FOXO4-DRI (Proxofim) for Senolytic Cell Clearance — Aging
Cell-penetrating peptide that disrupts FOXO4-p53 interaction to selectively clear senescent cells and promote tissue rejuvenation.
Overview
FOXO4-DRI is a modified D-retro-inverso peptide (also called Proxofim) that disrupts the FOXO4-p53 protein interaction in senescent cells, triggering selective apoptosis of these damaged cells while sparing healthy tissue. In preclinical studies (Baar et al., Cell 2017, PMID: 28340339), FOXO4-DRI achieved >50% clearance of senescent cells in aged mice, restored fur density, improved renal function, and restored testosterone levels to near-youthful levels. The peptide works by preventing p53 sequestration by FOXO4 in senescent cells, releasing p53 to the mitochondria where it activates the intrinsic apoptotic pathway. Unlike dasatinib+quercetin senolytics, FOXO4-DRI is highly selective for senescent cells. NOT FDA-approved. No human clinical trials have been completed. All current use is experimental. The D-amino acid retro-inverso design confers protease resistance and improved stability compared to native peptides.
Indications
- Age-related cellular senescence and tissue dysfunction
- Senolytic therapy for tissue rejuvenation (preclinical)
- Age-related hormonal decline (restored testosterone in aged mice)
- Complementary longevity protocol with other anti-aging interventions
Mechanism of Action
Aged and damaged cells enter permanent growth arrest (senescence), secreting inflammatory SASP factors that damage surrounding tissue
Dosing
| Compound | Dose | Frequency | Notes |
|---|---|---|---|
| FOXO4-DRI | 2-5 mg | Daily for 3-5 days per cycle | Lower dose for initial cycle; based on preclinical extrapolation |
| FOXO4-DRI | 5-10 mg | Daily for 5-7 days per cycle | Higher dose for subsequent cycles; 1 week on, 1-3 weeks off |
Evidence Grade
GRADE D
Safety & Contraindications
- NO human clinical trials completed - all evidence is preclinical (mouse studies)
- Not FDA-approved; available for research purposes only
- Theoretical risk of immune suppression from excessive senescent cell clearance
- Unknown long-term effects of repeated senolytic cycling in humans
- Must use intermittent dosing (cycling) to allow tissue recovery between treatments
- Requires medical supervision due to experimental nature