Research in plain language
Epitalon
What it is
Epitalon (also spelled Epithalon, sequence Ala-Glu-Asp-Gly, abbreviated AEDG) is a synthetic four-amino-acid peptide developed by Vladimir Khavinson's group in St. Petersburg as the minimal active fragment of the pineal-gland extract Epithalamin. It has been studied mostly in Russian-led animal and cell experiments as a candidate geroprotector, where it has been reported to activate telomerase in cultured human cells, shift gene expression, and modestly extend the lifespan of the longest-lived rodents and reduce some tumor rates.
How studies used it
- Model
- Mouse (female Swiss-derived SHR strain, 54 per group), aging cohort
- Studied for
- Aging and spontaneous tumor incidence (geroprotection)
- Dose
- Published as 1.0 microgram per mouse per injection. The paper did not report body weight; at a standard adult SHR mouse of about 25 g this is approximately 0.04 mg/kg (about 40 micrograms/kg). Per-kg figure is an approximation from a standard lab weight, not a reported weight.
- Dosing
- 5 consecutive days each month
- Route
- subcutaneous
- Duration
- From 3 months of age until natural death (about 2 years)
Effects measured: No effect on mean life span. Life span of the last 10% of survivors increased by 13.3% (P<0.01) and maximum life span by 12.3% versus controls. No change in total spontaneous tumor incidence, but leukemia development was 6.0-fold lower. Frequency of chromosome aberrations in bone marrow cells fell by 17.1% (P<0.05). The peptide slowed age-related loss of estrous cycling. No effect on food intake or body weight.
Side effects: No adverse events reported in this study; no effect on body weight or food consumption, authors described long-term administration as safe.
- Model
- Rat (female, three groups under different light regimens)
- Studied for
- Life span and spontaneous tumor development under standard, natural, and constant light
- Dose
- Published as 0.1 microgram per rat per injection. Body weight not reported; at a standard adult female rat of about 250 g this is roughly 0.0004 mg/kg (about 0.4 micrograms/kg). Per-kg figure is an approximation from a standard lab weight, not a reported weight.
- Dosing
- Once daily, 5 times per week
- Route
- subcutaneous
- Duration
- From 4 months of age until death
Effects measured: Under standard light/dark: no change in life span (null result). Under natural North-West Russian light: maximum life span extended by 95 days and the mean life span of the longest-lived 10% by 137 days; tumor development significantly inhibited. Under constant light: maximum life span extended by only 24 days and mean of the top 10% by 43 days, with negligible effect on tumors. The benefit was therefore confined to one lighting condition.
Side effects: No adverse events reported in this study.
- Model
- Rat (outbred male LIO, 80 animals in 4 groups), chemically induced colon cancer
- Studied for
- Colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH)
- Dose
- Published as 1 microgram of Epitalon per rat per injection (carcinogen DMH given at 21 mg/kg). Body weight of the animals was not reported; at a standard adult LIO rat of about 250 g, 1 microgram is roughly 0.004 mg/kg (about 4 micrograms/kg). Per-kg figure is an approximation from a standard lab weight, not a reported weight.
- Dosing
- 5 days per week (DMH given as weekly injections)
- Route
- subcutaneous
- Duration
- Across the whole experiment, or only after carcinogen, or only during carcinogen exposure, depending on group
Effects measured: Colon carcinomas developed in 90-100% of DMH-treated rats in all groups. Mean number of colon tumors per rat was 4.1 (saline control), 2.7 (Epitalon throughout, significant), 3.7 (Epitalon after carcinogen, not significant), and 2.9 (Epitalon during carcinogen, significant). In the throughout-treatment group tumors were smaller and incidence and multiplicity in ascending and descending colon were significantly reduced. A trend toward fewer rectal tumors and inhibition of jejunal and ileal tumors was also reported.
Side effects: No adverse events reported in this study.
- Model
- Cell culture (in vitro), human gingival mesenchymal stem cells (hGMSCs)
- Studied for
- Neurogenic differentiation / gene expression during neurogenesis
- Dose
- 0.01 micrograms/mL. Using the AEDG molecular weight of about 390 g/mol this is approximately 2.6 x 10^-8 M (about 26 nM).
- Dosing
- Added to culture medium
- Route
- in vitro
- Duration
- 1 week
Effects measured: AEDG/Epitalon increased mRNA expression of the neurogenic markers Nestin, GAP43, beta-Tubulin III and Doublecortin by 1.6 to 1.8 times, with matching increases at the protein level by immunofluorescence. Molecular modelling suggested the peptide binds linker histones H1/6 and H1/3 at specific DNA-interacting sites, proposed as an epigenetic mechanism.
Side effects: No adverse events reported in this study (in vitro; no toxicity endpoint).
- Model
- Cell culture (in vitro), telomerase-negative human fetal lung fibroblasts
- Studied for
- Telomerase activation and telomere length (cellular aging / Hayflick limit)
- Dose
- Molar concentration not stated in the published abstract; reported only as addition of Epithalon peptide to the fibroblast culture medium. Concentration could not be verified from the PubMed record.
- Dosing
- Added to culture medium across passages
- Route
- in vitro
- Duration
- Across serial passaging (controls stopped dividing at passage 34)
Effects measured: Adding Epithalon to telomerase-negative human fetal fibroblasts induced expression of the telomerase catalytic subunit, telomerase enzymatic activity, and telomere elongation. In the companion follow-up, peptide-treated cells with re-elongated telomeres made about 10 extra divisions (reaching passage 44 versus 34 in controls) and continued dividing, described by the authors as overcoming the Hayflick limit.
Side effects: No adverse events reported in this study (in vitro; no toxicity endpoint).
How solid the evidence is
The evidence for Epitalon is weak and should be read with caution. It is almost entirely preclinical (rodent and cell-culture) and dominated by a single research group around Vladimir Khavinson at one institute in St. Petersburg, so independent replication in Western peer-reviewed journals is sparse. Most reports are from the early-to-mid 2000s, are not large randomized controlled trials, and several are not in high-impact journals. The lifespan effects in animals are real but modest and selective: in the SHR mice (PMID 14501183) there was NO effect on mean life span and no change in total tumor count, only an effect on the longest-lived 10% and on leukemia specifically. The rat light-regimen study (PMID 18856211) is an honest mixed result, showing essentially NO lifespan benefit under standard light and a benefit only under one specific lighting condition, which signals the effect is conditional rather than robust. The two human-cell telomerase papers (PMID 12937682 and its follow-up) are in-vitro only, did not report the peptide concentration in their abstracts, and telomere lengthening in a dish does not establish any human anti-aging benefit. The neurogenesis study (PMID 32019204) is a clean in-vitro experiment but measures only marker gene/protein expression in stem cells, not a clinical outcome. Animal doses in these papers were given per animal (micrograms per mouse or rat), not per kilogram; the per-kg values shown here are approximations using standard laboratory body weights because the papers did not report the animals' weights. Crucially, there is little robust human Epitalon (the tetrapeptide) trial evidence: the often-cited human "geroprotector" and 12-year mortality data come from Epithalamin, the pineal-gland EXTRACT, which is a different preparation and should not be presented as evidence for the tetrapeptide. No serious adverse events were reported in these studies, but they were small, single-group or short, and not designed for safety. There is no established, validated human dosing protocol.
Sources
- 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.(PMID 14501183)
- 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. Bull Exp Biol Med. 2007;144(6):825-30.(PMID 18856211)
- Anisimov VN, Khavinson VKh, Popovich IG, Zabezhinski MA. Inhibitory effect of peptide Epitalon on colon carcinogenesis induced by 1,2-dimethylhydrazine in rats. Cancer Lett. 2002;183(1):1-8.(PMID 12049808)
- 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.(PMID 32019204)
- Khavinson VKh, Bondarev IE, Butyugov AA. Epithalon peptide induces telomerase activity and telomere elongation in human somatic cells. Bull Exp Biol Med. 2003;135(6):590-2.(PMID 12937682)
- Anisimov VN, Khavinson VKh, Zavarzina NIu, et al. Effect of pineal peptide on the parameters of the biological age and life span in mice (CBA strain, Epithalon). Ross Fiziol Zh Im I M Sechenova. 2001;87(1):125-36.(PMID 11227856)
- Khavinson VKh, Bondarev IE, Butyugov AA, Smirnova TD. Peptide promotes overcoming of the division limit in human somatic cell (Epithalon, Hayflick limit follow-up). Bull Exp Biol Med. 2004;137(5):503-6.(PMID 15455129)
- Goncharova ND, Khavinson VKh, Lapin BA. Regulatory effect of Epithalon on production of melatonin and cortisol in old monkeys. Bull Exp Biol Med. 2001;131(4):394-6.(PMID 11550036)
- Korkushko OV, Lapin BA, Goncharova ND, et al. Normalizing effect of the pineal gland peptides on the daily melatonin rhythm in old monkeys and elderly people (Epithalamin and Epitalon in humans + monkeys). Adv Gerontol. 2007;20(1):74-85.(PMID 17969590)
Study data, research use only. No established human dosing protocol.