Proxofim Peptide Studies in Cell Aging

Proxofim peptide, also known as FOXO4-DRI peptide, is a unique peptide that has garnered scientific attention due to research studies examining the peptide’s impact in mitigating cell senescence. Studies have suggested that the Proxofim peptide may potentially mitigate or reverse cellular senescence, a process where cells stop dividing and undergo irreversible growth arrest. Proxofim peptide is an abbreviation for: Forkhead Box O Transcription Factor 4-D-Retro-Inverso Peptide.⁽¹⁾ Proxofim peptide is considered to be similar to the FOXO4 protein, but with a modification of D-amino acids substituted for the protein’s original L-amino acids. This alteration appears to support the Proxofim peptide’s resistance to the regular clearance mechanism, potentially leading to an extended presence as compared to the FOXO4 protein.

Regarding ‘DRI’ Peptides

Retro Inverso Peptides, also known as DRI peptides, consist of reversed amino acid sequences, leading to a change in the structure’s chirality, with L-amino acids replaced by D-amino acids and vice versa. This structural modification appears to offer an advantage in possibly increasing resistance to peptide degradation, potentially prolonging their half-lives. D-amino acids are mirror images of the L-amino acids that naturally occur in biological proteins. Replacing L-amino acids with D-amino acids may offer a significant advantage, as the latter are more resistant to degradation, enhancing the protein structure’s durability.

How Does It Work?

The Proxofim peptide has been suggested by researchers to hold potential to mitigate the binding of the FOXO4 protein with the p53 protein. The p53 protein is considered to be an endogenous regulator of the cell cycle, including cell death. Specifically, when the FOXO4 protein binds with p53, it appears to prevent p53 from binding with DNA and initiating apoptosis and cell death. However, the presence of the Proxofim peptide appears to inhibit this binding process, allowing p53 to bind with DNA and facilitate the continuation and death of the cell cycle.⁽²⁾ Interestingly, the Proxofim peptide may be selective, targeting senescent cells that have become dysfunctional over time due to natural cell aging. By promoting apoptosis in these cells, the peptide may ultimately lead to improved biological functioning of the tissues, promoting cell growth and differentiation.

Research Studies on Proxofim (FOXO4-DRI) Peptide

Proxofim Peptide and Cell Senescence

The FOXO4 protein appears to function to protect senescent cells by preventing the binding of the p53 protein with DNA. However, the Proxofim peptide may be capable of blocking this natural protein, thus allowing p53 to bind with DNA and trigger apoptosis in senescent cells. This process is commonly referred to as the “rejuvenation” of biological systems by eliminating aged cells.⁽³⁾ By eliminating senescent cells, energy production may be redirected towards functioning cells, which may lead to improved development and system function. While the Proxofim peptide does not appear to completely halt the senescence process, studies suggest it may potentially slow it down through possibly preventing FOXO4-mediated senescence. It may result in various outcomes, such as cell death or the secretion of inflammatory factors contributing to age-related physiological decline. In the context of cell aging, irreparable cell damage over time may lead to a decrease in health span, which is defined as the duration of healthy cellular function during which an organism remains functional, and is distinct from the concept of lifespan.

The Proxofim peptide appears to mitigate cell damage and senescence, potentially increasing the health span of cells. In support of this theory, a 2017 study⁽⁴⁾ was conducted on aged mice to investigate the action of the peptide compound. The mice were either exposed to the Proxofim peptide or a placebo. The results indicated that the mice receiving the peptide appeared to exhibit improved fitness, better renal functioning, and increased fur density. Although there was no increase in lifespan observed, the findings suggest that the peptide may have led to better cellular and tissue function. As per Marjolein P. Baar et al.: “It is relevant to note that independent of aging and age-related diseases, FOXO4-DRI may be useful against the progression, stemness, and migration of malignant cancer. Given that SASP factors influence these, it will be particularly interesting to determine whether FOXO4-DRI affects those p53-wt cancer cells that have adopted a more migratory and stem-like state due to reprogramming by chronic SASP exposure. In any case, the here reported beneficial effects of FOXO4-DRI provide a wide range of possibilities for studying the potential of therapeutic removal of senescence against diseases for which few options are available.”⁽⁴⁾

Proxofim Peptide and Insulin Signaling

Studies⁽⁵⁾ suggest that the FOXO proteins may play a role in the insulin signaling pathway through the regulation of inhibitory functions related to cell metabolism, cell cycle, oxidative stress, senescence, and cell aging. Any deviation in the levels of FOXO proteins may lead to severe disorders. Although further research is necessary to fully understand the mechanism of action, it has been suggested by researchers that Proxofim peptide may potentially enhance the downstream action of insulin, leading to a reduction in excess blood sugar levels. This may potentially help prevent complications associated with altered FOXO levels and insulin signaling.

Proxofim Peptide and Cardiovascular Function

According to research,⁽⁶⁾ the possibility of failure of the cardiovascular system increases with time. This is attributed to decreased levels of the proteasome enzyme, which plays a vital role in identifying and removing damaged or dysfunctional cells. Over time, the number of damaged cells may increase due to reduced proteasome levels. The FOXO4 protein is considered responsible for regulating proteasome levels. However, its activity alone may not effectively reduce the number of damaged cells in aged organisms. It is believed that the Proxofim peptide could enhance natural processes of eliminating dysfunctional cells, potentially reducing the onset or occurances of cardiovascular issues.⁽⁷⁾

Proxofim Peptide and Neurodegenerative Diseases

Age-related cognitive impairment and the underlying mechanisms of neurodegenerative disorders, such as Alzheimer’s disease, are still unclear. However, it has been observed that proteasome enzyme activity changes in such cases, potentially contributing to cognitive decline.  Studies⁽⁸⁾ have suggested that proteasome activity is downregulated in neurodegenerative disorders like Parkinson’s, Alzheimer’s, and Prion diseases. However, it is unclear if this downregulation is a primary cause of these diseases. Further research has revealed that the levels of FOXO proteins appear to be altered in the central nervous system of models of neurodegenerative disorders.⁽⁹⁾ This has led to the hypothesis that exogenous FOXO protein, including the Proxofim peptide, may potentially help regulate optimal levels of FOXO proteins and prevent or alleviate the progression of neurodegenerative disorders associated with this mechanism. The study reports state that  “Forkhead box O (FoxO) transcription factors have been implicated in the mechanisms regulating aging and longevity. The functions of FoxOs are regulated by diverse post-translational modifications (e.g., phosphorylation, acetylation, ubiquitination, methylation and glycosylation). FoxOs exert both detrimental and protective effects on NDDs (Neurodegenerative diseases).”⁽⁹⁾

Proxofim Peptide and Hypogonadism

Late-onset hypogonadism (LOH) is characterized by reduced serum testosterone levels. This is considered to be due to the impaired functioning of the senescent Leydig cells, which are located adjacent to the tubules in the testicles. A study⁽¹⁰⁾ was conducted to explore the impact of the Proxofim peptide in research models of male LOH. An in vitro model composed of senescent Leydig cells, previously isolated from male mice and introduced with hydrogen peroxide, was utilized. Upon analysis, researchers suggested that FOXO4 cells appeared to possibly maintain the viability of these cells and mitigate their apoptosis. However, when these isolated senescent cells were exposed to Proxofim, results suggested the blockage of the FOXO4 protein, allowing the p53 protein to bind with DNA, leading to the apoptosis of the senescent Leydig cells. A further study was conducted in naturally aged mice, which suggested that Proxofim peptide may potentially have improved the functioning and overall function of Leydig cells, resulting in improved testicular functioning and increased testosterone secretion.

 
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References

1. Huang, Yuzhao et al. “Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes.” Frontiers in bioengineering and biotechnology vol. 9 677576. 29 Apr. 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116695/
2. Sun, Yan et al. “FOXO4 Inhibits the Migration and Metastasis of Colorectal Cancer by Regulating the APC2/β-Catenin Axis.” Frontiers in cell and developmental biology vol. 9 659731. 23 Sep. 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495124/
3. Krimpenfort P, Berns A. Rejuvenation by Therapeutic Elimination of Senescent Cells. Cell. 2017 Mar 23;169(1):3-5. https://pubmed.ncbi.nlm.nih.gov/28340347/
4. Marjolein P. Baar et al, Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Vol 169 Issue 1, https://doi.org/10.1016/j.cell.2017.02.031
5. Lee, S., & Dong, H. H. (2017). FoxO integration of insulin signaling with glucose and lipid metabolism. The Journal of endocrinology, 233(2), R67–R79. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480241/
6. Anne-Laure Bulteau, Luke I. Szweda, Bertrand Friguet, Age-Dependent Declines in Proteasome Activity in the Heart, Archives of Biochemistry and Biophysics, Volume 397, Issue 2, 2002, Pages 298-304, ISSN 0003-9861, https://doi.org/10.1006/abbi.2001.2663
7. Murtaza G, Khan AK, Rashid R, Muneer S, Hasan SMF, Chen J. FOXO Transcriptional Factors and Long-Term Living. Oxid Med Cell Longev. 2017;2017:3494289. doi: 10.1155/2017/3494289. Epub 2017 Aug 15. https://pubmed.ncbi.nlm.nih.gov/28894507
8. Ciechanover A, Brundin P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron. 2003 Oct 9;40(2):427-46. https://pubmed.ncbi.nlm.nih.gov/14556719
9. Wei Hu, Zhi Yang, Wenwen Yang, Mengzhen Han, Baoping Xu, Zihao Yu, Mingzhi Shen, Yang Yang, Roles of forkhead box O (FoxO) transcription factors in neurodegenerative diseases: A panoramic view, Progress in Neurobiology, Volume 181, 2019, 101645, ISSN 0301-0082, https://doi.org/10.1016/j.pneurobio.2019.101645
10. Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., Xia, K., Feng, X., Li, Y., Liang, X., Sun, X., Deng, C., & Liu, G. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging, 12(2), 1272–1284. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053614/