Peptides > FOX04-DRI


FOXO4-D-Retro-Inverso is a man-made, slightly altered variant of the standard FOXO4 protein. This modification extends the lifespan of the protein and enables it to disrupt the typical functioning of FOXO4. In research, FOXO4-DRI has demonstrated the ability to inhibit the usual interaction between FOXO4 and p53, leading to the removal of senescent cells, improved organ performance, and a reduction in the “biological age” of tissues. FOXO4-DRI also influences insulin signaling, cell cycle regulation, and oxidative stress signaling pathways. Moreover, FOXO4-DRI is a cell-penetrating peptide that has been proven to specifically trigger the programmed cell death of senescent cells, thereby reversing the aging effects in animal studies.

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1. Introduction to FOX04-DRI


2. “DRI” Retro Inverso Peptides Explained


3. Molecular Structure of FOX04-DRI


4. Effects Of FOX04-DRI

5. Research on FOX04-DRI

Introduction to FOX04-DRI

FOXO4 D-Retro-Inverso is a modified version of the FOXO4 gene’s protein, wherein the usual L amino acids have been substituted with D amino acids. Consequently, FOXO4-DRI exhibits reduced vulnerability to the body’s typical clearance processes, leading to an extended presence in the organism. Despite these modifications, FOXO4-DRI retains its ability to influence transcription and cellular pathways. Broadly speaking, FOXO4-DRI disrupts the regular functioning of FOXO4.

One particularly noteworthy aspect concerning aging and senescence is how FOXO4-DRI can disrupt the normal FOXO4 signaling during the cell cycle by preventing FOXO4 from binding to p53. The p53 protein plays a crucial role in controlling cell cycle progression and programmed cell death (apoptosis). FOXO4-DRI’s interaction with p53 hinders FOXO4 binding, allowing p53 to attach to DNA. This, in turn, enables the cell to proceed with apoptosis and ultimately perish. Interestingly, FOXO4-DRI seems to exert this effect primarily on senescent cells—cells that have ceased functioning or become dysfunctional due to aging. By targeting these malfunctioning cells, FOXO4-DRI contributes to the elimination of non-functional cells within tissues, thereby enhancing tissue functionality and promoting the growth and differentiation of younger, healthier cells. This results in improved biological function and, consequently, a reduction in “biological age.”

“DRI” Retro Inverso Peptides Explained

DRI-Retro Inverso Peptides Explained Retro-inverso peptides are linear peptides whose amino acid sequence is reversed and the α-center chirality of the amino acid subunits is inverted as well. Usually, these types of peptides are designed by including D-amino acids in the reverse sequence to help maintain side chain topology similar to that of the original L-amino acid peptide and make them more resistant to proteolytic degradation. Other reported synonyms for these peptides in the scientific literature are: Retro-Inverso Peptides, All-D-Retro Peptides, Retro-Enantio Peptides, Retro-Inverso Analogs, Retro-Inverso Analogues, Retro-Inverso Derivatives, and Retro-Inverso Isomers. D-amino acids represent conformational mirror images of natural L-amino acids occurring in natural proteins present in biological systems. Peptides that contain D-amino acids have advantages over peptides that just contain L-amino acids. In general, these types of peptides are less susceptible to proteolytic degradation and have a longer effective time when used as pharmaceuticals. Furthermore, the insertion of D-amino acids in selected sequence regions as sequence blocks containing only D-amino acids or in-between L-amino acids allows the design of peptide-based drugs that are bioactive and possess increased bioavailability in addition to being resistant to proteolysis. Furthermore, if properly designed, retro-inverso peptides can have binding characteristics similar to L-peptides. Retro-inverso peptides are useful candidates for the study of protein-protein interactions by designing peptidomimetics that mimic the shape of peptide epitopes, protein-protein, or protein-peptide interfases. Retro-inverso-peptides are attractive alternatives to L-peptides used as pharmaceuticals. These of peptide have been reported to elicit lower immunogenic responses compared to L-peptides.

Molecular Structure of FOX04-DRI

Sequence: H-D-Leu-D-Thr-D-Leu-D-Arg-D-Lys-D-Glu-D-Pro-D-Ala-D-Ser-D-Glu-D-Ile-D-Ala-D-Gln-D-Ser-D-Ile-D-Leu-D-Glu-D-Ala-D-Tyr-D-Ser-D-Gln-D-Asn-D-Gly-D-Trp-D-Ala-D-Asn-D-Arg-D-Arg-D-Ser-D-Gly-D-Gly-D-Lys-D-Arg-D-Pro-D-Pro-D-Pro-D-Arg-D-Arg-D-Arg-D-Gln-D-Arg-D-Arg-D-Lys-D-Lys-D-Arg-D-Gly-OH
Molecular Formula: C228H388N86O64
Molecular Weight: 5358.05
Synonyms: Forkhead box protein O4, Proxofim, FOXO4a, AFX, AFX1, MLLT7

Effects of FOX04-DRI

The relationship between FOXO4 and aging is complex and not fully understood. However, there is strong evidence indicating how the protein affects various mechanisms. Studies in the well-studied nematode C. elegans have shown that FOXO4 impacts insulin-like growth factor receptor signaling, which in turn affects cellular lifespan control, stress resistance, and gene regulation. Additionally, FOXO4 appears to interact with the p53 protein to regulate the cell cycle.

In its natural state, FOXO4 protects senescent cells by keeping the p53 protein, a regulator of the cell cycle, sequestered and unable to induce apoptosis. FOXO4-DRI disrupts this mechanism, allowing p53 to induce apoptosis in senescent cells, leading to an improvement in tissue homeostasis. This is often referred to as rejuvenation by therapeutic elimination of senescent cells. This process is somewhat analogous to pruning a fruit tree, where the removal of dead and damaged branches (senescent cells) redirects energy to healthier parts of the tree, promoting fruit production and growth. At the organ and tissue level, the removal of cells contributing to overall unhealthy function allows resources to be focused on healthy cells.

The accompanying diagram illustrates the factors contributing to senescence and the outcomes of senescence. It’s important to note that eliminating senescent cells does not fully alleviate stem cell exhaustion but may slow it down. However, it does help reduce chronic inflammation, a well-known driver of various conditions such as heart disease and stroke.

Irreparable damage, which refers to cellular damage beyond the body’s capacity to repair, stands as a primary limitation to health span. Health span, the duration during which an organism remains healthy and functions optimally, is typically shorter than lifespan. A decline in health span is synonymous with aging. While extending health span may not necessarily extend the number of years lived, it does enhance the quality of those years, allowing individuals to enjoy better health and functionality. In mouse studies, FOXO4 has been shown to enhance health span in aged mice, resulting in improved fitness, fur density, and kidney function. These mice may not live longer, but they experience better health even in old age, translating to reduced disability and fewer age-related conditions such as heart disease and musculoskeletal dysfunction.

Images showing improved fitness, as indicated by fur density, in a mouse treated with FOXO4-DRI after subjected to chemotoxic agents used to model aging:

Research on FOX04-DRI

  1. Insulin Signaling FOXO proteins have long been recognized as crucial regulators of insulin signaling, acting downstream of insulin and insulin-like growth factors. Studies in animal models have revealed that FOXO plays a role in mediating the inhibitory effects of insulin and insulin-like growth factor on various cellular processes, including metabolism, growth, differentiation, oxidative stress, and more. Mutations in FOXO have been linked to pathological alterations in insulin signaling, contributing to the development of metabolic diseases and cancer. In individuals with diabetes, changes in FOXO signaling lead to fasting hyperglycemia and hyperlipidemia, which are major contributors to diabetes-related complications such as kidney damage, stroke, heart attack, impaired wound healing, and others. Manipulating FOXO signaling in diabetes management could offer more targeted and effective approaches to prevent these serious complications. While the exact impact of FOXO4-DRI on insulin signaling remains unclear, there is a belief that this protein could enhance downstream insulin effects by reducing fasting blood sugar levels.

  2. Heart Disease Advanced age is a recognized risk factor for cardiovascular disease. This risk appears to be associated with a decline in proteasome activity within the heart. Proteasomes are responsible for eliminating oxidized and dysfunctional proteins within cells. Research in rats has shown an inverse relationship between age and proteasome activity, leading to the accumulation of damaged proteins in the heart. FOXO proteins play a role in regulating autophagy and proteasome activity. Elevated levels of FOXO4 are associated with increased proteasome activity, resulting in reduced protein oxidation and damage within specific tissues. It is plausible that FOXO4-DRI or its variants could be employed to enhance the heart’s natural cellular maintenance functions, potentially mitigating age-related alterations in cardiovascular function.

  3. Neurodegenerative Disease Age-related cognitive decline has a multifaceted origin, and even common diseases like Alzheimer’s are not fully comprehended by the medical community. There is some evidence suggesting that changes in proteasome activity may contribute to or exacerbate underlying neurodegenerative conditions. While it is unclear whether impaired proteasome activity is a primary cause or a secondary factor in diseases like Alzheimer’s, it has been observed in conditions such as Parkinson’s, Alzheimer’s, Huntington’s, and Prion disease. Proteasome dysfunction is also evident in amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). Researchers have discovered modifications to FOXO proteins within the central nervous system, prompting exploration into the potential utility of exogenous FOXO proteins in the treatment or prevention of neurodegenerative disorders. At the very least, there is optimism that modified FOXO proteins, including FOXO4-DRI, may offer a means of slowing down the progressive nature of neurodegenerative disorders.


FOXO4-DRI has been convincingly demonstrated to enhance apoptosis in senescent cells, leading to improved tissue function and overall health in animal models. The full scope of FOXO4-DRI’s effects is yet to be determined, but there is hope that this protein could shed light on age-related conditions such as dementia, heart disease, and the general decline in function associated with cellular senescence.

FOXO4-DRI has shown minimal side effects, low oral bioavailability, and excellent subcutaneous bioavailability in mice. However, it’s important to note that dosages in mice do not directly translate to human dosages. FOXO4-DRI is available for purchase at Peptide Sciences for educational and scientific research purposes only, and it is not intended for human consumption. Please only acquire FOXO4-DRI if you are a licensed researcher.

Article Author

The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.


The product information featured on this website pertains exclusively to in-vitro studies. In-vitro studies, also known as ‘in glass’ studies, are conducted outside of living organisms. It’s important to emphasize that these products do not constitute medicines or drugs and have not received FDA approval for the prevention, treatment, or cure of any medical conditions, ailments, or diseases. It is crucial to note that the introduction of these products into the bodies of humans or animals is strictly prohibited by law.