Epitalon

Epitalon is the synthetic tetrapeptide Ala-Glu-Asp-Gly. It is also written epithalon or epithalone, and abbreviated AEDG. It was designed in St Petersburg from the amino acid makeup of epithalamin, a peptide extract of bovine pineal gland. The two names are often confused. Epithalamin is the extract, and epitalon is the four-residue peptide. Later, mass spectrometry found the peptide directly in a pineal polypeptide complex.

Free amino acids and di-, tri- and pentapeptides were also present (Khavinson et al., 2017). A 2025 review sums up 25 years of in vitro, in vivo and in silico work. It notes that physicochemical and structural work on the peptide still lags behind the biological work (Araj et al., 2025).

Sequence and aliases come from PubChem.

Published work on epitalon falls into six areas. Each summary below states the model used. One caveat applies to the whole field. PubMed holds roughly 160 records that mention the peptide. About two thirds list V. Kh. Khavinson or V. N. Anisimov as an author. Both are from the St Petersburg Institute of Bioregulation and Gerontology. Many of these papers are in a small set of Russian-language journals. Replication by other groups exists, but it is recent and narrow. The only indexed study typed as a controlled clinical trial also comes from that group (Khavinson et al., 2002).

Model-organism survival studies

In Drosophila melanogaster, the peptide was added to the culture medium at the developmental stage. This was reported to raise the lifespan of adult flies by 11 to 16 percent. It was seen across a wide concentration range. There was no clear link between concentration and effect (Khavinson et al., 2000).

Female outbred SHR mice got the peptide monthly from three months of age until natural death. Mean survival did not change. The reported differences were a slower age-related change in estrous function and fewer chromosome aberrations in bone marrow cells. The last tenth of the cohort also survived 13.3 percent longer. And the leukemia rate was lower (Anisimov et al., 2003).

Tumor models in rodents

Female HER-2/neu transgenic mice got the peptide monthly from two months of age. This was linked to a lower cumulative number and smaller maximum size of mammary tumors. There was also a 3.7-fold drop in HER-2/neu messenger RNA in tumor tissue. A comparison dipeptide, Vilon, was linked to more mammary tumors and earlier onset, although it also partly lowered HER-2/neu messenger RNA (Anisimov et al., 2002). In rats exposed to 1,2-dimethylhydrazine, some groups got the peptide throughout or during carcinogen exposure. These groups had fewer colon tumors per animal than controls (Anisimov et al., 2002).

Telomerase and telomere length in cell culture

The most cited claim in this field is that the peptide induces telomerase activity. The first report added it to telomerase-negative human fetal fibroblast cultures. It described expression of the catalytic subunit, enzyme activity and telomere elongation (Khavinson et al., 2003). In 2025, an outside group in London added the peptide to breast cancer lines, normal epithelial cells and fibroblasts. It found telomere lengthening that rose with concentration.

In the normal cells this worked through hTERT and telomerase. In the cancer lines it worked through alternative lengthening of telomeres (Al-Dulaimi et al., 2025). Note that this paper carries a published correction (PMID 41240216). The St Petersburg group also studied human blood lymphocytes. It reported changes in relative telomere length in 7 of 11 participants, in both directions (Khavinson et al., 2019).

Oocyte and embryo models

Two outside groups have used the peptide in reproductive cell biology. One group cultured mouse oocytes aged after ovulation, with 0.1 mM of the peptide in the medium. At 24 hours, this was linked to lower reactive oxygen species and fewer spindle defects. It was also linked to higher mitochondrial membrane potential and less apoptosis (Yue et al., 2022). The other group worked on bovine in vitro embryo production. It used the peptide to activate telomerase in cumulus-oocyte complexes. It found gains in maturation rate and post-thaw blastocyst hatching (Ullah et al., 2025).

Endocrine and pineal studies, including a negative finding

In old rhesus monkeys, the peptide was reported to raise evening melatonin. It was also said to normalize the circadian pattern of cortisol (Khavinson et al., 2001). A later study in the same colony found that the peptide lowered basal glucose and insulin in old animals. It also sped glucose disappearance in them, with no change in young ones (Goncharova et al., 2005).

A perifusion study used pineal glands from young and old rats. It found no significant effect on melatonin secretion at concentrations from 10⁻⁴ to 10⁻⁶ M. The response to a beta-adrenergic agonist did not change either. The authors concluded that the peptide does not appear to control melatonin secretion in that preparation (Djeridane et al., 2003).

Proposed mechanism and recent cell work

The St Petersburg group suggests that short peptides bind directly to DNA and histones. In one study, fluorescence-labeled epitalon, pinealon and testagen entered the nucleus and nucleolus of HeLa cells. They also quenched the fluorescence of labeled short DNA strands in a sequence-dependent way (Fedoreyeva et al., 2011). Molecular modeling has been used to argue for preferential binding to histones H1/3 and H1/6. The same paper found higher expression of neurogenic markers in human gingival mesenchymal stem cells (Khavinson et al., 2020).

An Italian and Russian team used a scratch model with retinal pigment epithelial cells held in high glucose. It reported that the peptide restored delayed closure (Gatta et al., 2025).