What is FOXO4-DRI peptide?
FOXO4-DRI is a synthetic version of FOXO4, containing D amino acids instead of L amino acids. This modification allows it to retain the functionality of the original protein and longer shelf life and lower clearance from the body. Its most prominent function is the regulation of apoptosis in senescent cells. It inhibits FOXO4-p53 binding. Thus p53 can target pro-apoptotic genes and promote their expression. These proteins, in turn, bring about apoptosis of old cells, thereby reducing the old cell burden in tissues. This increases cellular differentiation, tissue repair, and regrowth and decreases “biological age.”
FOXO4 protein is a prominent member of the group of transcription factors that regulate growth and differentiation. It is abundant in tissues such as the placenta, ovaries, fat cells, testes, and adrenal glands. Post-translational modifications, especially those in the DNA binding domain of FOXO4 protein, modifiy its functionality as a transcription factor and regulation of pathways such as apoptosis, cellular senescence, insulin signaling, and senescence.
FOXO4-D-Retro-Inverso is a synthetic ad partially altered form of the original FOXO4 protein. The modification helps to enhance the half-life of the protein and allows it to obstruct the normal FOXO4 function. FOXO4-DRI has been found to prevent normal FOXO4 binding to p53, eliminating of senescent cells, enhancing organ function, and reducing “biological age.” FOXO4-DRI influences insulin signaling, cell cycle regulation, and oxidative stress signaling pathways. The peptide is permeable into cells and is shown to selectively induce senescent cell apoptosis, thereby reversing aging effects in animal studies.
AKA: Forkhead box protein O4, Proxofim, FOXO4a, AFX, AFX1, MLLT7
Molecular Formula: C228H388N86O64
Molecular Weight: 5358.05 g/mol
What are DRI (D–Retro-Inverso) peptides?
DRI peptides are synthetic variants of their natural counterparts. The synthetic alternatives have the sequence of amino acids reversed as well as the alpha chirality changed. Naturally occurring amino acids have L chiral configuration, while the DRI peptides are composed of D chiral amino acids. This protects the synthetic peptides from enzymatic degradation and longer bioavailability. This leads to prolonged functional viability. They are also suitable candidates for peptidomimetics for the study of protein-protein, protein-peptide, and peptide-peptide interactions. Biopharmaceuticals also prefer D peptides due to their resistance to degradation, longer bioavailability, and low immunogenicity compared to their L counterparts.
Role in control of aging and senescence
FOXO4 is known to help the perpetuation of aged or senescent cells. It binds to p53 and thereby prevents apoptotic death of the senescent cells. The DRI peptide prevents FOXO4-p53 interaction. Thus p53 activates apoptotic protein and induces cellular death. Thus the old cells are cleared from the tissues, which naturally allow for better tissue regeneration. Studies have shown treatment of the aging mice with the DRI peptide has improved tissue regeneration and healthspan. Healthspan refers to the tenure of lifespan wherein the body remains active. It decreases with age. Tissue renewal can certainly reduce the biological aging of tissues and thereby enhance the health span of an individual. The aged mice show a longer healthy life span, greater physical activity, lesser observed disability such as cardiac diseases and musculoskeletal dysfunction, etc.
Regulation of insulin signaling
FOXO proteins are known to regulate the influence of insulin signaling and insulin-like growth factors. Scientific evidence shows that the FOXO family of proteins act downstream of insulin signaling to regulate cellular growth, metabolism, differentiation, and oxidative stress. Mutations in FOXO genes have been shown to cause diabetic toxicity such as hyperglycemia and hyperlipidemia and even lead to cancer. In the context of diabetes, it could lead to heart attack, impaired wound healing, stroke, and kidney damage, to name a few.
Targeting FOXO signaling in the milieu of diabetes can lead to effective and targeted treatment regimens without any disease complications. The exact mechanism of FOXO4-DRI signaling is yet unknown. It is opined to reduce fasting blood sugar levels, thereby controlling diabetes.
Age is one of the critical factors which influence the onset of cardiac disease. The reason has been ascribed to loss of proteasome activity with age. Proteasome helps in the degradation of oxidized, modified, or damaged proteins, thereby keeping the cellular environment healthy. Reduction in proteasome functionality leads to the accumulation of toxic protein, which can be detrimental to cardiac tissues.
FOXO signaling increases autophagy and proteasomal activity in the heart. Thus the damaged proteins get cleared out of the cells. It is thought that FOXO4-DRI protein or any variant of it can promote proteasomal functions, thus enhancing the health of cardiac tissues and reducing the risk of cardiovascular disease.
The complex etiology of neurodegenerative diseases is yet to be completely understood. There is evidence that indicates the alteration in FOXO proteins to be a contributor to the disease etiology. A decrease in proteasomal activity enhances the underlying condition of Huntington’s disease, Alzheimer’s disease, Parkinson’s, and Prion disease. Hence, FOXO-DRI protein or other modified alternatives can be valuable in treating the conditions by substituting for the absence of native FOXO proteins.
The synthetic peptide thus holds a lot of promises concerning a stable alternative to indigenous FOXO4 protein. The composition allows it to retain the functionality of the original protein while overcoming the enzymatic degradation. Thus its bioavailability is enhanced with sustained physiological effects. More extensive and dedicated research has the potential to unravel the precise mechanism of the FOXO4-DRI protein in disease biology and amelioration such as diabetes, cancer, Alzheimer’s, Parkinson’s, cardiac disease, dementia, and cellular senescence.
At present, the peptide is available only for animal experiments, and human consumption has not been approved. The modified protein FOXO4-DRI shows excellent subcutaneous and low oral bioavailability in mice where it is administered.