EPITHALON

Epithalon (also known as Epitalon) is a synthetic tetrapeptide with the amino acid sequence Ala-Glu-Asp-Gly (AEDG), originally developed in the 1980s by Professor Vladimir Khavinson at the St. Petersburg Institute of Bioregulation and Gerontology. It was synthesized based on Epithalamin, a bovine pineal gland extract, and later confirmed to exist naturally in pineal tissue. Epithalon has been extensively studied for its geroprotective properties, primarily through activation of telomerase enzyme, modulation of pineal gland function, and enhancement of melatonin synthesis. Research over 25 years includes multiple in vitro, in vivo, and clinical trials demonstrating effects on lifespan extension, neuroprotection, antioxidant activity, and immune function. The peptide is approved for use in Russia but remains unapproved by the FDA and other regulatory agencies, available only as a research compound in most countries.

Longevity and Anti-Aging Effects

Epithalon demonstrates significant geroprotective properties across multiple species. In animal studies, treatment increased maximum lifespan by 12.3-13.3% in mice^[1] and up to 16-34% in various strains^[2]. The peptide extends the life span of the last 10% survivors by 13.3%^[1]. A human prospective cohort study of 266 people over age 60 showed that treatment with epithalamin (the parent compound) produced a 1.6-1.8-fold reduction in mortality over 6 years^[2].

Telomerase Activation and Cellular Protection

Research demonstrates that Epithalon activates telomerase enzyme, leading to telomere elongation in human somatic cells in vitro^[2]. The peptide increased telomere length by an average of 33.3% in lymphocytes^[2] and reduced chromosomal aberrations in bone marrow cells by 17.1%^[1]. It decreases senescence markers (p16, p21) in stem cells and slows age-related cellular deterioration^[2].

Neuroprotective Properties

Epithalon stimulates neurogenic gene expression, increasing Nestin, GAP43, β-Tubulin III, and Doublecortin mRNA expression by 1.6-1.8 times in human stem cells^[3]. The peptide demonstrates neuroprotective effects by reducing DNA damage in neurons, enhancing dendritic growth, and protecting against hypoxia-induced changes^[2]. It increases acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity by 10-25% in neuroblastoma cells^[2].

Visual Function and Retinal Health

In a clinical trial of 162 patients (ages 18-72) with retinitis pigmentosa, parabulbar injections of 5.0 µg per eye for 10 consecutive days produced positive clinical effects in 90% of cases^[2][4]. Visual acuity increased by 0.15-0.20 on average, visual field borders extended in all patients (64.8% showed 90-120 degree expansion), and absolute scotomas reduced in size or disappeared^[2]. The treatment protected retinal tissue in degeneration models, extending functional activity by 43.9%^[2].

Circadian Rhythm and Melatonin Regulation

A study of 75 women receiving sublingual Epithalon (0.5 mg/day for 20 days) showed melatonin excretion increased 1.6-fold versus placebo^[2]. The peptide influences the pineal gland, directly affecting melatonin synthesis by modulating AANAT and pCREB in pinealocyte cultures^[2]. In aged rhesus monkeys, it stimulated melatonin synthesis and normalized cortisol circadian rhythm^[2].

Antioxidant and Mitochondrial Support

Epithalon reduces reactive oxygen species (ROS) in mitochondria and decreases lipid peroxidation in brain tissue^[2]. At optimal concentration (0.1 mM), treatment significantly reduced ROS levels in aged oocytes^[5]. The peptide increases mitochondrial membrane potential and DNA copy number, enhancing catalase and SOD-1 expression^[2][5].

Reproductive Health

Research on oocytes demonstrates that Epithalon protects against post-ovulatory aging damage by decreasing spindle defects and abnormal distribution of cortical granules during 12-24 hour aging periods^[5]. It reduces early apoptosis of oocytes and maintains mitochondrial function, with potential applications in assisted reproductive technology^[5].

Immune Function

The peptide enhances thymus gland function and immune cell activity. It modulates mitogenic activity of murine thymocytes, reduces splenic lymphocyte apoptosis by 2.12-fold after gamma irradiation, and alters interleukin-2 mRNA levels^[2]. The compound improves immunological parameters across multiple species^[4].

Metabolic Effects

In aged rhesus monkeys (ages 20-27 years), Epithalon improved glucose tolerance, though this effect was not observed in young animals^[2]. Oral administration increased passive glucose transport by 2.2-fold in small intestine and active transport by 6-8 fold, while enhancing digestive enzyme activities (invertase, maltase, dipeptidase)^[2].

Clinical Safety Profile

Epithalon has been studied extensively in animal models and human clinical trials with a generally favorable safety profile. In the retinitis pigmentosa clinical trial involving 162 patients, no side effects were reported during the 10-day treatment course^[2]. A 15-year follow-up study showed that epithalamin (the parent compound) is well tolerated with no adverse events attributed to the peptide^[2]. Animal studies demonstrated no nephrotoxic effects, no significant impact on food consumption or body weight, and safety of long-term administration^[1][2].

Regulatory Status

Epithalon is not approved by the U.S. Food and Drug Administration (FDA) for any specific medical condition and has not been approved outside of Russia pending further study. The FDA includes Epithalon in its group of peptides that pose a risk of immunogenicity, warning that immune responses can be life-threatening. The compound is available only as a research compound in the U.S., EU, Canada, and Australia, and its use is considered experimental with long-term safety and efficacy not established in large-scale human trials.

Reported Side Effects

When side effects occur, they are typically mild and temporary. Common injection-related effects include inflammation, itching, swelling, or pain at the injection site that usually subside within 1-2 days. Some users report mild headaches, dizziness, occasional fatigue, or nausea. Animal studies initially showed decreased physical activity during the first 3 months of treatment, which then normalized^[2].

Theoretical Safety Concerns

There is theoretical concern about abnormal cell proliferation due to telomerase activation, as telomerase is active in many cancer cells. However, existing studies have not confirmed any increase in cancer risk. In fact, Epithalon did not influence total spontaneous tumor incidence but actually inhibited the development of leukemia 6.0-fold in animal studies^[1]. The peptide lowered tumor incidence in breast cancer-prone mice and reduced colon cancer incidence in chemically-induced models^[2].

Research Gaps and Missing Safety Data

A 2025 systematic review in the International Journal of Molecular Sciences identified critical missing safety information, stating that "information regarding critical issues about this peptide's safety is missing"^[2]. Specifically lacking are comprehensive short- and long-term toxicity studies, systematic genotoxicity assessments, carcinogenic potential evaluation, and documentation of food-drug and drug-drug interactions. Additional challenges include stability issues (short peptides typically degrade rapidly in vivo) and limited data on the eight possible stereoisomers (only the natural L-amino acid form has been extensively studied)^[2].

Contraindications and Precautions

Due to limited human safety data and the theoretical risk of immunogenicity flagged by the FDA, Epithalon should not be used without medical supervision. Long-term safety in humans has not been established through large-scale clinical trials. The peptide's mechanism of telomerase activation requires ongoing monitoring, though current evidence suggests a protective rather than harmful effect on tumor development.