Introduction
In 1973, the first evidence was published demonstrating that the administration of the low-molecular-weight pineal peptide extract, later named Epithalon, restored the estrus cycle in old female rats with persistent estrus syndrome. This administration also lowered the threshold of sensitivity of the hypothalamo-pituitary complex to feedback inhibition by estrogens in old animals. Since then, the effects of epithalon on the function of the reproductive, endocrine, neuroendocrine, and immune systems have been systematically studied. Research has shown the high biological activity of epithalon. Long-term treatment with the peptide preparation prolongs the life span of animals, slows down the aging of the reproductive system, improves immune function parameters, and inhibits the development of spontaneous tumors induced by some chemicals or X-irradiation and transplanted tumors.
Synthetic Tetrapeptide Epithalon Restores Disturbed Neuroendocrine Regulation in Senescent Monkeys
It is crucial to note that melatonin concentration in both young and senescent control monkeys at 9 p.m. exceeded that at 9 a.m., indicating increased melatonin secretion in the evening. Melatonin content in senescent control animals was significantly lower than in young controls, especially in the evening. This corresponds with published data on decreased melatonin content in aging human and animal blood. Notably, a significant increase in evening-time melatonin concentration was observed in epithalon-administered animals, exceeding control values by more than three times in 20–26-year-old epithalon-affected monkeys. However, epithalon did not significantly influence the basal production of adrenal androgens (DHEA, DHEAS), sex steroid hormones (estradiol and progesterone), and thyroxin.
Peptide Correction of Age-Related Pineal Disturbances in Monkeys
Administration of pineal peptides, epithalamin (at a dose of 5 mg/animal/day intramuscularly for 10 consecutive days) or epithalon (at a dose of 10 micrograms/animal/day intramuscularly for 7-10 consecutive days), induced a significant increase in night plasma melatonin in old monkeys. However, the treatment did not change melatonin levels in young monkeys. Given melatonin’s importance in regulating the diurnal rhythm of various organs and systems, applying epithalamin and epithalon is promising in correcting age-related hormonal imbalances and age-related pathologies.
Multiple Studies Show Epithalon Helped Stabilize Circadian Rhythms
Peptide preparations of the pineal gland, epithalamin (a complex of peptides isolated from the pineal gland) and epithalon (a synthetic tetrapeptide), restore night release of endogenous melatonin and normalize the hormone’s circadian rhythm in blood plasma. In elderly people, epithalamin and epithalon modulate the pineal gland’s functional state, increasing night melatonin levels in those with pineal gland functional insufficiency. The preparations, effectively increasing melatonin concentration without side effects, can be used in clinical geriatric practice.
Pineal Peptide Preparation Epithalamin Increases the Lifespan of Fruit Flies, Mice, and Rats
Epithalamin treatment decreased mortality rates by 52% in Drosophila melanogaster, 52% in rats, and 27% in C3H/Sn mice, though it did not change in SHR mice. Treatment with the pineal peptide increased median remaining life span in flies, C3H/Sn mice, and rats. Epithalamin increases melatonin synthesis and secretion in rats and inhibits free radical processes in rats and D. melanogaster. These antioxidative properties of epithalamin likely contribute to the increased lifespan observed in these different animal species.
Effect of Epithalon on Lifespan Increase in Drosophila Melanogaster
Epithalon significantly increased the lifespan of imagoes by 11–16% when applied at very low concentrations, ranging from 0.001×10–6 to 5×10–6 wt.% of culture medium for males and from 0.01×10–6 to 0.1×10–6 wt.% of culture medium for females.
Peptide Geroprotector from the Pituitary Gland Inhibits Rapid Aging of Elderly People: Results of 15-Year Follow-Up
Over three years, 39 coronary patients received regular courses of epithalamin in addition to basic therapy, while 40 coronary patients (control group) received basic therapy alone. Long-term treatment with epithalamin (six courses over three years) decelerated aging of the cardiovascular system, prevented age-associated impairment of physical endurance, normalized circadian rhythm of melatonin production, and carbohydrate and lipid metabolism. A significantly lower mortality rate in the group treated with epithalamin alongside basic therapy indicated the geroprotective effect of the pineal gland peptide preparation.
Epithalon Activates Chromatin in Old Age
Chromatin’s function is to efficiently package DNA into a small volume to fit into the cell nucleus, protecting the DNA structure and sequence. Packaging DNA into chromatin allows for mitosis and meiosis, prevents chromosome breakage, and controls gene expression and DNA replication. Data show that epithalon induces the activation of ribosomal genes, decondensation of pericentromeric structural heterochromatin, and the release of genes repressed due to age-related condensation of euchromatic chromosome regions. Epithalon has demonstrated its ability to activate chromatin by modifying heterochromatin and heterochromatinized chromosome regions in the cells of older individuals.
Epithalon Peptide Induces Telomerase Activity and Telomere Elongation in Human Somatic Cells and Overcomes the Hayflick Limit
Each cell contains DNA as an instruction manual for how to divide and grow. The DNA inside each cell is shielded by proteins called telomeres. During cellular division, a new cell must take some telomeres from its originating cell to shield the DNA of the new cell. The telomeres shorten after every cell division because the new cell can only take a portion of the telomeres from the previous cell, leaving the previous cell’s DNA unprotected.
Once there are no telomeres left to take, the cell stops dividing. This happens after a single cell divides and grows into about 64 other cells, known as the Hayflick limit. This limit exists because cells without shield material are more vulnerable to DNA damage. If a cell’s DNA becomes damaged, the cell may follow broken instructions, failing to eliminate itself through apoptosis as it should.
Epithalon increases telomere length by approximately 33% by increasing the telomerase enzyme that strengthens telomeres. Telomerase is a reverse transcriptase with two distinct functions: replicating pre-existing chromosome ends (telomeres) and healing broken chromosomes by adding telomeric sequences directly to non-telomeric DNA. Addition of epithalon to aging cells in culture induced elongation of telomeres to lengths comparable to those during early passages. Peptide-treated cells with elongated telomeres made ten extra divisions (44 passages) compared to the control and continued dividing. Thus, epithalon prolonged the vital cycle of normal human cells by overcoming the Hayflick limit.
Epithalon Didn’t Affect Spontaneous Tumor Incidence but Slowed the Development of Leukemia in a Study
Research found that treatment with epithalon did not influence total spontaneous tumor incidence but inhibited the development of leukemia by 6.0-fold compared to the control group.
Epithalon Reverses Hypophysectomy, Restoring Fibrinolysis and Reducing Blood Clotting in Chickens
Neonatal hypophysectomy in chickens, similar to that in old hens, leads to cellular and humoral immunity disturbances, pronounced hypercoagulation, and fibrinolysis depression 1.5 months post-surgery. Administration of epithalon significantly mitigates these effects, with a stronger impact observed in neonatally hypophysectomized chickens than in old hens.
Epithalon Lowers a Type of White Blood Cells Associated with Accelerated Aging
Melatonin prevents age-specific decreases in blood lymphocyte levels under standard photoperiod conditions (12 hours light/12 hours darkness). Contrary to melatonin, epithalon significantly reduces lymphocyte numbers and increases neutrophil numbers at certain ages. Leukocyte alkaline phosphatase activity increases with aging. Constant light conditions promote early increases in alkaline phosphatase activity (at 12 months), associated with accelerated pathological processes in the organism.
Epithalon Selectively Boosts Cytokine IL-2
IL-2, one of the first cytokines discovered and characterized, stimulates the growth of T cells and was termed T cell growth factor (TCGF). It also supports the growth and expansion of NK cells and other immune cells, such as B cells, at varying stages of development or activation. IL-2 is involved in activation-induced cell death of effector T cells. It plays a multifaceted and complex role in generating, expanding, and maintaining CD8 effector cells. IL-2 is required for optimal induction and differentiation of CD8 effector cells and may help determine the type of memory cells (central vs. effector) generated. Interestingly, in some situations, IL-2 can convert naive CD8 cells into memory-like cells with minimal TCR signaling.
IL-2 acts locally over short distances in an autocrine or paracrine fashion. Reflecting this property, IL-2 is found at very low levels in normal serum, and exogenously introduced IL-2 has a very short serum half-life. Paradoxically, given its role in T cell proliferation, IL-2 gene deletion or “knock-out” experiments in mice result in progressive lymphoid hyperplasia and the development of autoimmune diseases. This phenotype is now thought to be due to impaired regulatory T cell development, which requires IL-2 and is essential for maintaining the proper homeostatic balance of the immune system.
Epithalon Boosts Endorphins by Inhibiting the Enzyme that Destroys Them
Epithalon inhibited enkephalin-degrading enzymes from human serum, with dose-inhibitory effect curves for epithalon showing an IC50 value of 500 microM.
Epithalon Stimulates Neuronal Activity
Recording of spontaneous neuron discharges for 10–15 minutes was followed by intranasal administration of epithalon solution and recording of neuron activity for up to 30 minutes after doses of 30 ng per animal. Significant activation of neuron activity was observed several minutes after dosage, with an increase (by factors of 2–2.5) in discharge frequency. In some experiments, the effect of epithalon was multiphasic. The first peak of increased neuron discharge frequency at 5–7 minutes was followed by peaks at 11–12 and 17–18 minutes. The increase in discharge frequency occurred due to increased discharge frequency of already active neurons and the recruitment of previously silent neurons.
Conclusion
The extensive research on epithalon over the past two decades highlights its significant potential in experimental gerontology and oncology. Epithalon has shown promising results in restoring hormonal balance, stabilizing circadian rhythms, extending lifespan, activating chromatin, elongating telomeres, inhibiting tumor development, and enhancing immune function. These findings suggest that epithalon may play a crucial role in understanding aging processes and developing interventions to mitigate age-related decline. Continued research into epithalon and its mechanisms of action will provide further insights into its potential applications in the field of peptide research.