FOXO4-DRI Dosage

FOXO4-DRI, also known as Retro-Inverso FOXO4, is a lab-engineered version of the natural FOXO4 protein. Scientists slightly altered its structure to make it last longer in the body and interfere with the usual FOXO4 function. Research shows that FOXO40DRI stops FOXO4 from attaching to the p53 protein, a key step that enables the removal of aging, or senescent, cells from tissues. As a result, it may help enhance organ performance and reduce signs of aging at the cellular level.

This peptide has also been linked to changes in insulin response, cell cycle control, and the body’s management of oxidative stress. Because FOXO4-DRI can enter cells directly, it’s able to specifically trigger the death of old, non-functioning cells. In animal studies, this has led to outcomes that resemble the reversal of age-related decline.

Dosage Chart

Protocol / Source	Dosage & Administration	Frequency	Cycle Duration	Notes
Ben Greenfield Recommendation	3 mg subcutaneously	Every other day	6 days (1 cycle)	Cycle may be repeated 1–3x per year. Subcutaneous injection may slow absorption.
Unofficial Protocol 1	300 mcg/kg intravenously	Every other day	5 days	Very high dose, IV administration. Based on limited anecdotal reports.
Unofficial Protocol 2	60 mg subcutaneously	Twice per week	Not specified	Very large dose. No cycle duration clearly documented.
Self-Experimentation Guidance	—	—	—	Ben’s protocol considered the safest and most conservative starting point.
Storage (Lyophilized / Reconstituted)	Freeze-dried: Store at ~ -20°C (freezer)	—	—	If not using right away.
	Reconstituted: Store in refrigerator	—	Use within 1 week	Do not refreeze after reconstitution. Avoid heat, sunlight, repeated thawing

What Is FOXO4-D-Retro-Inverso (DRI)?

FOXO4-D-Retro-Inverso is a modified version of the protein created by the FOXO4 gene. In this form, the typical L amino acids are replaced with D amino acids. This structural change makes the protein more resistant to the body’s natural breakdown processes, allowing it to stay active longer. Even with this modification, it still influences cellular functions and gene activity. In essence, FOXO4-DRI disrupts the normal behavior of FOXO4 in the body.
One of the most important features of FOXO4-DRI, especially when it comes to aging, is its ability to stop FOXO4 from interacting with the p53 protein. Normally, p53 helps regulate the cell cycle and triggers apoptosis—the process by which cells self-destruct when damaged or old. By blocking FOXO4 from attaching to p53 to do its job, which allows aging or damaged cells to die off naturally.

What makes FOXO4-DRI particularly interesting is that its effects are focused almost exclusively on senescent cells that no longer divide or function properly due to aging. By eliminating these cells, FOXO4-DRI helps clear out biological “clutter,” supporting tissue repair and encouraging healthier, younger cells to grow. The result is improved overall function in tissues and a measurable reduction in what we consider “biological age.”

Potential Benefits of FOXO4-DRI

Insulin Signaling

FOXO proteins play a key role in how the body manages insulin signals, but they don’t act directly on insulin itself. Instead, they operate further down the pathway and respond to insulin-like growth factors. Studies using animal models have shown that FOXO proteins help regulate how cells respond to insulin, affecting processes such as metabolism, cell growth, stress response, and more.

When FOXO function is disrupted, it can lead to problems in how the body processes insulin, contributing to metabolic disorders and even cancer. In people with diabetes, changes in FOXO activity are linked to elevated blood sugar and cholesterol levels, especially during fasting. These issues can make diabetes more dangerous by increasing the risk of complications like heart attacks, strokes, poor wound healing, and kidney problems.

Improving FOXO regulations may offer a better way to manage these risks. Although the exact effect of FOXO4-DRI on insulin signaling isn’t fully understood yet, researchers believe it may help lower blood sugar levels by enhancing the body’s ability to respond to insulin more effectively.

Heart Disease

Getting older increases the risk of developing heart disease, and one reason for this may be a drop-in proteasome activity in heart tissue. Proteasomes play a key role in clearing out damaged or oxidized proteins that the body no longer needs. When this cleanup system slows down with age, those faulty proteins start to build up. Studies in rats have shown that as animals get older, their proteasome activity drops, leading to an accumulation of these harmful proteins in the heart.

FOXO proteins help regulate both autophagy proteasome functions. Higher levels of FOXO4, for instance, can increase proteasome activity, which helps reduce protein damage and oxidative stress in specific tissues. Based on this, FOXO4-DRI—or a related compound—might be useful in helping the heart maintain its natural repair systems. This could potentially ease age-related declines in cardiovascular health by supporting the heart-s ability to clean up and function more efficiently.

Neurodegenerative Disease

As people age, changes in brain function can become more noticeable, and the causes behind these changes are often complex. Even common conditions like Alzheimer’s disease remain only partially understood by scientists. Some research suggests that disruptions in proteasome activity, the system responsible for clearing out damaged proteins—may play a role in the onset or worsening of neurodegenerative diseases.

While it’s not entirely clear whether reduced proteasome function directly causes these disorders or simply contributes to them, this type of impairment has been observed in several conditions, including Alzheimer’s Parkinson’s, Huntington’s, Prion diseases, and ALS (also known as Lou Gehrig’s disease). These findings suggest a possible link between poor protein clearance in the brain and neurodegeneration.

Interestingly, FOXO proteins are known to change within the central nervous system. This has led scientists to consider whether introducing external FOXO proteins could help in treating or slowing these brain disorders. Although more studies are needed, there is growing hope that FOXO4-DRI or similar modified proteins might slow down the progression of neurodegenerative diseases by supporting healthier cellular maintenance in the brain.

Dosage Calculator
Given how new FOXO4-DRI is, there’s still a lot we don’t know, especially when it comes to finding the right dosage. Most dosing guidelines are speculative at best. The only somewhat reliable suggestion we’ve come across comes from Ben Greenfield, who recommends injecting 3 mg subcutaneously every other day for six days. He also notes that this short cycle can be repeated one to three times per year.

Outside of that, we’ve seen a few unofficial protocols mentioned, including:

300 mcg per kg administered intravenously every other day over a five-day period

60 mg injected subcutaneously twice a week

If we were ever to consider trying this peptide ourselves, we’d likely stick with Ben’s method.

Subcutaneous injections are thought to absorb more slowly, which may help the peptide stay active in the body longer.

Here are tips for storage:
If the FOXO4-DRI arrives in freeze-dried (lyophilized) form and won’t be used right away, you should keep it in the freezer around -20C.

Once reconstituted with sterile water, you should store it in the fridge and aim to use it within the same week.
Avoid putting the peptide back in the freezer after reconstitution.

Repeated freezing and thawing are no-go.

You should also make sure to keep it away from direct heat and sunlight.

Beyond these basics, there’s not a lot of established guidance. So, if we choose to explore FOXO4-DRI further, you should know that you are stepping into experimental territory and should proceed with caution.

Conclusion

Research has shown that FOXO4-DRI can trigger apoptosis—the natural process of cell death—in senescent cells. This effect has been linked to improved tissue function and better overall health in animal studies. While we still don’t fully understand the extent of its impact, early results suggest FOXO4-DRI could shed light on how to address age-related issues such as dementia, cardiovascular problems, and the general decline in cell function associated with aging.

In studies involving mice, FOXO4-DRI has shown minimal side effects and appears to be well-absorbed when administered orally or subcutaneously. However, it’s important to note that dosages effective in mice don’t directly translate to humans. Products like FOXO4-DRI, especially those offered by suppliers, are intended strictly for laboratory and educational use.

References:

1. 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
2. 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
3. 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 (Albany NY), 12, 1272–1284. https://doi.org/10.18632/aging.102682
4. Bourgeois, B., et al. (2025). The disordered p53 transactivation domain is the target of the cell‑penetrating peptide FOXO4‑DRI: insights into its molecular interaction and mechanism of action. Nature Communications (published online). https://doi.org/10.1038/s41467-025-60844-9
5. Lelarge, V., et al. (2024). Senolytics: from pharmacological inhibitors to novel peptides – FOXO4‑DRI shows selective senolytic activity in age‑related models. npj Aging and Mechanisms of Disease. https://doi.org/10.1038/s41514-024-00138-4
6. 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/
7. 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/
8. Babu MM, Luscombe NM, Aravind L, Gerstein M, Teichmann SA. Structure and evolution of transcriptional regulatory networks. Curr Opin Struct Biol. 2004 Jun;14(3):283-91. https://pubmed.ncbi.nlm.nih.gov/15193307/