FOXO4-DRI 10 MG

Description

FOXO4-DRI (D-Retro-Inverso): Mechanism and Anti-Aging Potential

FOXO4 D-Retro-Inverso (FOXO4-DRI) is a synthetic peptide designed to mimic the native FOXO4 protein but with a crucial modification: its L-amino acids are replaced with D-amino acids. This retro-inverso configuration significantly increases the molecule’s resistance to enzymatic degradation, extending its half-life and bioavailability within the body.

Despite this structural change, FOXO4-DRI retains the ability to interact with key cellular pathways, particularly those related to transcriptional regulation and cell cycle control. Its primary mode of action is inhibiting the normal interaction between FOXO4 and the tumor suppressor protein p53—a critical regulator of cell cycle progression and apoptosis.

In healthy cells, FOXO4 binds to p53 and prevents it from triggering apoptosis, allowing senescent cells—cells that are aged or damaged—to persist. FOXO4-DRI competitively binds to p53, preventing FOXO4 from doing so. This frees p53 to bind to DNA and activate the apoptotic process, leading to the selective elimination of senescent cells [2].

What makes this especially relevant in anti-aging research is the selectivity of FOXO4-DRI for senescent cells. It does not trigger apoptosis in normal, functional cells, but specifically targets the dysfunctional, aging cells that accumulate over time and impair tissue performance. By clearing out these cellular “dead weights,” FOXO4-DRI promotes:

• Improved tissue function
• Enhanced regeneration and differentiation of younger cells
• Reduction in inflammation and age-related dysfunction
• A measurable decrease in “biological age”

This peptide shows strong promise in preclinical models as a therapeutic avenue for reversing signs of aging at the cellular level, and remains under active investigation for its regenerative and life-extension potential.

FOXO4-DRI Structure

Source: Uniprot

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

FOXO4 and Aging: Cellular Senescence and Rejuvenation

The relationship between FOXO4 and aging is intricate and continues to be actively explored. Nonetheless, emerging research has begun to clarify how this protein contributes to age-related processes and cellular longevity.

Studies using C. elegans, a model organism in aging research, have shown that FOXO4 influences insulin-like growth factor (IGF) receptor signaling, a key pathway associated with lifespan regulation, stress resistance, and gene expression [3]. In mammals, FOXO4 plays an important role in cell cycle regulation through its interaction with p53, a critical tumor suppressor and apoptosis regulator.

In its natural state, FOXO4 binds to p53 and inhibits apoptosis in senescent cells—cells that have ceased dividing and often contribute to tissue dysfunction. While this may serve a protective function in certain contexts, it also allows these damaged cells to accumulate with age, disrupting tissue structure and function.

FOXO4-DRI disrupts this protective binding by competitively inhibiting FOXO4’s interaction with p53. This frees p53 to activate the apoptotic program, selectively targeting and eliminating senescent cells [4, 5]. The outcome is a restoration of tissue homeostasis and a reversal of age-related decline in organ function.

Researchers often describe this as “rejuvenation by therapeutic senescent cell clearance.” The analogy commonly used is pruning a fruit tree: removing dead and damaged branches enables the tree to direct its resources toward healthy growth and fruit production. Similarly, clearing senescent cells redirects biological energy and repair mechanisms toward younger, functional cells, enhancing regeneration and overall tissue health.

This process represents a promising avenue in anti-aging and regenerative medicine, with FOXO4-DRI offering a targeted strategy to combat age-associated tissue degeneration by harnessing the body’s natural apoptosis machinery.

Source: Journal of Cell Biology

Understanding Senescence: Causes and Consequences

This image illustrates the key factors that contribute to cellular senescence and the resulting outcomes. It’s important to note that while eliminating senescent cells does not fully reverse stem cell exhaustion, it may help slow its progression. More significantly, removing these dysfunctional cells reduces chronic inflammation, a well-recognized contributor to many age-related diseases such as cardiovascular disease, stroke, and others.

Irreparable Damage and Health Span

One of the major barriers to prolonged health is irreparable cellular damage—damage that the body can no longer repair effectively. This damage limits an organism’s health span, defined as the period during which an individual remains healthy and functions optimally. Typically, health span is shorter than lifespan, and a decline in health span is essentially what we observe as aging.

Extending health span may not necessarily increase the total years lived but can ensure that the years we do live are marked by better health, improved function, and reduced disability. This distinction is critical in aging research: focusing on quality of life rather than just longevity.

FOXO4-DRI and Health Span in Animal Models

In mouse studies, FOXO4-DRI treatment has been shown to improve health span in aged animals. Benefits observed include increased physical fitness, thicker fur density, and enhanced renal (kidney) function. Although these mice do not live significantly longer, their improved health translates into fewer age-related diseases such as heart disease and musculoskeletal problems [2]. This underscores FOXO4-DRI’s potential to promote healthier aging, reducing the burden of age-associated conditions and improving overall quality of life.

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:

Source: Pubmed.

FOXO4-DRI Research

1. Insulin Signaling

FOXO proteins are well-established regulators of insulin signaling, functioning downstream of insulin and insulin-like growth factors. Animal studies demonstrate that FOXO mediates insulin’s inhibitory effects on cellular metabolism, growth, differentiation, and oxidative stress. Mutations in FOXO are linked to disrupted insulin signaling, contributing to metabolic diseases and cancer. In diabetes, altered FOXO signaling causes fasting hyperglycemia and hyperlipidemia [6], which drive serious complications such as kidney damage, stroke, heart attack, and impaired wound healing. While the specific effects of FOXO4-DRI on insulin signaling remain unclear, it is hypothesized that FOXO4-DRI may improve insulin’s downstream effects by lowering fasting blood sugar levels.

2. Heart Disease

Aging increases the risk of cardiovascular disease, partly due to declines in cardiac proteasome activity. Proteasomes remove oxidized and damaged proteins, and research in rats shows that proteasome activity decreases with age, leading to an accumulation of damaged proteins in the heart [7]. FOXO proteins regulate both autophagy and proteasome function, and increased FOXO4 levels enhance proteasome activity, reducing protein oxidation and damage in tissues. This suggests that FOXO4-DRI or similar analogs could potentially support the heart’s natural protein quality control, slowing age-related cardiovascular decline [8].

3. Neurodegenerative Disease

Cognitive decline with age has a complex and not fully understood basis. Impaired proteasome function has been implicated in several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, Prion diseases, and ALS [9]. FOXO proteins are known to be modified in the central nervous system, prompting research into whether exogenous FOXO proteins might help treat or prevent neurodegeneration. FOXO4-DRI and related proteins offer hope as agents that could slow the progression of these debilitating disorders [10].

Summary

FOXO4-DRI has been clearly shown to induce apoptosis in senescent cells, leading to improved tissue function and overall health in animal models. While the full extent of FOXO4-DRI’s effects is still being explored, it holds promise for addressing age-related conditions such as dementia, heart disease, and functional decline driven by cellular senescence.

FOXO4-DRI exhibits minimal side effects, with low oral but excellent subcutaneous bioavailability in mice. Dosages effective in mice do not directly translate to humans. FOXO4-DRI products available from Peptide Sciences are intended strictly for educational and scientific research and are not approved for human consumption. Purchase is restricted to licensed researchers only.

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.

Scientific Journal Author

Dr. Peter de Keizer’s research group focuses on unraveling the molecular mechanisms that cause cellular senescence and how senescent cells contribute to aging and age-related diseases. A major component of their work addresses the role of senescence in late-stage therapy-resistant cancers. Their translational research aims to develop strategies to mitigate the harmful effects of senescent and senescent-like cancer cells, including their elimination.

Peter earned his MSc in Biomolecular Science from Utrecht University in 2004, completing the final part of his training at Harvard Medical School / Massachusetts General Hospital, where he specialized in therapy-resistant Glioblastoma, the deadliest form of brain cancer—a key research focus for his group. He completed his PhD in 2009 at UMC Utrecht, studying the regulation of FOXO proteins under stress and their role in tumor suppression.

Dr. Peter de Keizer is recognized as a leading scientist in the research and development of FOXO4-DRI. However, he does not endorse or advocate for the purchase, sale, or use of this product. There is no affiliation or relationship, explicit or implied, between Peptide Sciences and Dr. de Keizer. Citing him serves to acknowledge and credit the extensive research efforts by scientists studying this peptide. Dr. de Keizer is referenced in citation [2].

References

1.    W. Liu, Y. Song, J. Wang, H. Xiao, Y. Zhang, and B. Luo, “Dysregulation of FOXO transcription factors in Epstein-Barr virus-associated gastric carcinoma,” Virus Res., p. 197808, Nov. 2019.
2.     Baar, Marjolein P, et al. “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.” Cell, vol. 169, no. 1, 2017, pp. 132-147.e16, www.ncbi.nlm.nih.gov/pubmed/28340339, 10.1016/j.cell.2017.02.031. 
3.     A. T.-Y. Chen et al., “Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans,” Genetics, vol. 201, no. 2, pp. 613–629, Oct. 2015.
4.     P. Krimpenfort and A. Berns, “Rejuvenation by Therapeutic Elimination of Senescent Cells,” Cell, vol. 169, no. 1, pp. 3–5, 23 2017.
5.     “Senescence and aging: Causes, consequences, and therapeutic avenues | JCB.” [Online]. Available: http://jcb.rupress.org/content/217/1/65. [Accessed: 17-Nov-2019].
6.     S. Lee and H. H. Dong, “FoxO integration of insulin signaling with glucose and lipid metabolism,” J. Endocrinol., vol. 233, no. 2, pp. R67–R79, 2017.
7.     A.-L. Bulteau, L. I. Szweda, and B. Friguet, “Age-dependent declines in proteasome activity in the heart,” Arch. Biochem. Biophys., vol. 397, no. 2, pp. 298–304, Jan. 2002.
8.     G. Murtaza, A. K. Khan, R. Rashid, S. Muneer, S. M. F. Hasan, and J. Chen, “FOXO Transcriptional Factors and Long-Term Living,” Oxid. Med. Cell. Longev., vol. 2017, 2017.
9.     A. Ciechanover and P. Brundin, “The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg,” Neuron, vol. 40, no. 2, pp. 427–446, Oct. 2003.
10.   W. Hu et al., “Roles of forkhead box O (FoxO) transcription factors in neurodegenerative diseases: A panoramic view,” Prog. Neurobiol., vol. 181, p. 101645, Oct. 2019.

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The products offered on this website are intended solely for in-vitro studies. In-vitro studies (Latin: “in glass”) are conducted outside of living organisms. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat, or cure any medical condition, ailment, or disease. Introducing these products into the bodies of humans or animals in any form is strictly prohibited by law.