Senolytic & Telomere Peptides

In-vitro and preclinical literature on Epithalon, FOXO4-DRI: mechanisms, model systems and 10 PubMed-linked references.

✔ PubMed-linked citations ✔ In-vitro and preclinical only ✔ Research Use Only

This class groups short synthetic peptides studied in cellular-senescence and telomere-biology models. Two distinct research threads are represented: telomere/telomerase regulation, where the tetrapeptide Epithalon has been examined in cultured human fibroblasts and other cell lines for effects on hTERT expression, telomerase activity and telomere length; and senolysis, where the cell-penetrating peptide FOXO4-DRI has been used to disrupt the FOXO4-p53 interaction and induce apoptosis selectively in senescent cells in vitro and in mouse models. The literature is predominantly preclinical (cell culture and rodent), with a substantial fraction of the Epithalon work originating from a single research group, and includes at least one animal study reporting adverse hemodynamic effects of senescent-cell clearance. These compounds are supplied for laboratory research only; no clinical conclusions are supported by the studies cited here.

This page collects 10 peer-reviewed references across 2 compounds. Every citation links to its PubMed record so the primary source can be read in full. The selection is limited to in-vitro, ex-vivo and preclinical animal studies and mechanistic reviews; human clinical literature is deliberately excluded because Liv Pure products are supplied for laboratory research only.

Epithalon

Also known as: Epitalon; Epithalone; Ala-Glu-Asp-Gly (AEDG); synthetic tetrapeptide

Molecular target or pathway: Telomerase (hTERT) expression and telomerase activity; hypothesized sequence-specific binding to promoter DNA; reactive oxygen species and mitochondrial function in oocyte models

Origin: Synthetic tetrapeptide designed as an analog of a fraction of the bovine pineal extract Epithalamin

Epithalon is a synthetic four-residue peptide (Ala-Glu-Asp-Gly) originally derived from studies of pineal peptide preparations at the St. Petersburg Institute of Bioregulation and Gerontology. Early cell-culture work reported induction of the telomerase catalytic subunit, telomerase activity and telomere elongation in telomerase-negative human fetal fibroblasts, together with an extended replicative lifespan; a 2025 independent study reported dose-dependent telomere lengthening through hTERT upregulation in normal cells and ALT activation in cancer lines. Much of the historical literature comes from a single research group, and the mechanism by which a tetrapeptide would regulate gene transcription is based on computational binding models rather than direct structural evidence.

Liv Pure supplies Epithalon as a lyophilized research reagent with a lot-specific certificate of analysis.

Selected references

Khavinson VKh et al. (2003). Bulletin of Experimental Biology and Medicine. Telomerase-negative human fetal fibroblast culture. Addition of Epithalon to culture was associated with expression of the telomerase catalytic subunit, measurable telomerase enzymatic activity and telomere elongation, assessed by flow cytometry and FISH. PMID 12937682 · DOI
Khavinson VKh et al. (2004). Bulletin of Experimental Biology and Medicine. Primary human fetal pulmonary fibroblasts at late passage. Epithalon-treated late-passage fibroblasts showed telomere lengths comparable to early passages and underwent approximately 10 additional population doublings beyond the passage at which control cultures ceased dividing. PMID 15455129 · DOI
Khavinson VKh et al. (2003). Bulletin of Experimental Biology and Medicine. Conformational analysis and in silico DNA-binding modeling. Candidate nucleotide binding sites for the tetrapeptide were identified computationally in the promoter regions of the telomerase, RNA polymerase II and retinal F379 genes, supporting a hypothesis of direct transcriptional initiation. PMID 14666197 · DOI
Al-Dulaimi S et al. (2025). Biogerontology. Human normal epithelial cells and fibroblasts; 21NT and BT474 breast cancer cell lines. qPCR and immunofluorescence showed dose-dependent telomere length increases in normal cells accompanied by hTERT mRNA and telomerase upregulation, whereas cancer lines showed telomere extension associated with ALT activation. PMID 40908429 · DOI
Yue X et al. (2022). Aging (Albany NY). Post-ovulatory aged mouse oocytes in culture. Epitalon at 0.1 mM in culture medium was associated with lower intracellular ROS, fewer spindle and cortical granule abnormalities, higher mitochondrial membrane potential and mtDNA copy number, and reduced apoptosis over 24 h of in vitro aging. PMID 35413689 · DOI

FOXO4-DRI

Also known as: FOXO4 D-retro-inverso peptide; Proxofim; FOXO4-p53 interfering peptide; cell-penetrating D-amino-acid peptide

Molecular target or pathway: FOXO4-p53 protein-protein interaction; disruption is associated with p53 nuclear exclusion and cell-intrinsic apoptosis in senescent cells

Origin: Synthetic D-retro-inverso peptide derived from the FOXO4 forkhead domain sequence, fused to an HIV-TAT cell-penetrating sequence

FOXO4-DRI was designed by de Keizer and colleagues after identifying FOXO4 as a factor maintaining viability of senescent cells through its interaction with p53. The peptide is a retro-inverted D-amino-acid version of a FOXO4 segment coupled to a TAT domain, intended to be protease-resistant and cell-permeable. In vitro it has been reported to induce apoptosis selectively in senescent fibroblasts, Leydig cells and serially expanded chondrocytes; in mice it has been examined in doxorubicin-treated, progeroid and naturally aged animals, and a separate study reported that senescent-cell elimination by FOXO4-DRI or other senolytics was associated with adverse pulmonary hemodynamic changes, indicating context-dependent outcomes in animal models.

Liv Pure supplies FOXO4-DRI as a lyophilized research reagent with a lot-specific certificate of analysis.

Selected references

Baar MP et al. (2017). Cell. IR- and doxorubicin-induced senescent human IMR90 fibroblasts; XpdTTD/TTD progeroid and naturally aged mice. A FOXO4 D-retro-inverso peptide perturbed the FOXO4-p53 interaction, was associated with p53 nuclear exclusion and apoptosis selectively in senescent cells, and in mice was associated with changes in doxorubicin-induced chemotoxicity markers, fur density and renal function readouts. PMID 28340339 · DOI
Zhang C et al. (2020). Aging (Albany NY). Hydrogen-peroxide-induced senescent TM3 mouse Leydig cells; naturally aged mice. FOXO4-DRI was associated with p53 nuclear exclusion and apoptosis in senescent TM3 cells and, in aged mice, with altered testicular senescence markers and serum testosterone measurements. PMID 31959736 · DOI
Huang Y et al. (2021). Frontiers in Bioengineering and Biotechnology. In vitro-expanded primary human chondrocytes (PDL3 vs PDL9) and pellet culture. FOXO4-DRI treatment removed more than half of late-passage (PDL9) chondrocytes without significantly affecting early-passage cell number, reduced senescence markers, and pellets from pretreated cells expressed lower levels of SASP-related factors. PMID 33996787 · DOI
Born E et al. (2022). Circulation. P16-ATTAC and SM22-5-HTT+ mice, hypoxia and Sugen models; monocrotaline rats. Senescent-cell elimination by suicide gene, ABT263 or FOXO4-DRI was associated with loss of pulmonary endothelial cells and increased right ventricular systolic pressure and vessel remodeling, indicating that senolytic interventions can worsen pulmonary hemodynamics in these models. PMID 36515093 · DOI
Valentijn FA et al. (2017). Journal of Cell Communication and Signaling. Review. Reviewed mechanisms of cellular senescence in the kidney and senotherapeutic strategies, including INK-ATTAC transgene-mediated and FOXO4-DRI peptide-induced apoptosis of senescent cells in mouse models. PMID 29260442 · DOI

Frequently asked questions

What mechanisms are proposed for the peptides in this class?

The two compounds act through unrelated proposed mechanisms. Epithalon (Ala-Glu-Asp-Gly) has been reported to increase hTERT expression and telomerase enzymatic activity in cultured human fibroblasts, with a hypothesized (computationally modeled) direct binding to promoter DNA sequences. FOXO4-DRI is a D-retro-inverso peptide designed to compete with FOXO4 for binding to p53; in senescent cells this is associated with nuclear exclusion of p53 and cell-intrinsic apoptosis. Both mechanisms remain areas of active investigation rather than settled biology.

Which model systems appear in the literature for these compounds?

Epithalon has been studied mainly in cultured telomerase-negative human fetal fibroblasts, normal epithelial cells, breast-cancer cell lines, and in vitro-aged mouse oocytes, with older rodent studies on stress and immune endpoints. FOXO4-DRI has been characterized in IR- and doxorubicin-induced senescent human fibroblasts (IMR90), hydrogen-peroxide-induced senescent TM3 Leydig cells, serially passaged human chondrocytes, and in naturally aged, XpdTTD progeroid and pulmonary-hypertension mouse models. Common readouts include SA-beta-gal, p16/p21 expression, SASP factors, apoptosis assays, telomere qPCR/FISH and TRAP telomerase assays.

How should lyophilized peptides in this class be handled and stored in the laboratory?

Lyophilized peptides are generally stored desiccated at -20 °C or below and protected from light; reconstituted solutions are typically aliquoted and frozen to avoid repeated freeze-thaw cycles. Epithalon contains two acidic residues and is water-soluble; FOXO4-DRI is a larger cell-penetrating peptide built from D-amino acids for protease resistance, and published cell-culture work used serum-containing medium with defined micromolar concentrations and exposure times. Researchers should verify purity and identity by HPLC/MS on receipt and consult the primary literature for vehicle and solubility details relevant to their assay.

All compounds referenced on this page are supplied by Liv Pure for in-vitro laboratory research only and are not for human or animal use. Nothing on this page is medical advice, and no statement here has been evaluated by the Food and Drug Administration. Product identity and purity for each lot are documented on the certificate of analysis; our Testing and Quality page explains what those certificates do and do not measure. Browse the Senolytic & Telomere Peptides category to see current lots.

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