Cortagen’s Potential in Cellular Aging, Stress, and Regeneration

Cortagen (Ala-Glu-Asp-Pro) is a tetrapeptide that researchers have studied as a possible modulator of cellular programs tied to stress handling, cellular aging, other chromatin changes, cellular differentiation, and cellular repair. ⁽¹⁾ It is often classified as a part of the broader group of peptide bioregulators also called Khavinson’s peptides, as they were pioneered by the research of Khavinson et al.^(2). Researchers believe these molecules may act as regulators of gene activity potentially.

Cortagen is often discussed as a peptide that may shift how cells manage oxidative load and stress signaling, possibly by reducing lipid and protein oxidation markers while tuning stress-response gene networks. It is also posited to support pathways linked to cellular survival and apoptosis control, mitochondrial gene output, transport processes, and differentiation signals.

Cellular Stress and Cortagen

Cortagen may interfere with oxidative reactions such as lipid peroxidation, which may generate reactive carbonyl species that then might attack free amino groups on proteins. In a study by Kozina et al., the authors suggest that the peptide may possess an indirect, antioxidant-like mechanism without a direct radical scavenging potential. ⁽³⁾

In laboratory settings, Cortagen was applied to neural cells in protein-rich medium, and according to Kozina et al., the peptide exposure apparently “decreased the content of LPO products and reduced oxidative modification of proteins”. The LPO products refer to lipid peroxidation metabolites. They also suggest that Cortagen may act more on the initiation and propagation phases of lipid oxidation than on downstream adduct accumulation.

The researchers also posited that Cortagen may have reduced protein carbonyl groups, which may otherwise serve as markers of oxidative protein modification. According to their observations, the neural fraction appeared markedly decreased, and in the extracellular protein-rich fraction, carbonyls apparently fell by about a 15% reduction. This combination supports the authors’ view that Cortagen may dampen lipid-driven protein damage indirectly by lowering the supply of reactive lipid species.

According to another experiment, Cortagen may shift how cells manage stress not only by dampening oxidative damage markers, but also by tuning transcriptional programs related to transport, maintenance, and stress tolerance. In a microarray study by Anisimov et al., a short Cortagen exposure was associated with a targeted shift in gene programs related to the cells’ stress response. ⁽⁴⁾ Some of the genes interacted with were linked by researchers to carrier proteins and membrane transport, and to DNA synthesis and replication. Cortagen also increased several mitochondrial-encoded transcripts (16S, COX3, ND5), which may reflect a shift in mitochondrial gene output or mitochondrial content.

The researchers commented that their dataset points toward stress-response and survival signaling. Cortagen apparently increased Pass1 and Hsc70, which sit in stress-protein networks involved in protein stabilization under cellular load. It also may have up-regulated Bmp2 and Wnt4, genes in signaling families tied to cell death control, and increased Eps15 and Eps15-rs, which participate in receptor trafficking and mitogenic signal routing.

Cellular Aging

Research by Lezhava et al. suggests that Cortagen may be a chromatin state modulator that may partially reverse chromatin compaction that is linked to cellular aging in cultured cells, with downstream gene activation as the implied functional outcome. ⁽⁵⁾ The authors suggested that cellular aging may be accompanied by broader heterochromatinization and epigenetic closing of genomic regions that were previously accessible, which might silence sets of genes.

Upon Cortagen experimentation, they apparently observed data suggesting that deheterochromatinization of satellite stalk-associated heterochromatin and a possible rise in ribosomal gene transcription. This may better support the cell’s synthetic programs through rRNA production, with chromatin remodeling as the enabling step.

In parallel, the researchers may have also observed increases in sister chromatid exchange frequency in selected chromosome groups. Sister chromatid exchanges are typically reduced in compacted regions, so these observations may also indicate decondensation of facultative heterochromatin and possible release of previously repressed genes. This potential action may be targeted to more dynamic, regulation-relevant domains rather than structural repeats.

Cellular Differentiation and Cortagen

A more recent research by Khavinson et al.posits that Cortagen may modulate cellular differentiation programs. ⁽⁶⁾ The researchers experimented with pluripotent ectodermal cells, which were cultured alongside the peptide, which apparently caused the cells to take a variety of differentiation routes, including different epidermal and mesenchymal cell cultures. In contrast, the control cells that were not exposed to the peptide reportedly developed into atypical epidermal cells. This pattern supports the idea that Cortagen may act through gene-regulatory mechanisms as a potential tuner of lineage decisions, possibly by changing chromatin accessibility, methylation state, or transcription factor availability in early differentiation gene networks of laboratory cell cultures

Cellular Regeneration and Cortagen

In work led by Turchaninova et al., researchers evaluated Cortagen’s potential for cellular regeneration, specifically in experiments with nerve cells. ⁽⁷⁾ The researchers transected sciatic nerve trunks and then attempted to support their regeneration via epineural microsutures. They exposed some of the nerve cells to the peptide, while others were employed as controls. The cellular regeneration was assessed by estimating the length of the nerve segment that is regaining impulse conduction during the experimentation.

Compared with saline controls, Cortagen-exposed nerve cells reportedly had a longer conducting segment, rising from 18.3 ± 1.5 mm to 23.3 ± 0.4 mm, which corresponded to a theoretical 27% increase. The researchers also commented that the better-supported cellular regeneration may have “manifested in a 40% increase of conduction velocity. Specifically, they observed an apparent increase in conduction velocity from 13.9 ± 1.6 to 19.4 ± 1.1 m/s.

The control group apparently indicated a slower regrowth. The researchers interpreted the faster conduction as a marker of more advanced functional maturation of regenerating nerve cells and fibers. Early regenerates typically conduct slowly due to small diameter and incomplete myelination, so the Cortagen-associated increase in velocity may be a sign of better-supported myelin development and/or larger nerve fiber calibre.

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References:

1. Adriani, Walter, et al. “Modulatory effects of cortexin and cortagen on locomotor activity and anxiety-related behavior in mice.” The Open Neuropsychopharmacology Journal 2.1 (2009): 22-29.
2. Khavinson, V. Kh, N. S. Lin’kova, and S. I. Tarnovskaya. “Short peptides regulate gene expression.” Bulletin of experimental biology and medicine 162.2 (2016): 288-292.
3. Kozina, L. S. “Effects of bioactive tetrapeptides on free-radical processes.” Bulletin of experimental biology and medicine 143.6 (2007): 744-746.
4. Anisimov SV, Khavinson VKh, Anisimov VN. Elucidation of the effect of brain cortex tetrapeptide Cortagen on gene expression in the mouse heart by microarray. Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):87-93. PMID: 15159690.
5. Lezhava, Teimuraz, et al. “Epigenetic Regulation of “Aged” Heterochromatin by Peptide Bioregulator Cortagen.” International Journal of Peptide Research and Therapeutics 21.1 (2015): 157-163.
6. Khavinson V, Linkova N, Diatlova A, Trofimova S. Peptide Regulation of Cell Differentiation. Stem Cell Rev Rep. 2020 Feb;16(1):118-125. doi: 10.1007/s12015-019-09938-8. PMID: 31808038.
7. Turchaninova LN, Kolosova LI, Malinin VV, Moiseeva AB, Nozdrachev AD, Khavinson VK. Effect of tetrapeptide cortagen on regeneration of sciatic nerve. Bull Exp Biol Med. 2000 Dec;130(12):1172-4. PMID: 11276314.