Epithalon is a synthetic version of a tiny natural molecule called AEDG, built from four amino acids (protein building blocks): alanine, glutamic acid, aspartic acid, and glycine. It was designed in Russia to copy the effects of Epithalamin, an extract made from the pineal gland - a pea-sized gland in the brain that controls your body clock and makes the sleep hormone melatonin. For over two decades, one research group (led by Vladimir Khavinson) has published dozens of studies on it, almost all in mice, rats, fruit flies, and cell cultures, looking at lifespan, cancer prevention, and telomeres (the protective caps on the ends of your chromosomes that shorten as you age). Real human trial data is extremely limited. Most of what circulates online about Epithalon as an 'anti-aging peptide' rests on this animal and lab-dish research, not on studies in people.
How strong is the evidence?
Of the 40 papers reviewed, the large majority are animal studies (mostly mice and rats, plus one fruit-fly study) or lab-dish/cell-line experiments, nearly all from the same Russian research group. A small number are labeled as involving 'human' material, but on close reading most of these are lab experiments using human cells or human blood samples treated in a dish, not clinical trials where people took the peptide and were followed for outcomes. Only one paper describes an actual finding in living people (a change in a urine hormone marker in middle-aged adults), and it does not report a dose or trial design in its abstract. There are no randomized controlled trials, no FDA review, and no large or independent human safety studies. This puts Epithalon solidly in preclinical territory, with only a thread of very thin human data on top.
Uses
What people use it for
Longevity and anti-aging research
Animal / labEpithalon is best known as a research subject in the science of aging (gerontology). Studies have tested whether it can extend lifespan and slow age-related decline, almost entirely in mice, rats, and fruit flies.
Restoring the body's day-night clock (circadian rhythm)
Some human dataResearchers have studied whether it can restore normal melatonin and cortisol patterns that flatten out with age, in aged rhesus monkeys and in some human data on melatonin-related hormone markers.
Cancer-prevention research in animals
Animal / labA long series of mouse and rat studies tested whether Epithalon could slow or prevent breast, colon, and other cancers, mostly in mice bred to develop tumors easily.
Telomere and cell-aging research tool
Animal / labScientists use Epithalon in lab dishes to study telomerase, the enzyme that rebuilds telomeres, as a way to understand the biology of cell aging - both in normal cells and, separately, in cancer cells.
Potential benefits
What it may help with
Lengthened lifespan in mice and fruit flies
Animal / labAcross several studies from the same lab, mice and fruit flies given Epithalon lived longer on average, and the last surviving 10% of animals in a group lived notably longer too. Effects were modest (roughly 10-15% increases in lifespan measures) and were not seen in every strain or every lighting condition tested.
Fewer tumors in cancer-prone mice
Animal / labIn mice genetically prone to breast cancer, and in rats given a chemical that causes colon cancer, Epithalon reduced the number of tumors, slowed their growth, and cut down on cancer spreading to other organs. One study also found a large drop in leukemia in treated mice.
Restored day-night hormone rhythm
Some human dataIn old rhesus monkeys, Epithalon brought back a stronger nighttime surge of melatonin. In a human study of middle-aged adults, it was linked to a rise in a urine marker of melatonin production and to more normal activity of body-clock genes in blood cells.
Telomere lengthening in cells (lab dish)
Animal / labIn human cell lines (both normal cells and some cancer cell lines) and in human blood cells treated outside the body, Epithalon increased activity of telomerase, the enzyme that rebuilds telomeres, and in some experiments measurably lengthened telomeres. This is a lab finding on cells, not proof it lengthens telomeres inside a living person.
Antioxidant, protective effect on stressed cells
Animal / labIn lab-dish models, Epithalon reduced oxidative damage and improved health markers in aging egg cells (oocytes), diabetes-damaged retina cells, and stem cells kept in culture for a long time.
Supports stem cell and nerve cell differentiation in the lab
Animal / labMultiple lab-dish studies found Epithalon can push stem cells toward becoming nerve-like cells and can help cultured neurons grow more branches, while also lowering markers of cell aging in these cultures.
What to watch for
Side effects & risks
- Mild
- Moderate
Human safety profile is essentially undocumented
Because there are no real human clinical trials in this research, side effects that people report from using Epithalon on their own (like injection site soreness, headaches, or other reactions) have not been systematically studied or confirmed. Anyone using it is working without real human safety data.
- Moderate
Theoretical cancer-growth concern from telomerase activation
Telomerase, the enzyme Epithalon switches on, is the same enzyme cancer cells hijack to become effectively immortal. One lab study found Epithalon increased telomere-lengthening activity in cancer cell lines as well as normal cells. This doesn't mean it causes cancer, but it's a real biological reason to be cautious, especially for anyone with a personal or strong family history of cancer.
Dosing
Dosing — what studies used
There is no dose of Epithalon established by human clinical trials. Every dosing detail that exists in this research comes from animal studies, using doses scaled to a mouse or rat's tiny body weight, which cannot simply be scaled up to a human dose. The one paper with an actual human data point (a hormone marker change in middle-aged adults) does not report the dose, route, or schedule used in its abstract. Any specific milligram amounts you see quoted online for human use (for example, injection cycles lasting 10-20 days) come from outside the research reviewed here and are not backed by the studies in this file.
Cancer-prone mice (HER2/neu breast cancer model), lifelong dosing
Animal study1 microgram per mouse (roughly 30-40 micrograms per kilogram of body weight)
5 consecutive days each month · Started at 2 months of age, continued until the animal's natural death · Subcutaneous injection
This is the core longevity/cancer-prevention protocol from the main research group behind Epithalon. It is a lifelong mouse dosing schedule, not a human protocol. Worth noting: three of these four papers report the 1-microgram-per-mouse dose, but one of them (PMID 12459848) states the dose as '1 mg' given 5 times a week. That figure is roughly a thousand times higher than the others and out of step with the rest of the group's work, so it is most likely a typo in that abstract rather than a real difference in dosing.
Rat colon-cancer studies
Animal study0.1 to 1 microgram per rat
5 days per week · 5 weeks up to 6 months, depending on the study phase being tested · Subcutaneous injection
Used to test whether the peptide could block or slow chemically induced colon tumors when given before, during, or after the cancer-causing exposure.
Rat brain-activity study, single dose
Animal study30 nanograms per rat
Single dose · Brain activity measured for 30 minutes afterward · Intranasal
This was a one-off experiment to see if the peptide could reach and activate brain cells without an injection - not a treatment protocol.
No study in this file measures how long Epithalon lasts in the human body. As a very short chain of just four amino acids, it would be expected to break down quickly, but that has not actually been measured here. Treat any specific human dosing schedule you encounter elsewhere as unverified, since it doesn't come from the clinical research reviewed for this page.
These figures describe what researchers used in studies. They are not a recommendation or a prescription.
Mechanism
How it works
Epithalon is built to copy a natural signal made by your pineal gland, a small gland deep in the brain that controls your sleep-wake clock and makes melatonin. In animal studies, it helped restore a more youthful pattern of melatonin and cortisol release as animals aged. Separately, in lab-dish experiments on cells, it turns on a gene program that includes telomerase, an enzyme that rebuilds the protective caps (telomeres) on the ends of chromosomes, which normally get shorter every time a cell divides. Shorter telomeres are one of the signs scientists use to track cell aging, so keeping them longer is one theory for why this peptide might act as an anti-aging tool. It also appears to act as an antioxidant (protecting cells from a type of cell damage called oxidative stress) and to switch certain genes involved in cell division and tumor suppression on or off. All of this comes from animal and cell-dish research; how much of it actually happens inside a living human body has not been established.
Who should avoid it
- Anyone with a personal or strong family history of cancer should be especially cautious, given that the peptide activates telomerase, the same enzyme cancer cells exploit to keep dividing indefinitely.
- Not appropriate during pregnancy or breastfeeding - there is no safety data in this context at all.
- Not appropriate for children - no data exists in this population.
- Anyone considering it should not treat it as a substitute for medical care with proven, dosed, human-tested treatments, since it has no approved medical use and no confirmed human dosing.
Interactions to know
- No human drug interaction studies exist for Epithalon.
- Because it appears to affect melatonin production, it could plausibly interact with melatonin supplements or other sleep and circadian-rhythm medications, but this has not been formally studied.
- No data on interactions with hormone therapies, cancer treatments, or immune-suppressing drugs, despite its effects on cell growth pathways in animal studies.
The papers that matter most
Key studies
A recent, comprehensive review of 25 years of Epitalon research; confirms the evidence base is overwhelmingly lab and animal work, with real uncertainty still remaining about its exact mechanism.
Overview of Epitalon-Highly Bioactive Pineal Tetrapeptide with Promising Properties
The foundational paper laying out the 'peptide theory of ageing' behind Epithalon, describing lifespan extension in mice, flies, and monkeys, and referencing early clinical work with the related extract Epithalamin.
Peptides and Ageing
One of the key lifespan and cancer-prevention studies: lifelong low-dose Epithalon modestly extended lifespan and meaningfully reduced breast tumor development in cancer-prone mice.
Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice
The most direct look at Epithalon's telomere effect in human cells; it lengthened telomeres in both normal and cancer cell lines in a dish, which is promising for the anti-aging story but also raises a theoretical cancer-growth caution.
Epitalon increases telomere length in human cell lines through telomerase upregulation or ALT activity
One of the only papers with an actual human data point: linked to a rise in a urine melatonin marker and more normal body-clock gene activity in people with reduced pineal function, though the abstract doesn't report the dose used.
AEDG peptide regulates human circadian rhythms genes expression during pineal gland accelerated aging
Tested the peptide directly on human blood cells outside the body; found telomere length changes in most people tested, but results were inconsistent - lengthening in some, shortening in others.
Effect of Peptide AEDG on Telomere Length and Mitotic Index of PHA-Stimulated Human Blood Lymphocytes
Bottom line
Epithalon has a genuinely interesting, decades-long body of animal and lab-dish research behind it, showing modest lifespan extension, cancer-slowing effects, and telomere-lengthening activity in mice, rats, and cells. But almost none of that has been tested in real human clinical trials, dosing for people has never been established, and the same telomerase activity that makes it exciting for aging is also something cancer cells use to keep growing. Treat it as a promising but unproven research compound, not a proven anti-aging treatment.
Research papers
Studies we have on file for Epithalon. Tap a title to open it on PubMed. Labels like “animal” or “human trial” are rough guides.
40 papers
Overview of Epitalon-Highly Bioactive Pineal Tetrapeptide with Promising Properties.
Epitalon, also known as Epithalon or Epithalone, is a tetrapeptide, Ala-Glu-Asp-Gly (AEDG), which was synthesized based on the amino acids composition of Epithalamin, a bovine pineal gland extract, prior to its discovery in pineal gland polypeptide complex solution. During the last 25 years, this compound has been extensively studied using in vitro, in vivo, and in silico methods. The results of these studies indicate significant geroprotective and neuroendocrine effects of Epitalone, resulting from its antioxidant, neuro-protective, and antimutagenic effects, originating from both specific and nonspecific mechanisms. Although it has been demonstrated that Epitalon exerts, among other effects, a direct influence on melatonin synthesis, alters the mRNA levels of interleukin-2, modulates the mitogenic activity of murine thymocytes, and enhances the activity of various enzymes, including AChE, BuChE, and telomerase, it remains uncertain whether these are the sole mechanisms of action of this compound. Moreover, despite the considerable volume of research on the biological and pharmacodynamic characteristics of Epitalon, the quantity of physico-chemical and structural investigations of this peptide remains quite limited. This review aims to conclude the most important findings from such studies, thus presenting the current state of knowledge on Epitalon.
Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions.
Therapeutic peptides are emerging as promising adjuncts in the management of orthopaedic injuries, grounded in their ability to modulate molecular signaling networks central to cellular medicine. By acting on key pathways such as PI3K/Akt, mTOR, MAPK, TGF-β, and AMPK, peptides exert influence over tissue regeneration, inflammation resolution, and neuromuscular recovery. Wound-healing peptides such as BPC-157, TB-500, and GHK-Cu promote angiogenesis, integrin-mediated extracellular matrix remodeling, and fibroblast activation, whereas growth hormone secretagogues like ipamorelin, CJC-1295, tesamorelin, sermorelin, and AOD-9604 activate IGF-1 signaling and satellite cell repair. Recovery-enhancing agents such as epithalon, delta sleep-inducing peptide, and pinealon target circadian and mitochondrial regulators, and neuroactive peptides like selank, semax, and dihexa enhance brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity. Although preclinical studies are promising, there is a current lack of clinical trials. This review integrates current mechanistic insights with orthopaedic relevance, emphasizing safety, efficacy, and future directions for responsible integration into musculoskeletal care.
Peptides and Ageing.
A technology has been developed for manufacturing of biologically active complex peptide preparations from extracts of different tissues. In particular, the pineal preparation (Epithalamin) augments the in vitro outgrowth of explants from the pineal gland but not from other tissues, the latter being stimulated by peptide preparations from respective tissues. Epithalamin increases melatonin production by the pineal gland of rats, improves immunological parameters in rats and mice, produces anticarcinogenic effects in different experimental models, stimulates antioxidant defenses, and restores the reproductive function in old rats. These effects are combined in the ability of Epithalamin to increase the lifespan in rats, mice, and fruit flies. Many of these effects are reproduced in clinical trials, which have demonstrated the geroprotector activity of Epithalamin in humans. Among the effects of the thymic preparation Thymalin, those related to its ability to stimulate immunity are the most prominent. This ability is associated with anticarcinogenic and geroprotector activities. Clinical trials of the peptide preparations obtained from other organs including the prostate, the cerebral cortex, and the eye retina, have demonstrated beneficial effects reflected by the improvement of the conditions of respective organs. Based on the data about the amino acid compositions of the peptide preparations, novel principles of the design of biologically active short peptides possessing tissue-specific activities has been developed. Dipeptides specific for the thymus and tetrapeptides specific for the heart, liver, brain cortex, and pineal glands stimulate the in vitro outgrowth of explants of respective organs. Interestingly, for eye retina and the pineal gland, a common tetrapeptide Ala-Glu-Asp-Gly (Epitalon) has been designed, probably reflecting the common embryonal origin of these two organs. Epitalon reproduces the effects of Epithalamin including those related to its geroprotector activity. In particular, Epitalon increases the lifespan of mice and fruit flies and restores the circadian rhythms of melatonin and cortisol production in old rhesus monkeys. At the same time, Epitalon prolongs the functional integrity of the eye retina in Campbell rats with hereditary Retinitis Pigmentosa and improves the visual functions in patients with pigmental retinal degeneration. Changes in gene expression were observed to be produced by the short peptide preparations. Therefore, the effects of Epitalon are suggested to be mediated by transcriptional machinery common for the pineal gland and the retina and, probably, for regulation of melatonin production in fruit flies. Based on three decades of studies of the peptide preparations, the peptide theory of ageing has been put forward. According this theory, ageing is an evolutionary determined biological process of changes in gene expression resulting in impaired synthesis of regulatory and tissue-specific peptides in organs and tissues, which provokes their structural and functional changes and the development of diseases. Correspondingly, correction of such disorders by means of stimulation of peptide production in the organism or through their delivery can promote the normalisation of disturbed body functions.
Peptide Regulation of Cell Differentiation.
Short peptides are molecules with small molecular weight, capable of penetrating the cell membrane and nuclear membrane for epigenetic regulation of gene expression, including the genes responsible for cell differentiation. The direction of cell differentiation induction depends on the peptide structure and concentration. AEDG and AEDP peptides induce differentiation of pluripotent cells in the epidermis, mesenchyme and nervous tissue. Peptides KE, AED, KED, AEDG and AAAAEKAAAAEKAAAAEK activate neural differentiation. Peptides AEDL and KEDW induce lung and pancreatic cell differentiation. Differentiation of immune cells is stimulated by KE, DS, (Nα-(γ-E)-E), K(Н-E-OH)-OH, AED, KED, EDA, and KEDG peptides. IRW, GRGDS and YCWSQYLCY peptides activate osteogenic differentiation of stem cells. KE, AEDL, and AEDG peptides also induce plant cells differentiation. Short peptides can take part in activation of the signaling pathways regulating expression of differentiation genes. They can interact with histones changing the availability of genes for transcription, regulate gene methylation and activate or inhibit their expression, as well as directly interact with the DNA. Research in the area of directed stem cell differentiation by peptide regulation is of special importance for developing innovative approaches to molecular medicine and cell therapy.
Epitalon increases telomere length in human cell lines through telomerase upregulation or ALT activity.
Epitalon, a naturally occurring tetrapeptide, is known for its anti-aging effects on mammalian cells. This happens through the induction of telomerase enzyme activity, resulting in the extension of telomere length. A strong link exists between telomere length and aging-related diseases. Therefore, telomeres are considered to be one of the biomarkers of aging, and increasing or maintaining telomere length may contribute to healthy aging and longevity. Epitalon has been the subject of several anti-aging studies however, quantitative data on the biomolecular pathway leading to telomere length increase, hTERT mRNA expression, telomerase enzyme activity, and ALT activation have not been extensively studied in different cell types. In this article, the breast cancer cell lines 21NT, BT474, and normal epithelial and fibroblast cells were treated with epitalon then DNA, RNA, and proteins were extracted. qPCR and Immunofluorescence analysis demonstrated dose-dependent telomere length extension in normal cells through hTERT and telomerase upregulation. In cancer cells, significant telomere length extension also occurred through ALT (Alternative Lengthening of Telomeres) activation. Only a minor increase in ALT activity was observed in Normal cells, thereby showing that it was specific to cancer cells. Our data suggests that epitalon can extend telomere length in normal healthy mammalian cells through the upregulation of hTERT mRNA expression and telomerase enzyme activity.
Short Peptides Protect Oral Stem Cells from Ageing.
Primary stem cells, after several cell divisions, enter into a senescence state, that is characterized by alterations to spindle-shape typical morphology. This concern is one of the main problems in the use of human mesenchymal stem cells (hMSCs) in clinical applications which demand cells in large numbers. Short peptides had geroprotective properties and stimulated stem cell differentiation. The aim of the study is to demonstrate the role of AEDG and KED peptides in maintaining oral hMSCs morphology and functions over long-term expansion. 2 types of hMSCs were investigated: human periodontal ligament stem cells (hPLSCs) and human gingival mesenchymal stem cells (hGMSCs). Cells at the 25th passage were divided into 3 groups: 1 - control (without adding peptide), 2 - treated with AEDG peptide, 3 - treated with KED peptide. Cell cultures were analyzed by an immunofluorescence method and RT-PCR on the p16 and p21 senescence markers expression. AEDG peptide decreased p16 and p21 mRNA expression by 1.56-2.44 times in comparison with the control group. KED peptide decreased p16 and p21 mRNA expression by 1.82-3.23 times in comparison with the control group. These results were confirmed by immunofluorescent visualization. AEDG and KED peptides could be used as supplementary substances in a culture medium to delay the expression of senescence markers in long term stem cell cultivation in order to promote the large-scale in vitro expansion necessarily required for stem cell therapy clinical application. The data obtained confirm the geroprotective effect of AEDG and KED peptide, which was shown early in animal and cells models.
The Antioxidant Tetrapeptide Epitalon Enhances Delayed Wound Healing in an in Vitro Model of Diabetic Retinopathy.
Diabetic retinopathy (DR) is the most common complication of diabetes mellitus and a leading cause of vision loss. Short peptides, such as di-, tri-, and tetrapeptides, have various beneficial activities, including antioxidant, antimicrobial, and anti-inflammatory effects. This study aims to test the hypothesis that the antioxidant effect of the synthetic tetrapeptide AEDG (Ala-Glu-Asp-Gly, Epitalon) improves the delayed healing process associated with hyperglycemia in DR, using a high glucose (HG)-injured human retinal pigment epithelial cell line (ARPE-19). We found that HG exposure delayed wound healing in ARPE-19 cells and increased intracellular levels of reactive oxygen species (ROS), while decreasing antioxidant gene expression. HG also induced epithelial-mesenchymal transition (EMT) and upregulated fibrosis-related genes, suggesting that HG-induced EMT contributes to subretinal fibrosis, the end-stage of eye diseases, including proliferative DR. The antioxidant Epitalon restored impaired wound healing in HG-injured ARPE-19 cells by inhibiting hyperglycemia-induced EMT and fibrosis. These findings support using the antioxidant agent Epitalon as a promising therapeutic strategy for DR to improve retinal wound healing compromised by hyperglycemia. More mechanistic investigations are needed to confirm Epitalon's benefits and safety. Developing ophthalmic forms of Epitalon may enhance its delivery directly to the retina, potentially improving its therapeutic efficacy.
An Efficient Data-Gathering Routing Protocol for Underwater Wireless Sensor Networks.
Most applications of underwater wireless sensor networks (UWSNs) demand reliable data delivery over a longer period in an efficient and timely manner. However, the harsh and unpredictable underwater environment makes routing more challenging as compared to terrestrial WSNs. Most of the existing schemes deploy mobile sensors or a mobile sink (MS) to maximize data gathering. However, the relatively high deployment cost prevents their usage in most applications. Thus, this paper presents an autonomous underwater vehicle (AUV)-aided efficient data-gathering (AEDG) routing protocol for reliable data delivery in UWSNs. To prolong the network lifetime, AEDG employs an AUV for data collection from gateways and uses a shortest path tree (SPT) algorithm while associating sensor nodes with the gateways. The AEDG protocol also limits the number of associated nodes with the gateway nodes to minimize the network energy consumption and to prevent the gateways from overloading. Moreover, gateways are rotated with the passage of time to balance the energy consumption of the network. To prevent data loss, AEDG allows dynamic data collection at the AUV depending on the limited number of member nodes that are associated with each gateway. We also develop a sub-optimal elliptical trajectory of AUV by using a connected dominating set (CDS) to further facilitate network throughput maximization. The performance of the AEDG is validated via simulations, which demonstrate the effectiveness of AEDG in comparison to two existing UWSN routing protocols in terms of the selected performance metrics.
Epitalon protects against post-ovulatory aging-related damage of mouse oocytes in vitro.
The developmental potential of oocytes decreases with time after ovulation in vivo or in vitro. Epitalon is a synthetic short peptide made of four amino acids (alanine, glutamic acid, aspartic acid, and glycine), based on a natural peptide called epithalamion extracted from the pineal gland. It is a potent antioxidant, comparable to melatonin, that may confer longevity benefits. The current study aims to test the protective effects of Epitalon on the quality of post-ovulatory aging oocytes. Epitalon at 0.1mM was added to the culture medium, and the quality of oocytes was evaluated at 6h, 12h, and 24h of culture. We found that 0.1mM Epitalon reduced intracellular reactive oxygen species. Epitalon treatment significantly decreased frequency of spindle defects and abnormal distribution of cortical granules during aging for 12h and 24h, while increased mitochondrial membrane potential and DNA copy number of mitochondria, thus decreasing apoptosis of oocytes by 24h of in vitro aging. Our results suggest that Epitalon can delay the aging process of oocytes in vitro via modulating mitochondrial activity and ROS levels.
AEDG Peptide (Epitalon) Stimulates Gene Expression and Protein Synthesis during Neurogenesis: Possible Epigenetic Mechanism.
It was shown that AEDG peptide (Ala-Glu-Asp-Gly, Epitalon) regulates the function of the pineal gland, the retina, and the brain. AEDG peptide increases longevity in animals and decreases experimental cancerogenesis. AEDG peptide induces neuronal cell differentiation in retinal and human periodontal ligament stem cells. The aim of the study was to investigate the influence of AEDG peptide on neurogenic differentiation gene expression and protein synthesis in human gingival mesenchymal stem cells, and to suggest the basis for the epigenetic mechanism of this process. AEDG peptide increased the synthesis of neurogenic differentiation markers: Nestin, GAP43, β Tubulin III, Doublecortin in hGMSCs. AEDG peptide increased Nestin, GAP43, β Tubulin III and Doublecortin mRNA expression by 1.6-1.8 times in hGMSCs. Molecular modelling method showed, that AEDG peptide preferably binds with H1/6 and H1/3 histones in His-Pro-Ser-Tyr-Met-Ala-His-Pro-Ala-Arg-Lys and Tyr-Arg-Lys-Thr-Gln sites, which interact with DNA. These results correspond to previous experimental data. AEDG peptide and histones H1/3, H1/6 binding may be one of the mechanisms which provides an increase of Nestin, GAP43, β Tubulin III, and Doublecortin neuronal differentiation gene transcription. AEDG peptide can epigenetically regulate neuronal differentiation gene expression and protein synthesis in human stem cells.
[Aging of the pineal gland].
The age-related changes in the pineal gland are functional rather than organic, which makes their correction or prevention more tenable. The amelioration or inhibition of some age-related impairments of the pineal gland were observed with dietary restriction and the use of S-adenosylmethionine or MAO-A inhibitors. A threefold increase in nocturnal melatonin peaks occurs in old rhesus monkeys treated with a synthetic peptide Ala-Glu-Asp-Gly (Epithalon) designed basing on the amino acid content of a pineal peptide extract Epithalamin. Other effects of Epithalon markedly overlap with melatonin effects. Besides life extension in mice and fruit flies, Epithalon effects include the postponing vision loss in Campbell rats with hereditary pigmental dystrophy. A uniting aspect of such a range of activities might be the participation of transcription factors, since they are often highly conservative in evolution and, on the other hand, may be strictly tissue-specific. The targets of Epithalon may include transfactors that in mammals are specific for the pineal gland and retina and exhibit impaired functions in the aged pineal gland.
Studies of the effects of Vilon and Epithalon on gene expression in mouse heart using DNA-microarray technology.
Expression of 15,247 clones from a cDNA library in the heart of mice receiving Vilon and Epithalon was studied by DNA-microarray technology. We revealed 300 clones (1.94% of the total count), whose expression changed more than by 2 times. Vilon changed expression of 36 clones, while Epithalon modulated expression of 98 clones. Combined treatment with Vilon and Epithalon changed expression of 144 clones. Vilon alone or in combination with Epithalon activated expression of 157 clones (maximally by 6.13 times) and inhibited expression of 23 clones (maximally by 2.79 times). Epithalon alone or in combination with Vilon activated expression of 194 clones (maximally by 6.61 times) and inhibited expression of 48 clones (maximally by 2.71 times). Our results demonstrate the specific effects of Epithalon and Vilon on gene expression.
[AEDG peptide regulates human circadian rhythms genes expression during pineal gland accelerated aging.].
Night work provides biorhythms desynchronization, disorder of melatonin-producing function and accelerated pineal gland aging. One of the promising geroprotectors restoring the pineal melatonin synthesis is the AEDG (Ala-Glu-Asp-Gly) peptide. AEDG peptide increases in 1,7 times the 6-sulfatoxymelatonin (6-SOMT) excretion in the urine of middle-aged people. Moreover, AEDG peptide normalized circadian Clock and Csnk1e genes hyper expression in leukocytes in 1,9-2,1 times and increases the Cry2 gene hypo expression in peripheral blood lymphocytes in 2 times in people with reduced melatonin-producing epiphysis function. The geroprotective effect of the AEDG peptide is based on its ability to restore the epiphysis melatonin-producing function by means regulation of human circadian genes expression.
Therapeutic peptides in gerontology: mechanisms and applications for healthy aging.
Peptide therapeutics represent an emerging frontier in gerontological medicine, targeting fundamental hallmarks of aging including metabolic dysfunction, telomere attrition, tissue repair impairment, and hormonal decline. To comprehensively review the mechanisms, clinical applications, evidence base, and safety profiles of therapeutic peptides with demonstrated or potential applications in healthy aging and age-related conditions. A comprehensive narrative review was conducted through systematic searches of PubMed, Scopus, and regulatory databases (FDA, WADA) from inception through January 2026. Search terms included "peptide therapeutics," "aging," "gerontology," "healthspan," combined with specific peptide names (tirzepatide, epitalon, GHK-Cu, BPC-157, TB-500, Semax, CJC-1295, ipamorelin, bremelanotide). Peer-reviewed articles, clinical trials, regulatory documents, and preclinical studies were evaluated. A total of 20 primary sources were selected based on relevance, methodological quality, and contribution to understanding peptide mechanisms and clinical outcomes in aging populations. Nine peptides were identified spanning diverse aging interventions: metabolic restoration (tirzepatide), telomere biology (epitalon), dermal regeneration (GHK-Cu), tissue repair (BPC-157, TB-500), neuroprotection (Semax), growth hormone modulation (CJC-1295, ipamorelin), and sexual function (bremelanotide). FDA-approved agents demonstrated robust safety profiles from large-scale trials. Non-approved peptides showed promising preclinical and limited clinical evidence but lack long-term safety data and systematic validation. Significant knowledge gaps include optimal dosing regimens, combination therapy effects, and biomarkers for monitoring efficacy. Therapeutic peptides offer mechanistically diverse approaches to multiple aging hallmarks. While FDA-approved agents demonstrate clinical potential, investigational peptides require rigorous validation through well-designed clinical trials to establish safety and efficacy for healthspan extension.
Epithalon decelerates aging and suppresses development of breast adenocarcinomas in transgenic her-2/neu mice.
Female transgenic FVB/N mice carrying the breast cancer gene HER-2/neu received epithalon (Ala-Glu-Asp-Gly) in a dose of 1 mg subcutaneously 5 times a week to from the 2nd month of life to death. Epithalon prolonged the average and maximum lifetimes of mice by 13.5 (p<0.05) and 13.9%, respectively. The peptide prolonged the average lifetime of animals without neoplasms (by 34.2%, p<0.05). Epithalon decelerated the development of age-related disturbances in reproductive activity and suppressed the formation of neoplasms. The peptide decreased the incidence of breast adenocarcinomas, lungs metastases (by 1.6 times, p<0.05), and multiple tumors (by 2 times). Epithalon 3.7-fold increased the number of mice without breast tumors (p<0.05), while the number of animals with 6 or more breast tumors decreased by 3 times (p<0.05). Epithalon prolonged the lifetime of mice with breast tumors by 1.4 times (p<0.05). These results indicate that Epithalon possesses geroprotective activity and inhibits breast carcinogenesis in transgenic mice, which is probably related to suppression of HER-2/neu expression.
Effect of the synthetic pineal peptide epitalon on spontaneous carcinogenesis in female C3H/He mice.
The potential preventive effect of the synthetic pineal peptide Epitalon (Ala-Glu-Asp-Gly) on spontaneous tumorigenesis in mice was studied. One-year-old female C3H/He mice were kept for 6.5 months under standard conditions. Epitalon was injected at a dose of 0.1 microg, 5 times a week. Long-term exposure to Epitalon in small doses did not show any toxic effect. Treatment with Epitalon decreased the number of tumor-bearing mice with malignant tumors and prevented the development of metastases. Spontaneous tumors of the reproductive organs (mammary glands and ovaries) were predominant in both groups of mice (control and experimental). The mammary gland tumors were different variants of invasive ductal carcinomas. In the ovaries, granulosa-cell tumors were found. Tumors were in the minority in other organs and had benign characteristics. In control mice, metastases were found in 3 out of 9 tumor-bearing mice, all of them being from tumors of the reproductive organs. Treatment with Epitalon slowed down the development of metastases from spontaneous tumors, and no metastases were found in the experimental mice. These data highlight the antimetastatic effect of Epitalon as part of its oncostatic properties.
Effect of short peptides on neuronal differentiation of stem cells.
It has been demonstrated that short peptides play an important role in the transmission of biological information, modulation of transcription, and restoring genetically conditioned alterations occurring with age. Peptidergic regulation of homeostasis occupies an important place in physiological processes, which lead to the aging of cells, tissues, and organs, consisting in the involution of major regulatory systems-the nervous, the endocrine, and the immune. The effect of AED (Ala-Glu-Asp), KED (Lys-Glu-Asp), KE (Lys-Glu), AEDG (Ala-Glu-Asp-Gly) peptides and their compound on neuronal differentiation of human periodontal ligament stem cells (hPDLSCs) was studied by immunofluorescence and western blot analysis. Growth-Associated Protein 43 (GAP43), which implements neurotransmission mechanisms and neuroplasticity, demonstrated an increased expression in hPDLSCs cultured with a compound of all studied peptides and with KED alone. The peptide compound and KED, increase the expression of Nestin (neurofilament protein), expressed in early neuronal precursors in hPDLSCs cultures. Thus, the compound of peptides AEDG, KE, AED, and KED could promote the neuronal differentiation of hPDLSCs and be a promising tool for the study of peptides as a modulator of neurogenesis in neurodegenerative diseases studied in animal models.
Effects of intranasal administration of epitalon on neuron activity in the rat neocortex.
This report discusses the properties of the synthetic tetrapeptide epitalon (Ala-Glu-Asp-Gly), synthesized on the basis of an epiphyseal peptide extract. Intranasal administration of epitalon was selected as a noninvasive means of applying the agent to the CNS by bypassing the blood-brain barrier. The aim of the present work was to assess the characteristics of the action of epitalon on the frequency of spontaneous neuron activity in the cerebral cortex of white rats. Studies were performed using male Wistar rats anesthetized with urethane (1 g/kg). Extracellular activity of cortical neurons was recorded with a glass microelectrode of resistance 1-2 MOmega. Recording of spontaneous neuron discharges for 10-15 min was followed by intranasal administration of epitalon solution and recording of neuron activity to 30 min after doses of 30 ng per animal. Significant activation of neuron activity was seen several minutes after dosage, with an increase (by factors of 2-2.5) in discharge frequency. In some experiments, the effect of epitalon was multiphasic. The first peak of increased neuron discharge frequency at 5-7 min was followed by peaks at 11-12 and 17-18 min. The increase in discharge frequency occurred because of an increase in the discharge frequency of neurons which were already active and the recruitment of previously silent neurons. At least the first peak of increased neuron activity following exposure to epitalon was found to be associated with the direct action of the peptide on cortical cells.
Effect of Ala-Glu-Asp-Gly peptide on life span and development of spontaneous tumors in female rats exposed to different illumination regimes.
The effects of Ala-Glu-Asp-Gly peptide (Epithalon) on the life span and development of spontaneous tumors were studied in female rats exposed to standard, natural for North-Western Russia, and constant illumination. The mean life span of animals exposed to constant or natural illumination decreased by 13.5 and 25.5%, the maximum by 9 and 7 months, respectively, and spontaneous tumors developed much more rapidly than in animals living under conditions of the standard light regimen. Epithalon (0.1 microg daily 5 times a week from the age of 4 months) did not change the life span of rats living under conditions of standard day/night regimen, while in rats exposed to the natural and constant light it promoted prolongation of the maximum life span by 95 and 24 days, respectively. Epithalon prolonged the mean life span of the last 10% of rats exposed to natural and constant illumination, treated with Epithalon, by 137 and 43 days, respectively. This peptide exhibited virtually no effect on the development of spontaneous tumors in rats exposed to standard and constant illumination, but significantly inhibited their development in rats exposed to natural light.
Inhibitory effect of peptide Epitalon on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats.
The effect of synthetic pineal peptide Epitalon (Ala-Glu-Asp-Gly) on colon carcinogenesis was firstly studied in rats. Eighty 2-month-old outbred male LIO rats were subdivided into four groups and were weekly exposed to five subcutaneous injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg body weight. Additionally, 5 days a week, some of the rats were given subcutaneous injections of saline at a dose of 0.1 ml during the whole experiment (group 1, control) or Epitalon at a single dose of 1 microg during the whole experiment (group 2), Epitalon after termination of carcinogen injections (group 3) or during the period of DMH exposure (group 4). Colon carcinomas developed in 90-100% of DMH-treated rats. The number of total colon tumors per rat was 4.1; 2.7; 3.7; 2.9 in groups 1, 2, 3, 4, respectively (the difference in groups 2 and 4 compared with group 1 is significant). In rats from group 2, colon tumors were smaller than in control animals. In group 2, the incidence, as well the multiplicity of tumors in ascending and descending colon, were significantly decreased in comparison with group 1. In group 4, the mean number of tumors per rat was significantly decreased, too. A trend to decrease the number of tumors in the rectum in rats from groups 2, 3 and 4, treated with Epitalon was found. Epitalon inhibited also the development of tumors in jejunum and ileum. Thus, our results demonstrated an inhibitory effect of Epitalon on chemically induced bowel carcinogenesis in rats.
Identification of Peptide AEDG in the Polypeptide Complex of the Pineal Gland.
The polypeptide complex of the epiphysis and the peptide AEDG, constructed on the basis of its amino acid analysis, exert similar biological effects. Both bioregulators normalize melatonin synthesis in the pineal gland, functioning of the brain, eye retina, cardiovascular, endocrine, and immune systems; they also act as antioxidants, stress-protectors, and geroprotectors. Within the epiphysis polypeptide complex, free amino acids (3.26%), dipeptides (23.19%), tripeptides (50.72%), tetrapeptides (22.10%), and pentapeptides (0.72%) were revealed by mass spectrometry and HPLC. Peptide AEDG was detected among the tetrapeptides of the epiphysis polypeptide complex by selective reaction monitoring method. The biological effects of the epiphysis polypeptide complex are determined by the effect of its component AEDG.
Epitalon-activated telomerase enhance bovine oocyte maturation rate and post-thawed embryo development.
Telomerase is highly expressed in oocyte cumulus cells and plays a significant role in follicular development and oocyte maturation. In this study, we hypothesized that in vitro culture conditions may affect telomerase activity during in vitro embryo production (IVP) and that its activation may improve embryo quality. We first examined telomerase protein levels and localization in bovine cumulus-oocyte complexes via immunofluorescence assays. The results showed that healthy cumulus-oocyte complexes have the nuclear localization of the telomerase while the degraded cumulus-oocyte complex had reduced telomerase levels and that telomerase was localized in the cytoplasm. We activated telomerase via Epitalon, a tetrapeptide with the amino acid sequence Ala-Glut-Asp-Gly. We observed a significant improvement in the oocyte maturation rate compared with the control group (p < 0.05). Furthermore, telomerase activity was significantly compromised in post-thawed embryos, and Epitalon treatment significantly improved blastocyst hatching rate and implantation potential (p < 0.05). Moreover, we performed qPCR, reactive oxygen species, and JC-1 (ΔΨm) assays to evaluate the effect of Epitalon on the health of in vitro mature oocytes, cumulus cells, and post-thawed blastocysts, and the result showed that Epitalon highly enhances the quality and health of the oocyte, cumulus cell, and post-thawed blastocyst. Our results suggest that telomerase activation via Epitalon improves bovine in vitro embryo production.
[Effect of epitalon and melatonin on life span and spontaneous carcinogenesis in senescence accelerated mice (SAM)].
Female senescence accelerated mice SAMP-1. (prone) and SAMR-1 (resistant) were exposed 5 times a week monthly to melatonin (with drinking water 20mg/ml during the night hours) or to s.c. injections of epitalon (Ala-Glu-Asp-Gly) at a single dose 1mkg/mouse. Control mice were intact or exposed to injection of 0.1 ml normal saline. The body weight and temperature, food consumption, estrous function were monitored regularly. The life span and tumor incidence were evaluated as well. As age advanced, the weight increased whereas food consumption and body temperature did not change. There was no significant substrain difference in these parameters. Exposure to melatonin or epitalon also failed to influence those indices. As age advanced, the incidence of irregular estrous cycles increased both in SAMP-1 and SAMR-1, whereas the treatment with both melatonin and epitalon prevented such disturbances. SAMP-1 revealed some features of accelerated aging as compared to SAMR-1. The mean life span of the 10% of the last survivors among treated SAMP-1 was shorter than that of SAMR-1, aging rate increased and mortality doubling time decreased. There was a direct correlation between body mass of the two substrains at the age of 3 and 12 months matched by body mass increase and longer life span. Melatonin or epitalon treatment was followed by longer mean and maximum survival in the 10% of the last survivors among SAMP-1. Melatonin involved decreased aging rate and increased mortality doubling time. Malignant lymphomas predominated in SAM without any significant difference in frequency between the substrains. While melatonin failed to influence tumor incidence or term of detection in SAMP-1, neither did epitalon affect frequency. However, it was followed by longer survival in tumor-free animals. No link between melatonin or epitalon treatment, on the one hand, and carcinogenesis, on the other, was reported in SAMR-1.
Short Peptides Protect Fibroblast-Derived Induced Neurons from Age-Related Changes.
Neurons become more vulnerable to stress factors with age, which leads to increased oxidative DNA damage, decreased activity of mitochondria and lysosomes, increased levels of p16, decreased LaminB1 proteins, and the depletion of the dendritic tree. These changes are exacerbated in vulnerable neuronal populations during the development of neurodegenerative diseases. Glu-Asp-Arg (EDR) and Lys-Glu-Asp (KED), and Ala-Glu-Asp-Gly (AEDG) peptides have previously demonstrated neuroprotective effects in various models of Alzheimer's disease. In this study, we investigated the influence of EDR, KED, and AEDG peptides on the aging of fibroblast-derived induced neurons. We used a new in vitro cellular model of human neuronal aging based on the transdifferentiation of aged dermal fibroblasts from elderly donors into induced cortical neurons. All peptides promote the arborization of the dendritic tree, increasing both the number of primary processes and the total length of dendrites. Tripeptides have no effect on the activity of mitochondria and lysosomes and the level of p16 protein in induced neurons. EDR peptide reduces oxidative DNA damage in induced neurons derived from elderly donor fibroblasts. Short peptides partially protect induced neurons from age-related changes and stimulate dendritogenesis in neurons. They can be recommended for use as neuroprotective agents.
Epitalon and colon carcinogenesis in rats: proliferative activity and apoptosis in colon tumors and mucosa.
The effect of the synthetic pineal peptide Epitalon (Ala-Glu-Asp-Gly) on proliferative activity in colon tumors, and in mucosal epithelial cells adjacent to and located far from tumors was studied in rats. To evaluate the effect of Epitalon on different stages of carcinogenesis, different treatment regimens were used: during the tumor initiation stage, during the tumor-promotion stage, or during the entire process of tumor development. Eighty 2-month-old male LIO rats were exposed weekly to five subcutaneous injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg body weight. Rats were divided into four groups. Control rats (group 1) received saline at a dose of 0.1 ml during the entire experiment. Rats in group 2 were treated with Epitalon at a dose of 1 micro g, five times a week, for 6 months, from the first injection of DMH till the end of the experiment. Rats in group 3 were treated with Epitalon after termination of the carcinogen injections. Rats in group 4 were treated with Epitalon only during the period of DMH exposure (for the first 5 weeks of the experiment). DMH induced proliferation of the secretory epithelium, and this phenomenon was accompanied by a decrease in the size of the stromal area and the area of lymph infiltration in colon tumors and in the colon mucosa adjacent to the tumors (group 1). Epitalon attenuated this effect, especially when the treatment was continued throughout the experiment (group 2). It increased the stromal areas, as well as that of lymphoid infiltration in the colon mucosa adjacent to the tumors. The intensity of lymphoid infiltration was activated in both the colon mucosa adjacent to a tumor and in the tumor. Mitotic activity of tumor cells was significantly inhibited by Epitalon when the treatment was given throughout the experiment (group 2). In parallel, a high level of apoptosis was seen in the same group. Thus, the strongest inhibitory effect of Epitalon on carcinogenesis in the colon mucosa was manifested when the treatment was continued throughout the experiment.
Tissue-specific effects of peptides.
Synthetic peptides (cytogens) Cortagen, Epithalon, Livagen, and Vilon stimulated the growth of explants from rat brain cortex, subcortical structures, liver, and thymus, respectively, in organotypic cultures. These peptides produced tissue-specific effects: they stimulated the growth of explants from tissues, whose cytomedins (peptide complexes) were used for chemical synthesis.
Effect of Peptide AEDG on Telomere Length and Mitotic Index of PHA-Stimulated Human Blood Lymphocytes.
We studied the effect of peptide AEDG on telomere length and mitotic index of PHA-stimulated blood lymphocytes from young (18-22 years, N=5) and middle-aged (49-54 years, N=6) men. In the younger age group, no significant changes in the mitotic index were detected, while in the middle-aged group, a decrease in this parameter was found in one case. The relative length of telomeric regions of metaphase chromosomes was evaluated by in situ fluorescence hybridization with DNA probes specific to telomeres. After incubation with peptide AEDG, significant changes in the relative telomere length were found in 7 of 11 individuals (3 cases in the younger age group and 4 cases in the middle age group). Significant increase in telomere length after exposure to peptide AEDG was revealed in 5 cases, including two individuals of the younger age group (by 41 and 55%) and three individuals of the middle age group (by 156, 18, and 76%). In one individual of the younger age group and in one of the middle-age group, a significant decrease in telomere length (by 37 and 15%, respectively) was found. A tendency to normalization of telomere lengths was noted: this parameter increased in individuals with initially lower telomere length relative to the group mean value and decreased in individuals with initially longer telomeres compared to the mean length in the group.
Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.
Female FVB/N HER-2/neu transgenic mice from the age of 2 months were subcutaneously injected with saline, the peptide Epitalon(R) (Ala-Glu-Asp-Gly) or with the peptide Vilon(R) (Lys-Glu) in a single dose of 1 microg/mouse for 5 consecutive days every month. Epitalon treatment reduced the cumulative number and the maximum size of tumors (p < 0.05). Furthermore, the number of mice bearing 1 mammary tumor was increased, whereas the number of mice bearing 2 or more mammary tumors was reduced in Epitalon-treated in comparison to saline-treated animals (p < 0.05). The size but not the number of lung metastases was reduced in Epitalon-treated compared to saline-treated mice (p < 0.05). The treatment with Vilon produced significant negative effects when compared to the control group, with an increased incidence of mammary cancer development (p < 0.05), a shorter mean latent period of tumors (p < 0.05) and an increased cumulative number of tumors (p < 0.05). A 3.7-fold reduction in the expression of HER-2/neu mRNA was found in mammary tumors from HER-2/neu transgenic mice treated with Epitalon compared to control animals. The expression of mRNA for HER-2/neu was also partially reduced in Vilon-treated mice, but it remained significantly higher in Vilon- than in Epitalon-treated animals (1.9-fold increase). The data demonstrate the inhibitory effect of Epitalon in the development of spontaneous mammary tumors in HER-2/neu mice, suggesting that a downregulation of HER-2/neu gene expression in mammary adenocarcinoma may be responsible, at least in part, for the antitumor effect of the peptide.
Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice.
From the age of 3 months until their natural deaths, female outbred Swiss-derived SHR mice were subcutaneously injected on 5 consecutive days every month with 0.1 ml of normal saline (control) or with 1.0 microg/mouse (approximately 30-40 microg/kg) of tetrapeptide Epitalon (Ala-Glu-Asp-Gly) dissolved in 0.1 ml saline. There were 54 mice in each group. The results of this study show that treatment with Epitalon did not influence food consumption, body weight or mean life span of mice. However, it slowed down the age-related switching-off of estrous function and decreased the frequency of chromosome aberrations in bone marrow cells (by 17.1%, P<0.05). It also increased by 13.3% the life span of the last 10% of the survivors (P<0.01) and by 12.3% the maximum life span in comparison with the control group. We also found that treatment with Epitalon did not influence total spontaneous tumor incidence, but inhibited the development of leukemia (6.0-fold), as compared with the control group. The data obtained suggest a geroprotector activity of Epitalon and the safety of its long-term administration in mice.
The Influence of Short Peptides on Cell Senescence and Neuronal Differentiation.
It has been previously shown that some short peptides are involved in various cellular processes, such as transcription modulation and regulation of differentiation mechanisms. In particular, the effect of peptides on the neuronal differentiation of human periodontal ligament stem cells has been demonstrated. The goal of this study was to assess the effect of KED, EDR, and AEDG short peptides in stimulating the transdifferentiation of fetal MSCs into induced neuronal cells and prevention of their senescence. We applied a novel in vitro technique for neuronal cell generation, which combines the use of microRNAs, transcription factors, and small molecules to transdifferentiate fetal mesenchymal stem cells into induced cortical neurons. It was shown that the application of AEDG and KED short peptides at the end of the transdifferentiation process decreases the expression of the cell cycle marker p21 by 15% and beta-galactosidase activity by 1.51-2.4 times. However, short peptides did not affect the expression levels of TUj-1 and LaminB1, whose expression also changes during neuronal differentiation. The experiments indicate the potential of AEDG and KED short peptides as modulators of neurogenesis and geroprotectors and suggest that they can be used as stimulators of neuronal differentiation.
Epitalon influences pineal secretion in stress-exposed rats in the daytime.
The content of C-Fos protein was tested in rat pinealocytes in the norm and stress and in case of intranasal administration of Epitalon (Ala-Glu-Asp-Gly), which regulated pineal secretion processes, presumably, via protooncogenes. Intact and osmotic-stress-exposed rats were used for the immunohistochemical detection of C-Fos protein. All animals were intranasally administered with Epitalon, the last infusion made in two hours before the biopsy. Simultaneously, light microscopy of the pineal parenchyma was performed in all groups of animals. A slight but significant C-Fos increase was observed only in stress-exposed pinealocytes of rats after intranasal Epitalon infusions. C-Fos was irregularly distributed throughout pineal cells. In stress, the clusters of 5 10 cells containing C-Fos in their cytoplasm were detected. The dilation of capillaries and pericapillary space induced by an osmotic stress was partially reduced by the intranasal infusions of Epitalon. Tetrapeptide Epitalon is synthesised on the basis of the amino acid composition of pineal peptide extract Epithalamin. Epitalon modulates pineal secretion only under a stress impact but never in the norm. It prevents osmotic-stress-induced pathologic changes in the pineal parenchyma structure. Besides, the physiological activity of Epitalon seems to be mediated by the activation of protooncogenes in pinealocytes.
Effect of epitalon on the lifespan increase in Drosophila melanogaster.
The geroprotector activity of epitalon, a synthetic tetrapeptide Ala-Glu-Asp-Gly, was studied on the Drosophila melanogaster wild strain Canton-S. The substance was added to the culture medium only at the developmental stage (from egg to larva). Epitalon significantly increased the lifespan (LS) of imagoes by 11-16% when applied at unprecedented low concentrations-from 0.001 x 10(-6) to 5 x 10(-6) wt.% of culture medium for males and from 0.01 x 10(-6) to 0.1 x 10(-6) wt.% of culture medium for females. The increase in LS did not depend on the substance dose. Effective concentrations of epitalon were 16,000-80,000,000 times lower than those of melatonin. The possible mechanisms of the antioxidant and regulatory effects of epitalon are discussed.
Effect of melatonin and tetrapeptide on gene expression in mouse brain.
A microchip technique was used to study expression of 16,897 clones from a cDNA library in the brain of mice receiving melatonin or tetrapeptide Epithalon (Ala-Glu-Asp-Gly). Expression of 53 transcripts in mouse brain underwent significant changes after treatment with the preparations. Melatonin and Epithalon modified expression of 38 and 22 transcripts, respectively. These preparations produced similar changes in the expression of 6 transcripts. Expression of 1 transcript (Rp119) was inhibited by melatonin, but induced by Epithalon. The target genes are physiologically related to the cell cycle, apoptosis, biosynthesis, processing, and transport of nucleic acids. Comparative study of gene expression in the brain and heart of CBA mice receiving melatonin and Epithalon suggest that these preparations have a tissue-specific biological effect.
Peptides: Prospects for Use in the Treatment of COVID-19.
There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.
Epithalon inhibits tumor growth and expression of HER-2/neu oncogene in breast tumors in transgenic mice characterized by accelerated aging.
Female transgenic FVB mice carrying breast cancer gene HER-2/neu were monthly injected with Vilon or Epithalon (1 microgram subcutaneously for 5 consecutive days) starting from the 2nd month of life. Epithalon markedly inhibited neoplasm development: the maximum size of breast adenocarcinomas was 33% lower than in the control (p < 0.05). The intensity of HER-2/neu mRNA expression in breast tumors of Epithalon-treated mice was 3.7 times lower than in control animals. These results indicate that Epithalon inhibits breast tumor development in transgenic mice, which is probably related to suppression of HER-2/neu expression.
Effect of epithalon on the incidence of chromosome aberrations in senescence-accelerated mice.
The incidence of chromosome aberrations in bone marrow cells of 12-month-old SAMP-1 female mice characterized by accelerated aging was 1.8 times higher than in wild-type SAMR-1 females and 2.2 times higher than in SHR females of the same age. Treatment with Epithalon (Ala-Glu-Asp-Gly) starting from the age of 2 months decreased the incidence of chromosome aberrations in SAMP-1, SAMR-1, and SHR mice by 20%, 30.1%, and 17.9%, respectively, compared to age-matched controls (p<0.05). Treatment with melatonin (given with drinking water in a dose of 20 mg/liter in night hours) had no effect on the incidence of chromosome aberrations in SHR mice. These data indicate antimutagenic effect of Epithalon, which probably underlies the geroprotective effect of this peptide.
Effect of vilon and epithalon on activity of enzymes in epithelial and subepithelial layers in small intestine of old rats.
Per os administration of Vilon (Lys-Glu) or Epithalon (Ala-Glu-Asp-Gly) to aged Wistar rats for 1 month significantly increased activity of membrane enzymes maltase and alkaline phosphatase in epithelial layer of the small intestine. In addition, Vilon significantly increased activity of cytosolic glycyl-L-leucine dipeptidase in the stromal and seromuscular layers of the small intestine in comparison with the control rats not treated with this agent. These findings suggest improvement of trophic and barrier functions of the small intestine and corroborate the hypothesis on the existence of not only epithelial, but also subepithelial enzymatic barrier supporting the enzyme system in the small intestine, especially in aged animals.
[The influence of peptides on the morphofunctional state of old rats kidneys.].
More than a quarter of the elderly and senile age population suffers from kidney pathology. For this reason, a prophylaxis of kidney diseases with the safe and effective nephroprotectors is a priority of gerontology. An influence of polypeptide kidney complex (PKC), peptides AED, EDL, AEDG on the functional state of old rats kidneys was studied in research. Administration of PKC, peptides AED and EDL increased diuresis by 1,2-1,4 times. PKC and peptide AED reduced urine protein level and protein excretion by 1,5-2,8 times. PKC, peptides AED and EDL increased distal sodium transport by 1,2-1,3 times. Peptides AED and EDL increased sodium excretion by 1,3 and 1,6 times, respectively. Renal effects of peptide AEDG resulted in a reduction of glomerular filtration rate by 21%, decrease in urine protein level by 3,1 times and protein excretion - by 2,5 times. Peptide AEDG reduced absolute sodium reabsorption by 1,3 times and increased distal sodium transport by 1,4 times. Realization of glomerular-tubular and tubular-tubular balances is verified by correlation between glomerular filtration rate (GFR) and absolute sodium reabsorption, proximal and distal sodium reabsorption. In kidney tissue a stimulation of the antioxidant enzymes activity on the background of inhibition of the peroxidation processes intensity was observed, which in complex with morphological data evidences the absence of nephrotoxic effects. PKC, peptides AED, EDL and AEDG may be considered as nephroprotective agents in kidney aging.
LCP2 mediates SUV39H1-driven cellular senescence-related chemoresistance in natural killer/T-cell lymphoma.
Natural killer/T-cell lymphoma (NKTCL) is an aggressive haematological malignancy with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. The mechanisms underlying multidrug resistance in NKTCL remain unclear and present an urgent challenge that must be addressed during clinical treatment. Multidrug-resistant NKTCL models were established using adriamycin (ADM), and cellular senescence was confirmed by markers including P16, P21, and senescence-associated β-galactosidase (SA-β-gal). Proteomic sequencing of plasma from clinical patients and resistant cells identified LCP2 as a key protein. Phosphoproteomics, mass spectrometry, and co-immunoprecipitation analyses revealed LCP2's role in mediating senescence-associated chemoresistance. An in vivo ageing microenvironment model was used to assess whether targeting the LCP2-mediated axis could eliminate chemoresistant senescent cells. Results show that ADM-resistant NKTCL cells exhibited phenotypic and senescence features. Of these, LCP2 expression was significantly reduced in the plasma of R/R NKTCL patients and in chemoresistant cells, correlating inversely with senescence marker SA-β-gal. Moreover, LCP2 knockdown enhanced the chemoresistance, senescent-associated secretory phenotype secretion, and G0/G1 cell cycle arrest in NKTCL cells. Mechanistically, LCP2 deficiency activated the IQGAP2/LaminA/C/SUV39H1 axis, thus driving DNA damage, telomere stress-induced senescence, and facilitating the formation of an immunosuppressive microenvironment. Importantly, targeting this axis with Epitalon and Chaetocin can partially eliminate therapy-induced senescent cells, enhance response to chemotherapeutics, and alleviate the immunosuppressive microenvironment to a certain extent in vivo. In conclusion, this study is the first to uncover LCP2 as a critical biomarker of senescence-related chemoresistance in NKTCL, providing a theoretical basis for the clinical translation of senolytics for treating R/R NKTCL.
Effect of Vilon and Epithalon on glucose and glycine absorption in various regions of small intestine in aged rats.
Vilon (Lys-Glu) and Epithalon (Ala-Glu-Asp-Gly) administered orally for 1 month improved transport characteristics of the small intestine in aged rats. Vilon enhanced passive glucose accumulation in the serous fluid in inverted sac made from the distal region of the small intestine, while Epithalon enhanced this process in the medial region. Vilon stimulated active glucose accumulation in the serous sac of the medial small intestine, Epithalon - in the proximal and distal small intestinal segments. Glycine absorption increased only in the proximal intestinal segment under the effect of Epithalon.
Quick links (PubMed)
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