What it is:

Epitalon (also spelled Epithalon or Epithalone) is a tetrapeptide (Ala-Glu-Asp-Gly; AEDG); molecular weight ~390 Da; synthetic version based on Epithalamin, a bovine pineal gland polypeptide extract; first detected in physiological human pineal gland extract in 2017; naturally occurring but produced in very small amounts in humans.

Mechanism of action: Activates telomerase enzyme (hTERT subunit) leading to telomere elongation; in cancer cells, activates Alternative Lengthening of Telomeres (ALT) pathway; binds preferentially to methylated cytosine in DNA and histone proteins H1.3/H1.6 for epigenetic regulation; stimulates melatonin synthesis in pineal gland (via increased AANAT enzyme and pCREB transcription factor); modulates interleukin-2 (IL-2) mRNA levels in splenocytes; increases antioxidant enzyme activity (SOD, catalase, NQO1); influences multiple gene pathways (31.2% of human genes show ≥50% change; 59% upregulated, 41% downregulated); upregulates DNA repair genes; reduces lipid peroxidation and reactive oxygen species; modulates sphingomyelin pathway and neutral sphingomyelinase activity; affects STAT1 phosphorylation and inflammatory pathways; tissue-specific activity (strongest effects on pineal gland and subcortical structures).
Pharmacokinetics: Small stable tetrapeptide; crosses blood-brain barrier; can be administered subcutaneously, intramuscularly, or intranasally; oral bioavailability uncertain (described as "low-hydrolysable" suggesting possible oral activity, but most studies use injection); tissue distribution includes brain, pineal gland, thymus, spleen, liver, heart; half-life and clearance rates not well characterized in humans; effects persist beyond plasma presence due to gene expression changes.
Telomere and cellular effects: Increases telomere length by 33.3% on average in human somatic cells; normal cells (fibroblasts, epithelial): telomere elongation through telomerase upregulation (requires 3-week treatment); cancer cells: telomere elongation through ALT activation (occurs within 4 days); extends replicative lifespan beyond Hayflick limit (fibroblasts continued dividing past 44th passage vs 34th in controls); increases telomere length dose-dependently (0.2–1 µg/mL effective range; 0.1 µg/mL may inhibit cancer cells); hTERT mRNA upregulation: 12-fold in 21NT cells, 5-fold in BT474 cells at 0.5–1 µg/mL; telomerase activity increased 4-fold (IBR.3) to 26-fold (HMEC) in normal cells; ALT activity increased 10-fold in 21NT cancer cells, 3-fold in BT474; no significant ALT activation in normal cells; induces PML body formation in cancer cells (marker of ALT); human clinical studies show significant telomere length increases in blood cells of patients aged 60–80.
Longevity and mortality (preclinical and clinical): Increases lifespan in Drosophila melanogaster by up to 16% (at 16,000-fold lower concentrations than melatonin for similar effects); extends maximum lifespan in CBA mice (oldest control: 24 months; oldest treated: 34 months; 4-fold more mice reached 23 months, p<0.01); increases last 10% survivor lifespan in SHR mice by 13.3%; human clinical trial (Korkushko et al., 2006): 70 elderly adults (~65 years) with cardiovascular disease treated with epithalamin (parent compound) for 3 years, followed 12 years total; 28% decreased overall mortality; 2-fold lower cardiovascular disease-specific mortality; treatment normalized circadian melatonin rhythm, improved carbohydrate/lipid metabolism, and physical endurance.
Antioxidant and anti-inflammatory effects: Reduces lipid peroxidation in brain and liver; lowers conjugated hydroperoxides and Schiff bases in aged Drosophila; inhibits reactive oxygen formation in mitochondria and cytosol; increases antioxidant enzyme activity (SOD up, catalase up, NQO1 up); quenches free radicals in brain tissue of aged mice; reduces 8-hydroxydeoxyguanosine (DNA damage marker) in neurons; lowers TNF-α and IL-6 levels; modulates NF-κB p65 and p38 MAPK pathways; IL-2 mRNA elevated after 5 hours in splenocytes; protects against LPS-induced inflammation in macrophages.
Pineal gland and circadian effects: Stimulates melatonin synthesis in aged rats and elderly humans with pineal dysfunction; increases AANAT enzyme and pCREB transcription factor in pinealocytes; restores melatonin circadian rhythm; protects aged human pineal cells from aging process (selective tissue-specific effect); normalizes circadian rhythm production in elderly adults; no effect on acute melatonin release in isolated pineal glands (effects likely occur through chronic modulation).
Neuroendocrine and immune effects: Increases CD4+ population in bone marrow of aged mice; increases CD8+ cells in spleen of aged mice; decreases undifferentiated CD5+ cells; increases B-cell marker CD20 expression; enhances thymic serum factor (TSF) in thymus tissue; modulates thymocyte mitogenic activity (ultra-low dose effects at 10⁻¹⁷–10⁻¹⁵ M); increases acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity by 10–25%; increases secretion of soluble amyloid precursor protein (APP) by 20%; modulates neprilysin (NEP) and insulin-degrading enzyme (IDE) mRNA under hypoxia.
Anti-cancer and anti-mutagenic effects: Reduces overall tumor incidence in CBA mice (p<0.05) and tumor multiplicity; decreases breast adenocarcinoma incidence in FVB/N HER-2/neu transgenic mice (p<0.05); reduces tumor size in specific tissues; lowers HER-2/neu mRNA expression 3.7-fold; decreases chromosomal aberrations in bone marrow by 17.1% (SHR mice); antimutagenic effects confirmed in sperm head abnormalities and micronuclei assays; suppresses 70% of 54 metastatic colon cancer gene signatures at 1 µM; upregulates 84 DNA repair genes and 10 caspase genes; inhibits 1,2-dimethylhydrazine-induced colon carcinogenesis in rats; most effective when applied before, during, and after cancer occurrence.
Stem cell and differentiation effects: Increases expression of epidermal stem cell markers (integrins, p63) in basal keratinocytes; enhances VEGF and basic fibroblast growth factor secretion in mesenchymal stem/stromal cells (dose-dependent); induces differentiation of Xenopus laevis pluripotent cells into neural tissue (at 10, 50, 100 ng/mL only); increases Nestin and GAP43 transcription in gingival mesenchymal stem cells (p<0.01); upregulates β-tubulin III and Doublecortin mRNA; reduces senescence markers p16 and p21 by 1.56–2.44 times in periodontal ligament stem cells.
Cardiovascular and organ protection: Modulates gastric endocrine cells (serotonin-, gastrin-, somatostatin-producing cells); normalizes pepsin activity during aging; improves oocyte quality (reduces ROS, fragmentation, DNA damage, apoptosis; improves mitochondrial membrane potential); accelerates oocyte maturation and improves blastocyst expansion/hatching rates; hepatoprotective in various models.
Gene expression effects (quantitative): 15,247 genes investigated in heart tissue; 194 genes activated up to 6.61-fold; 48 genes inhibited up to 2.71-fold; 16,897 transcripts studied in brain tissue; major differences vs melatonin treatment; effects connected to nucleic acid transport/synthesis, apoptosis, cell cycle regulation; upregulates 47 DNA repair genes, downregulates 5; broad epigenetic and chromatin remodeling effects in lymphocytes.