007. 144(6): p. 825-830. doi: 10.1007/s10517-007-0441-z
- Rosenfeld, S. V., Togo, E. F., Mikheev, V. S., Popovich, I. G., Zabezhinskii, M. A., Khavinson, V. K., Anisimov, V. N., Effect of Epithalon on the Incidence of Chromosome Aberrations in Senescence-Accelerated Mice. Bulletin of Experimental Biology and Medicine, 2002. 133(3): p. 274-276. Rosenfeld2002. doi: 10.1023/a:1015899003974
- Anisimov, V. N., Khavinson, V. K., Mikhailova, O. N., Biogerontology in Russia: from past to future. Biogerontology, 2011. 12(1): p. 47-60. doi: 10.1007/s10522-010-9307-2
- Kossoy, G., Anisimov, V. N., Ben-Hur, H., Kossoy, N., Zusman, I., Effect of the Synthetic Pineal Peptide Epitalon on Spontaneous Carcinogenesis in Female C3H/He Mice. In Vivo, 2006. 20(2): p. 253-257.
- Bilski, B., Rzymski, P., Tomczyk, K., Rzymska, I., The impact of factors in work environment (especially shift and night work) on neoplasia of female reproductive organs. Journal of Medical Science, 2016. 84(4): p. 223-228.
- Kozina, L. S., Arutjunyan, A. V., Khavinson, V. K., Antioxidant properties of geroprotective peptides of the pineal gland. Archives of Gerontology and Geriatrics, 2007. 44: p. 213-216. doi: 10.1016/j.archger.2007.01.029
- Pateyk, A. V., Baranchugova, L. M., Rusaeva, N. S., Obydenko, V. I., Kuznik, B. I., Effect of Peptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly on the Morphology of the Thymus in Hypophysectomized Young and Old Birds. Bulletin of Experimental Biology and Medicine, 2013. 154(5): p. 681-685. doi: 10.1007/s10517-013-2029-0
- Линькова, Н. С., Кузник, Б. И., Хавинсон, В. Х., Пептид Ala-Glu-Asp-Gly и интерферон гамма: роль в иммунном ответе при старении. Успехи геронтологии, 2012. 25(3): p. 478-482.
- Коркушко, О. В., Лапин, Б. А., Гончарова, Н. Д., Хавинсон, В. Х., Шатило, В. Б., Венгерин, А. А., Антонюк-Щеглова, И. А., Магдич, Л. В., Нормализующее влияние пептидов эпифиза на суточный ритм мелатонина у старых обезьян и людей пожилого возраста. Успехи геронтологии, 2007. 20(1): p. 74-85.
- Korenevsky, A., Milyutina, Y., Kozina, L., Arutjunyan, A., Role of Reactive Oxygen Species in Premature Ageing of the Female Reproductive Function.Current aging science, 2016. 09. doi: 10.2174/1874609809666161006111645
- Khavinson, V., Razumovsky, M., Trofimova, S., Grigorian, R., Razumovskaya, A., Pineal-regulating tetrapeptide epitalon improves eye retina condition in retinitis pigmentosa. Neuroendocrinology Letters, 2002. 23(4): p. 365-369.
- Dzhokhadze, T. A., Buadze, T., Rubanov, K. D., Kiriia, N. A., Lezhava, T. A., [Genome instability in pulmonary tuberculosis before and after treatment].Georgian medical news, 2013(224): p. 77-81.
- Lezhava, T., Buadze, T., Jokhadze, T., Monaselidze, J., Gaiozishvili, M., Rubanovi, K., Kiria, N., Normalization of Epigenetic Change in the Genome by Peptide Bioregulator (Ala–Glu–Asp–Gly) in Pulmonary Tuberculosis. International Journal of Peptide Research and Therapeutics, 2019. 25(2): p. 555-563. doi: 10.1007/s10989-018-9699-4
