Epitalon Research
The short-peptide epithalon has been shown to promote proliferation of lymphocytes from the thymus during aging. This is important, as declining expression of lymphocyte interferon gamma is tightly implicated with decreasing immune function in the elderly. It is specifically postulated that epithalon can increase lymphocyte interferon gamma production, thus improving immune function in the elderly. [1]
Rat studies have shown benefit for premature aging when epithalon was combined with melatonin. Specifically the Russian scientists Korenevsky, et al, studied estrogen cycles in young, mature, and aging female rats in light polluted environments (eg, little darkness, which is typically necessary for melatonin production). Using a combination of epithalon and melatonin they were able to stabilize and correct a variety of impairments of the hypothalamic-pituitary-gonadal (HPG) axis, which specifically overcame adverse environmental influences. [2] This is particularly important to consider given the urban human environment, as some studies have shown light pollution to increase cancer risks. [3, 4, 5]
A summary analysis of available rodent research was written by Anisimov VN, discussing the known effects of shift work, and prolonged light exposure on rats and their development of breast cancer. The study further commented on the same findings in human flight attendants, night shift workers, and on decreased risk in blind women, all in accordance with rat experiments. Treatment with epithalon has been shown to reduce cancer risks in rats, and the article commented on how this might be useful in human women for reduction in breast cancer risk. [6]
An interesting theory of aging has been put forth by Khavinson VKh, that involves epithalon. The idea is that aging is an evolution-determined biological process of changes in expression of genes, which result in impaired synthesis of regulatory chemicals, provoking change and development of disease. Given the Hayflick limit (the number of times a cell line can divide prior to its limitations and demise), and the known telomere-lengthening effects of epithalon, it is thought that the administration of the peptide may overcome these genetic limitations, and promote normalized body functions, that is, extend healthy life. [7]
Epithalamin (precursor to epithalon), was shown to stimulate neurites in cultured chick embryonic cortical and subcortical brain structures, and on dorsal root ganglion structures in culture. It is suggested that epithalamin stimulates growth of brain and spinal nerves. [8]
Clinical Studies with Epithalon (epitalon)
Memory disorders have been studied in rats as well, with epithalon showing substantial decrease in extent of memory disorders in old rats undergoing standardized maze testing. [9]
Female mice were studied for spontaneous tumorigenesis (cancer development) under lab conditions. Epithalon was given to the experiment group 5 days a week in small doses (0.1 microgram). Long term use of epithalon showed no toxic effects. Additionally the treatment group decreased the number and severity of cancers, and those that did develop cancers had no metastases. This highlights the anti-metastatic effect of epithalon. [10]
Kozina, et al, studied various antioxidant agents including superoxide dismutase (SOD), glutathione peroxidase, melatonin, and others, as well as epithalon, to evaluate mechanisms of action. Epithalon was found to have potentially more benefit than melatonin, already known to have quite potent antioxidant function, and it also stimulates expression of SOD, ceruloplasmin, and other antioxidant enzymes. The experiment showed various benefits of pineal peptides for protection against aging, including epithalon. [11]
Female rhesus monkeys were studied for glucose tolerance and insulin values in response to a glucose load. Epithalon corrected the age-related decrease in glucose tolerance and restored the dynamics of insulin levels in response to glucose. [12]
Rats with hereditary pigmentary retinal degeneration were studied, establishing epithalon protected the retina and improved its function compared to control rats. [13]
Drosophila melanogaster (common fruit fly) was exposed to epithalon during the developmental stage (egg to larva). Epithalon exposed flies had an increased lifespan from 11-16% when applied at extremely low concentrations (as low as .001 x 10-6 wt% of culture medium). Of interest, the increase in lifespan did not depend on the dose of epithalon. [14]
Retinitis Pigmentosa was studied in rats with a positive improvement in 90% of the test subjects. [15]
Epithalamin, a precursor of epithalon, was found to stimulate effect on melatonin synthesis in elderly people. This resulted in deeper sleep. [16] Melatonin supplementation and increased levels have been shown to improve complications with Alzhemiers disease, amyotrophic lateral sclerosis, jet lag, and nocturnal hypertension. [17]
Korkushko, et al, studied epithalamin in patients with coronary artery disease over a 15-year period. Over three years the study group of 39 patients received 6 courses of epithalamin, a precursor to epithalon. Physical endurance, melatonin production, and carbohydrate and lipid metabolism were all better in the study group than the control group. Significantly lower mortality was seen in the study group than in the control group over a 15-year followup period. [18]
Further cardiovascular research has shown that elderly women treated with epithalamin show improved lipid metabolism, and reductions in arterial blood pressure, both of which contribute to decreased overall cardiovascular risks. [19]
Primate studies have shown benefit in the use of epithalon for diabetes. Gonchorova, et al, studied the levels of glucose, insulin, and melatonin in older rhesus monkeys (20-27 years) and compared them to younger monkeys (6-8 years). Epithalon administration had little effect on the younger monkeys, but had substantial improvement in the elevated levels of glucose and insulin, as well as lower levels of melatonin, in older primates. [20] This has particular importance specifically in Type 2 Diabetes, as elevated insulin and resistance to insulin are diagnostic keys to the disease in humans; improving insulin resistance is of significance to improving the disease process.
Additional diabetes studies, specifically into diabetic retinopathy when combined with retinalamine. The combined administration completely restored antioxidant activity and lipid hydroperoxide levels in the patients. The pair were recommended by the investigators for correcting pathological changes to the retina in diabetic patients. [21]
Russian investigators in a multi-center trial state that epithalamin, a precursor to epithalon, can extend life. Khavinson and Morozof show in their 2003 study that elderly patients who were treated for 2-3 years with epithalamin, thymalin, or a combination of both, and then followed for 6-8 years, had substantial decreases in respiratory diseases, ischemic heart disease, hypertension, osteoarthritis, osteoporosis. An additional group underwent combined treatment annually for 6 years and decreased their mortality by 4.1 times relative to the control group. To quote the study, “The combined data confirmed the high geroprotective efficacy of Thymalin and Epithalamin and the expediency of their application in medicine and social care for health maintenance and age-related pathology prevention in persons over 60 to prolong their active longevity.” [22]
Epithalamin was shown to improve functional stability and quality of cardiovascular and cerebrovascular system regulation, showing improvement in hemodynamic parameters in the patients treated. [23]
100 women with locally advanced cervical carcinoma were enrolled in a study comparing traditional radiation therapy alone (control group), to combined treatment with chemotherapy and radiation therapy, with epithalamin. Dosing was epithalamin 100mg IM, 5-fluorouracil 2g/m2 and displatin 100mg/m2 IVas standard chemotherapy protocol. The study group showed short-term improvement in tumor size of 18.8%, with study end reduction of 14%. One-year survival was 25.4% better than control, and three-year survival was 12.5% better. [24]
A 1998 study on non-insulin dependent diabetics (type 2 diabetics) with epithalamin was performed to evaluate carbohydrate metabolism and cardiac function in the same study. Carbohydrate metabolism was improved, dropping hemoglobin A1C (a three-month averaging test to evaluate diabetes progress), and improving insulin sensitivity. Additionally blood pressure was shown to improve, and left ventricular diastolic function improved (improving a specific finding of heart failure). [25]
Further study into human aging with epithalamin was published in 2006. The 12-year study was carried out with elderly patients with coronary artery disease. The patients were treated every six months for 3 years, and then received repeat treatment in years 5, 8, 10 and 12. The patients received 10mg by intramuscular injection daily for 5 days for each course of treatment, resulting in 100mg annually, or 300mg for the entirety of the first three years. All doses took place at 10am, as this produced best melatonin response in the evening. All patients also received standardized treatment including aspirin, long-acting nitrates, beta-blockers and/or ACE-inhibitors. Functional age of the treated patients decreased by 3.2 +/- 1.5 years. Subsequent treatment courses promoted stabilization of this effect. Cardiovascular mortality was 50% lower in the treatment group than in the control group at the end of 12 years. [26]
References
1 - Adv Gerontol. 2012;25(3):478-82. [Peptide Ala-Glu-Asp-Gly and interferon gamma: their role in immune response during aging]. [Article in Russian] Lin'kova NS, Kuznik BI, Khavinson VKh.
2 - Adv Gerontol. 2013;26(2):263-274. [Protective effect of melatonin and epithalon on hypothalamic regulation of reproduction in female rats in its premature aging model and on estrous cycles in senescent animals in various lighting regimes]. [Article in Russian; Abstract available in Russian from the publisher] Korenevsky AV1, Milyutina YP1, Bukalyov AV2, Baranova YP2, Vinogradova IA2, Arutjunyan AV1.
3 - J Basic Clin Physiol Pharmacol. 2017 Jul 26;28(4):295-313. doi: 10.1515/jbcpp-2016-0116. Artificial light-at-night - a novel lifestyle risk factor for metabolic disorder and cancer morbidity. Zubidat AE1, Haim A1.
4 - Chronobiol Int. 2017;34(2):203-211. doi: 10.1080/07420528.2016.1259241. Epub 2016 Dec 20. The association between artificial light at night and prostate cancer in Gwangju City and South Jeolla Province of South Korea. Kim KY1, Lee E2, Kim YJ2, Kim J2.
5 - Integr Cancer Ther. 2017 Dec;16(4):451-463. doi: 10.1177/1534735416678983. Epub 2016 Nov 29. Illuminating a Risk for Breast Cancer: A Preliminary Ecological Study on the Association Between Streetlight and Breast Cancer. Keshet-Sitton A1, Or-Chen K1, Huber E1, Haim A1.
6 - Crit Rev Oncol Hematol. 2003 Jun;46(3):221-34. The role of pineal gland in breast cancer development.Anisimov VN1.
7 - Neuro Endocrinol Lett. 2002;23 Suppl 3:11-144. Peptides and Ageing. Khavinson VKh1.
8 - Neurosci Behav Physiol. 2000 May-Jun;30(3):261-5. Studies of cytokines in nerve tissue cultures. Chalisova NI1, Khavinson VK.
9 - Eksp Klin Farmakol. 2006 Nov-Dec;69(6):13-6. [Comparative study of the effects of melatonin and epitalon on the protracted memory under the shuttle labyrinth test conditions in rats in the course of aging]. [Article in Russian] Vinogradova IA.
10 - In Vivo. 2006 Mar-Apr;20(2):253-7. Effect of the synthetic pineal peptide epitalon on spontaneous carcinogenesis in female C3H/He mice. Kossoy G1, Anisimov VN, Ben-Hur H, Kossoy N, Zusman I.
11 - Arch Gerontol Geriatr. 2007;44 Suppl 1:213-6. Antioxidant properties of geroprotective peptides of the pineal gland. Kozina LS1, Arutjunyan AV, Khavinson VKh.
12 - Bull Exp Biol Med. 2004 Jul;138(1):80-3. Peptide correction of age-related hormonal dysfunction of the pancreas in monkeys. Goncharova ND1, Vengerin AA, Khavinson VKh, Lapin BA.
13 - Bull Exp Biol Med. 2002 Jan;133(1):87-9. Effect of epithalon on age-specific changes in the retina in rats with hereditary pigmentary dystrophy. Khavinson VKh1, Razumovskii MI, Trofimova SV, Grigor'yan RA, Chaban TV, Oleinik TL, Razumovskaya AM.
14 - Mech Ageing Dev. 2000 Dec 1;120(1-3):141-9. Effect of epitalon on the lifespan increase in Drosophila melanogaster. Khavinson VK1, Izmaylov DM, Obukhova LK, Malinin VV.
15 - Neuro Endocrinol Lett. 2002 Aug;23(4):365-8. Pineal-regulating tetrapeptide epitalon improves eye retina condition in retinitis pigmentosa. Khavinson V1, Razumovsky M, Trofimova S, Grigorian R, Razumovskaya A.
16 – Adv Gerontol. 2017;30(3):422-426. [Pineamin increased pineal melatonin synthesis in elderly people]. [Article in Russian; Abstract available in Russian from the publisher]
Trofimova SV1, Linkova NS1,2, Klimenko AA3, Kvetnaia TV1, Khavinson VK1,4.
17 – https://nccih.nih.gov/health/melatonin#hed3
18 - Bull Exp Biol Med. 2011 Jul;151(3):366-9. Peptide geroprotector from the pituitary gland inhibits rapid aging of elderly people: results of 15-year follow-up. [Article in English, Russian] Korkushko OV1, Khavinson VKh, Shatilo VB, Antonyk-Sheglova IA.
19 - Adv Gerontol. 2008;21(1):132-42. [Effect of the pineal gland peptide preparation on the diurnal profile of arterial pressure in middle-aged and elderly women with ischemic heart disease and arterial hypertension]. [Article in Russian] Merkur'eva GA, Ryzhak GA.
20 - Exp Gerontol. 2005 Jan-Feb;40(1-2):51-7. Pineal peptides restore the age-related disturbances in hormonal functions of the pineal gland and the pancreas. Goncharova ND1, Vengerin AA, Khavinson VKh, Lapin BA.
21 - Eksp Klin Farmakol. 2004 Sep-Oct;67(5):60-2. [The effect of cytomedines on the hemostatic and antioxidant potential of patients in the early stage of diabetic retinopathy].
[Article in Russian] Gavrilova NA, Fedorova TN, Trofimova SV, Pimenov IV, Lanevskaia NI.
22 - Neuro Endocrinol Lett. 2003 Jun-Aug;24(3-4):233-40. Peptides of pineal gland and thymus prolong human life. Khavinson VKh1, Morozov VG.
23 - Klin Med (Mosk). 2002;80(5):30-4. [Optimization of cardiovascular function by peptide bio-regulators]. [Article in Russian] Cherkashin VA, Semin GF, Veretenko AA.
H - Neurosci Behav Physiol. 2000 May-Jun;30(3):261-5. Studies of cytokines in nerve tissue cultures. Chalisova NI1, Khavinson VK.
24 - Vopr Onkol. 1999;45(4):420-3. [Long-term results of comprehensive treatment for cervical cancer with poor prognosis]. [Article in Russian] Vishnevskaia EE1, Kosenko IA.
25 - Klin Med (Mosk). 1998;76(9):45-8. [Epithalamin effects on carbohydrate metabolism and cardiovascular system in patients with non-insulin dependent diabetes mellitus]. [Article in Russian] Shustov SB, Khavinson VKh, Shutak TS, Romashevskiĭ BV.
26 - Bull Exp Biol Med. 2006 Sep;142(3):356-9. Geroprotective effect of epithalamine (pineal gland peptide preparation) in elderly subjects with accelerated aging. [Article in English, Russian] Korkushko OV1, Khavinson VKh, Shatilo VB, Antonyuk-Shcheglova IA.
