Epithalon

What Epithalon is

Epithalon (also written Epitalon, and in the Russian literature often simply AEDG) is a synthetic tetrapeptide with the sequence Ala-Glu-Asp-Gly. It was not isolated from any tissue. It was designed in the 1990s by Vladimir Khavinson and colleagues at the St Petersburg Institute of Bioregulation and Gerontology, who reasoned from the amino acid composition of Epithalamin, a polypeptide extract of bovine pineal gland the same group had studied since the 1970s, that a short peptide built from its most abundant residues might reproduce the extract's activity [14]. The Institute's later work reports that a peptide of this sequence can be detected in pineal extract, but the research material has always been made by chemical synthesis, and the name is the group's coinage rather than a chemical name.

Three structural points matter for a laboratory. The peptide is very short, four residues, three of them acidic, and at neutral pH carries a net charge of about −3, which makes it highly water-soluble and prone to binding cations. It contains no cysteine, no aromatic residue and no non-natural amino acid, so there is no disulphide to protect, no lipid chain and, importantly for analysis, essentially no UV absorbance above 220 nm. And with a molecular weight under 400 Da it sits at the boundary between a peptide and a small molecule, with consequences for handling and analysis that follow below.

Research-grade Epithalon is supplied as a white lyophilised powder, usually as the acetate or trifluoroacetate salt. The reference identifiers for the free peptide are in the table; the figures on any batch certificate should agree with them within the precision of the method used.

How the literature describes its mechanism

No receptor for Epithalon has been identified and no binding partner has been demonstrated by a direct biophysical method. The originating group's position is that very short peptides of this kind pass into the nucleus and act on chromatin, binding DNA or histones and so altering transcription of particular genes. The evidence offered for this is almost entirely computational and inferential.

The most concrete version of the argument is a 2020 paper in Molecules by Khavinson and collaborators at the University of Chieti. Human gingival mesenchymal stem cells from five donors were cultured for a week with AEDG at 0.01 µg/mL, and the authors reported increases of roughly 1.6- to 1.8-fold in the mRNA for nestin, GAP43, β-tubulin III and doublecortin, with corresponding immunofluorescence. Alongside this they ran molecular docking of the tetrapeptide against histone models and found the most favourable predicted binding to the linker histones H1/3 and H1/6, at sites that contact DNA. The docking was not tested experimentally, and the paper presents the epigenetic mechanism as a hypothesis [3].

The second strand is the telomerase claim, which is the reason the compound is discussed at all outside Russia. In 2003 Khavinson, Bondarev and Butyugov reported in the Bulletin of Experimental Biology and Medicine that adding Epithalon to a culture of normal human somatic cells, which do not ordinarily express telomerase, induced telomerase activity, elongated telomeres and allowed the culture to divide past its usual limit [1]. The paper is three pages long, describes a single cell type from a single source, does not report replicates or statistics in the form a reader would now expect, and was never followed by a full-length paper with the methods set out. A 2019 report from the Institute measured telomere length by fluorescence in situ hybridisation in stimulated lymphocytes from eleven men and found that it changed significantly in seven, lengthening in five and shortening in two; the authors called this a normalising effect [2]. A sceptical reader would call it a mixed result in a small sample.

The first independent test of the claim was published only in 2025. Al-Dulaimi, Thomas, Matta and Roberts at Brunel University London treated two breast cancer lines and two normal cell types (IBR.3 fibroblasts and HMEC mammary epithelial cells) with Epithalon at 0.1 to 1.0 µg/mL and measured telomere length by qPCR, hTERT mRNA, telomerase activity by TRAP and alternative lengthening of telomeres (ALT) by the C-circle assay. They reported telomere lengthening in all four cell types; in the normal cells this came with increased hTERT mRNA and TRAP activity after three weeks, while in the cancer lines TRAP activity did not rise and the lengthening was attributed to ALT. Treatment durations differed between cell types, the panel is small, and the paper carries a published correction, so it is a first replication rather than a definitive one, but it is the only one that exists [4].

The third strand concerns the pineal gland itself. Because Epithalon was designed as a surrogate for a pineal extract, the Institute has repeatedly reported that it restores melatonin production and circadian rhythm in aged animals and elderly people, and that Epithalamin and Epithalon share antioxidant properties, measured as reduced lipid peroxidation and increased superoxide dismutase activity in rodent tissue [10]. These claims are embedded in the clinical reports discussed below rather than established by dedicated pharmacology, and the Araj review notes that at least one isolated-pineal preparation showed no effect on melatonin release [14].

For an in-vitro programme, then, the published readouts are telomere length and telomerase activity, histone interaction (modelled, not measured), neural-lineage marker expression and oxidative-stress markers, at concentrations from 0.01 to 1 µg/mL.

The research record

The research record on Epithalon is large by count, spans in-vitro, animal and human work, and runs over thirty years, yet almost all of it comes from a single institution. A reader assessing it should hold that fact in mind throughout.

Rodent lifespan and tumour studies. The Institute's collaboration with Vladimir Anisimov at the Petrov Institute of Oncology produced the best-documented animal work. In 2001 Anisimov, Khavinson, Mikhalski and Yashin published, in Mechanisms of Ageing and Development, a study of 50 female CBA mice given saline, the thymic dipeptide Lys-Glu or Ala-Glu-Asp-Gly subcutaneously for five consecutive days each month from six months of age until death. The tetrapeptide group showed a 5.3% increase in mean survival, a ten-month increase in maximum lifespan and fewer spontaneous tumours, mainly lung adenomas [5]. A 2003 study in Biogerontology repeated the design in 54 outbred SHR mice per group, at 1 µg per mouse from three months of age. Here mean lifespan was unchanged, 456 days against 455; the last 10% of survivors lived 13% longer (803 against 709 days); overall tumour incidence was the same (32% against 36%); mammary adenocarcinomas were if anything more frequent in the treated group (17 against 12, not significant); and the only tumour type that fell was leukaemia, from six cases to one. Chromosome aberrations in bone marrow at twelve months were 17% lower, on four animals per group [7]. A 2002 paper in the International Journal of Cancer, with co-authors in Ancona and Bologna, reported fewer and smaller mammary adenocarcinomas in HER-2/neu transgenic mice and lower expression of the transgene [6]. A 2007 rat study found no effect on lifespan under standard lighting, with an effect on maximum lifespan appearing only in animals kept under constant or natural northern light, which shorten lifespan on their own [8]. Rosenfeld and colleagues reported in 2002 that the peptide reduced bone-marrow chromosome aberrations in senescence-accelerated SAMP-1 mice and two other strains by 18 to 30%, while melatonin in the same design had no effect [9].

Read together, the rodent studies are consistent on a modest effect on the tail of the survival curve and on chromosome aberrations, and inconsistent on tumour incidence and mean lifespan. The same two laboratories conducted all of them, and no independent rodent lifespan study has been published.

Elderly-patient studies. The Institute and the Kiev Institute of Gerontology have reported long-term studies in elderly patients with coronary disease, published in 2006 and 2011 and described as randomised. They used Epithalamin, the bovine pineal extract, not the synthetic tetrapeptide; the 2011 title's "pituitary" is a translation error for pineal. In the 2011 report, 39 patients received six courses of Epithalamin over three years alongside standard treatment and 40 received standard treatment alone, and the authors reported slower cardiovascular ageing, normalisation of the melatonin circadian rhythm and lower mortality over fifteen years [12]; the 2006 report gives a 28% difference in deaths over twelve years [11]. The weaknesses are evident from the abstracts: no placebo, no blinding, no description of the allocation method, a small sample, outcome measures such as "functional age" devised by the authors, and no reproduction elsewhere. The retinitis pigmentosa series and the circadian study in women that the Institute also cites share these limitations [14]. These studies are background on the extract from which Epithalon was derived; they are not evidence about the synthetic peptide.

Independent work. Until 2025 there was, to our knowledge, no primary research on Epithalon from a laboratory without an author in common with St Petersburg. The Brunel telomere study is discussed above [4]. A 2025 paper from Chieti reported improved scratch-wound closure in an in-vitro model of diabetic retinopathy; Khavinson is a co-author, so it is a collaboration rather than an independent test [13]. The 2025 review by Araj and colleagues in the International Journal of Molecular Sciences is the first attempt from outside the originating group to collect the literature. The authors conclude that the mechanism remains unclear, that toxicity, genotoxicity and carcinogenicity have not been adequately characterised, that several studies report null or contradictory findings depending on strain, age and dose, and that physicochemical data on the peptide are "very limited" [14].

Regulatory trials. No clinical trial of Epithalon has been registered with the US, UK or EU authorities, and nothing resembling a formal toxicology package has been published. The safety statements in the Institute's reviews record the absence of reported adverse events in its own studies; they are not the output of a regulatory programme.

Taking the record as a whole. Epithalon is a chemically simple, well-defined tetrapeptide with a thirty-year literature of modest and partly inconsistent effects in rodents, an in-vitro telomerase claim that waited twenty-two years for a first independent replication, and a body of clinical reports that concern a different material. The evidence base is, with the exceptions noted, the work of one research group. That is a legitimate basis for in-vitro research into a well-defined question. It is not a basis for claims about ageing in humans, and this page makes none.

Regulatory status in the United Kingdom

Epithalon is not licensed as a medicine in the UK or anywhere else. The bovine extract Epithalamin was registered as a medicinal product in Russia; Epithalon, the synthetic tetrapeptide, has not been approved as an active pharmaceutical ingredient in any jurisdiction [14]. It has no pharmacopoeial monograph and no approved therapeutic use. BuyUK Peptides supplies it as a research chemical for in-vitro laboratory use under the Terms of Sale. It is not for human or veterinary administration. Purchasers must be 18 or over and are responsible for ensuring their use of the material complies with the laws and institutional rules that apply to them. Our guide to the UK rules on research compounds sets this out in more detail.

Epithalon is not named on the World Anti-Doping Agency's 2026 Prohibited List, and UK Anti-Doping has issued no specific notice about it. That is not clearance. Section S0 of the List prohibits at all times "any pharmacological substance which is not addressed by any of the subsequent sections of the List and with no current approval by any governmental regulatory health authority for human therapeutic use", naming BPC-157 only as an example of the class [15]. Epithalon meets that definition, and any researcher whose institution is subject to anti-doping rules should treat it as prohibited under S0.

Handling, storage and stability

Epithalon is supplied lyophilised in a glass vial with a rubber stopper and an aluminium flip-off crimp. It is one of the simplest materials in the catalogue to handle: no disulphide, no lipid, no aromatic residue and nothing to oxidise. The Asp-Gly bond is the one feature that needs a specific note.

Sealed vial. Store at 2–8 °C for routine use and at −20 °C or below for storage beyond a few months. Protect from light as a precaution. The powder is hygroscopic, as short acidic peptide salts tend to be: allow a cold vial to reach room temperature before opening and recap promptly.

Reconstitution. For most in-vitro work the compound is reconstituted in sterile water or the buffer of the assay. A tetrapeptide with three carboxylates dissolves essentially on contact; add the solvent down the side of the vial and swirl. There is no need for sonication, warming or co-solvent. A 10 mg vial reconstituted in 1 mL gives roughly 25 mM, and a solution of the free acid at that concentration is distinctly acidic; if the assay is pH-sensitive, prepare the stock in buffered medium or check the pH after dissolution. The reconstitution calculator gives the volume to add for a target concentration.

Reconstituted solution. Keep at 2–8 °C. The chemical liability of the sequence is the Asp-Gly motif at positions 3–4, the classic site of succinimide formation and isomerisation to the iso-aspartyl peptide, which proceeds in aqueous solution at neutral and mildly basic pH over days to weeks. The iso-aspartyl product has the same mass as the parent, so it is invisible to routine LC-MS. The conservative practice is to prepare working solutions fresh, use a stock within 14 days at 2–8 °C, and aliquot and freeze at −20 °C or below for longer storage. Avoid phosphate buffer above pH 7.5 for storage.

Solubility. Epithalon is freely soluble in water and all common aqueous buffers. It does not foam, aggregate or adsorb appreciably to plastic, and a standard 0.22 µm membrane is adequate for sterile filtration. Because it carries three carboxylates it binds calcium and magnesium; at millimolar concentrations in culture medium that can alter the free ion concentration, and a vehicle control matched for pH and ionic strength is good practice.

What a sound certificate for Epithalon looks like

Every batch we release carries an independent certificate of analysis, and the figures from it are transcribed on the product page and in the certificate register. For Epithalon a certificate should contain the following, and a reader should be able to check each item against this monograph. Two of the standard peptide tests behave differently for a molecule this small.

Purity by RP-HPLC. Reversed-phase HPLC on a C18 column reports purity as the area of the main peak as a percentage of all integrated peaks. For Epithalon the detection wavelength matters more than usual: with no aromatic residue the peptide absorbs only through its amide bonds, so detection must be at 210–214 nm, and a certificate reporting purity at 254 or 280 nm has measured nothing. The peptide is also very polar and elutes early on C18, so a chromatogram showing the main peak resolved from the solvent front is more informative than a number alone. A good batch shows purity of 98% or above, and above 99% is routine for a four-residue sequence. The principal impurities are deletion sequences and, in older material, the iso-aspartyl isomer.

Identity by LC-MS. Electrospray mass spectrometry confirms that the main peak has the expected mass. For Epithalon the average molecular weight is 390.35 Da and the monoisotopic mass is 390.14 Da. A molecule this small appears almost exclusively as the singly charged ion, [M+H]+ 391.1 in positive mode or [M−H]− 389.1 in negative mode, and the observed mass should agree with theory to within 0.3 Da. Sodium adducts at +22 and loss of water at −18 are common artefacts for a polyacidic peptide and should not be mistaken for impurities.

Net peptide content. Lyophilised peptides contain bound water and counter-ions, and for a short, highly charged peptide the counter-ion fraction is larger than usual: a trifluoroacetate salt of Epithalon can be 20–30% TFA by mass. Net peptide content, where reported, expresses the fraction that is actual peptide. For a compound whose published effects are concentration-dependent over a tenfold range, this figure matters for preparing stocks of accurate concentration.

Endotoxin. Where the batch has been tested, a limulus amoebocyte lysate (LAL) result is reported in endotoxin units per milligram. This is relevant to the stem-cell and lymphocyte assays in which Epithalon is most often studied, where endotoxin alters gene expression on its own.

Our guide to reading a certificate of analysis goes through a complete report line by line.

Related compounds

Epithalon is grouped here with other short, unlipidated, cysteine-free peptides that handle similarly at the bench but have little else in common. KPV, the C-terminal tripeptide of α-melanocyte-stimulating hormone, is the closest analogue in size and solubility, and has a literature on inflammatory signalling that, unlike Epithalon's, comes from several independent laboratories. MOTS-c, a mitochondrial-encoded 16-residue peptide, is the other compound in the catalogue discussed in the context of ageing, and is a useful contrast: its proposed AMPK mechanism has direct biochemical support and multiple independent groups behind it. NAD+ is not a peptide, but it is the compound most often set beside Epithalon in discussions of cellular ageing, and the two together illustrate the distance between a metabolite with a defined role in dozens of enzyme reactions and a tetrapeptide with no identified target.

Frequently asked questions

Is Epithalon the same as Epithalamin? No. Epithalamin is a polypeptide extract of bovine pineal gland; Epithalon is a synthetic four-residue peptide designed to stand in for it [14]. The long-term clinical reports from St Petersburg and Kiev used the extract, not the peptide [11, 12].

Does Epithalon activate telomerase? The originating group reported that it did, in one short paper in 2003 [1]. The first independent test, from Brunel University London in 2025, found increased hTERT expression, telomerase activity and telomere length in two normal cell types, and lengthening by a different mechanism in two cancer lines [4]. That is one replication in a small panel of cells, and no independent in-vivo test exists.

Are there any human trials? Not of Epithalon. The clinical studies from the originating group used Epithalamin and were small, unblinded and without placebo [11, 12]. No trial of Epithalon is registered in the UK, the EU or the United States.

Is it on the WADA list? It is not named, but it falls within the S0 definition of non-approved substances, which are prohibited at all times [15].

How long does a sealed vial last? Short lyophilised peptides of this kind are stable for years at −20 °C and for many months at 2–8 °C. In solution the Asp-Gly bond slowly isomerises, so working solutions should be made fresh. The batch certificate reports the test date.

Is this material for human use? No. It is supplied for in-vitro research only.

References

1. Khavinson VKh, Bondarev IE, Butyugov AA. Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bulletin of Experimental Biology and Medicine. 2003;135(6):590–592. doi:10.1023/A:1025493705728. PMID 12937682.
2. Khavinson VKh, Pendina AA, Efimova OA, et al. Effect of peptide AEDG on telomere length and mitotic index of PHA-stimulated human blood lymphocytes. Bulletin of Experimental Biology and Medicine. 2019;168(1):141–144. doi:10.1007/s10517-019-04664-0.
3. Khavinson V, Diomede F, Mironova E, et al. AEDG peptide (Epitalon) stimulates gene expression and protein synthesis during neurogenesis: possible epigenetic mechanism. Molecules. 2020;25(3):609. doi:10.3390/molecules25030609.
4. Al-Dulaimi S, Thomas R, Matta S, Roberts T. Epitalon increases telomere length in human cell lines through telomerase upregulation or ALT activity. Biogerontology. 2025;26(5):178. doi:10.1007/s10522-025-10315-x. PMID 40908429.
5. Anisimov VN, Khavinson VKh, Mikhalski AI, Yashin AI. Effect of synthetic thymic and pineal peptides on biomarkers of ageing, survival and spontaneous tumour incidence in female CBA mice. Mechanisms of Ageing and Development. 2001;122(1):41–68. doi:10.1016/S0047-6374(00)00184-6.
6. Anisimov VN, Khavinson VKh, Provinciali M, et al. Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. International Journal of Cancer. 2002;101(1):7–10. doi:10.1002/ijc.10570. PMID 12209581.
7. Anisimov VN, Khavinson VKh, Popovich IG, et al. Effect of Epitalon on biomarkers of aging, life span and spontaneous tumor incidence in female Swiss-derived SHR mice. Biogerontology. 2003;4(4):193–202. doi:10.1023/A:1025114230714.
8. Vinogradova IA, Bukalev AV, Zabezhinski MA, Semenchenko AV, Khavinson VKh, Anisimov VN. Effect of Ala-Glu-Asp-Gly peptide on life span and development of spontaneous tumors in female rats exposed to different illumination regimes. Bulletin of Experimental Biology and Medicine. 2007;144(6):825–830. doi:10.1007/s10517-007-0441-z. PMID 18856211.
9. Rosenfeld SV, Togo EF, Mikheev VS, et al. Effect of Epithalon on the incidence of chromosome aberrations in senescence-accelerated mice. Bulletin of Experimental Biology and Medicine. 2002;133(3):274–276. doi:10.1023/A:1015899003974. PMID 12360351.
10. Kozina LS, Arutjunyan AV, Khavinson VKh. Antioxidant properties of geroprotective peptides of the pineal gland. Archives of Gerontology and Geriatrics. 2007;44(Suppl 1):213–216. doi:10.1016/j.archger.2007.01.029. PMID 17317455.
11. Korkushko OV, Khavinson VKh, Shatilo VB, Antonyuk-Shcheglova IA. Geroprotective effect of epithalamine (pineal gland peptide preparation) in elderly subjects with accelerated aging. Bulletin of Experimental Biology and Medicine. 2006;142(3):356–359. doi:10.1007/s10517-006-0365-z. PMID 17426848.
12. Korkushko OV, Khavinson VKh, Shatilo VB, Antonyk-Sheglova IA. Peptide geroprotector from the pituitary gland inhibits rapid aging of elderly people: results of 15-year follow-up. Bulletin of Experimental Biology and Medicine. 2011;151(3):366–369. doi:10.1007/s10517-011-1332-x. PMID 22451889.
13. Gatta M, Dovizio M, Milillo C, et al. The antioxidant tetrapeptide Epitalon enhances delayed wound healing in an in vitro model of diabetic retinopathy. Stem Cell Reviews and Reports. 2025;21(6):1822–1834. doi:10.1007/s12015-025-10911-x. PMID 40493162.
14. Araj SK, Brzezik J, Mądra-Gackowska K, Szeleszczuk Ł. Overview of Epitalon: highly bioactive pineal tetrapeptide with promising properties. International Journal of Molecular Sciences. 2025;26(6):2691. doi:10.3390/ijms26062691. PMID 40141333.
15. World Anti-Doping Agency. The Prohibited List 2026. Effective 1 January 2026. wada-ama.org/en/prohibited-list.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.