Synthetic FOXO4 called FOXO4-DRI has D amino acids rather than L amino acids. This adjustment is made so that the peptide might keep working like the original protein, but with a longer shelf life and requiring less clearance from the body.
Studies suggest its primary role seems to be in senescent cell apoptosis regulation [i]. The p53 may target pro-apoptotic genes and increase their expression if FOXO4-p53 interaction is inhibited. These proteins may induce apoptosis in aged cells, lowering the number of cells that otherwise accumulate in tissues. This reduces “biological age” and promotes cellular differentiation, tissue repair, and new growth. Among the family of transcription factors with the capacity to control development and differentiation, research suggests that the FOXO4 protein stands out.
The placenta, ovaries, fat cells, testes, and adrenal glands are considered rich sources of this protein. Findings imply that changes in the DNA-binding domain of the FOXO4 protein after translation seem to affect the transcription factor’s ability to regulate processes, including apoptosis, cellular senescence, insulin signaling, and usual senescence.
Synthetic and chemically altered, FOXO4-D-Retro-Inverso is a variant of the natural FOXO4 protein. Investigations purport that this tweak was created to lengthen the protein’s half-life, and now it may block FOXO4’s regular activity. Preventing normal FOXO4 binding to p53 through FOXO4-DRI has been suggested to remove senescent cells, improve organ function, and slow “biological age.” The cell cycle, oxidative stress, and the insulin signaling pathways may all be affected by FOXO4-DRI, as speculated by researchers. Scientists have hypothesized that the peptide may enter cells and specifically cause apoptosis in senescent cells, potentially mitigating some age-associated impacts as seen in animal study results.
FOXO4-DRI Peptide Research
DRI peptides are manufactured analogs of naturally occurring peptides. The synthesized alternatives feature a modified alpha chirality and an inverted amino acid sequence [ii]. Unlike amino acids in nature, which all have an L chiral configuration, the DRI peptides seem to be made entirely of D chiral amino acids. This can potentially extend the bioavailability of the synthetic peptides by protecting them from enzymatic breakdown. This may result in a longer period of useful life. They may also be useful as peptidomimetic candidates for investigating protein, peptide, and peptide-peptide interactions. Biopharmaceuticals favor D peptides over L as they are considered to have higher stability, greater bioavailability, and lower immunogenicity.
FOXO4-DRI Peptide, Aging and Senescence
There is speculation that FOXO4 may promote the survival of senescent cells. Studies suggest it seems to bind to p53, perhaps blocking its ability to trigger senescent cell apoptosis [iii]. Inhibition of FOXO4-p53 interaction by the DRI peptide suggests that p53 may activate an apoptotic protein and promote cell death. As a result, tissues may have a greater opportunity to regenerate after removing old cells. DRI peptides have been speculated to promote tissue regeneration and healthspan in aged mice. The term “healthspan” describes how long an organism can keep physiological functions running normally. With age, such functions weaken. Tissue regeneration has been suggested to slow biological aging of tissues. Mice that were allowed to mature naturally lived longer, appeared more active, and had less impairment than their younger counterparts.
FOXO4-DRI and Insulin Signaling
Studies suggest that FOXO proteins may modulate the effects of insulin signaling and insulin-like growth factors. Data suggests that the FOXO family of proteins may govern cellular development, metabolism, differentiation, and oxidative stress via acting downstream of insulin signaling. Diabetic toxicity, including hyperglycemia, hyperlipidemia, and cancer, has been linked to mutations in the FOXO genes. Diabetic complications include, but are not limited to, cardiovascular disease, poor wound healing, stroke, and kidney damage [iv]. There has been no definitive discovery of the FOXO4-DRI signaling pathway.
FOXO4-DRI Peptide and Heart Studies
Age-related decline in proteasome activity has been implicated as the root cause of cardial dysfunction. Proteins that have been oxidized, changed, or damaged are degraded by the proteasome to maintain a healthy cellular environment. Decreased proteasome activity causes hazardous proteins to accumulate, which may harm cardiac tissues [v]. Research suggests that increased autophagy and proteasomal activity in the heart may possibly be cleared by FOXO signaling. The FOXO4-DRI protein, or a variation thereof, has been hypothesized to encourage proteasomal processes, improving heart tissue health and decreasing the likelihood of cardiovascular disease.
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References
[i] Huang Y, He Y, Makarcyzk MJ, Lin H. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Front Bioeng Biotechnol. 2021 Apr 29;9:677576. doi: 10.3389/fbioe.2021.677576. PMID: 33996787; PMCID: PMC8116695.
[ii] Doti N, Mardirossian M, Sandomenico A, Ruvo M, Caporale A. Recent Applications of Retro-Inverso Peptides. Int J Mol Sci. 2021 Aug 12;22(16):8677. doi: 10.3390/ijms22168677. PMID: 34445382; PMCID: PMC8395423.
[iii] Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031. PMID: 28340339; PMCID: PMC5556182.
[iv] Murakami T, Inagaki N, Kondoh H. Cellular Senescence in Diabetes Mellitus: Distinct Senotherapeutic Strategies for Adipose Tissue and Pancreatic ? Cells. Front Endocrinol (Lausanne). 2022 Mar 31;13:869414. doi: 10.3389/fendo.2022.869414. PMID: 35432205; PMCID: PMC9009089.
[v] Zhu M, Zhang QJ, Wang L, Li H, Liu ZP. FoxO4 inhibits atherosclerosis through its function in bone marrow derived cells. Atherosclerosis. 2011 Dec;219(2):492-8. doi: 10.1016/j.atherosclerosis.2011.09.038. Epub 2011 Oct 2. PMID: 22005198; PMCID: PMC3226872.
