Side-by-side comparison of mechanisms, dosing, interactions, and stacking potential.
| FOXO4-DRI | MOTS-c | |
|---|---|---|
| Category | Peptides | Peptides |
| Standard Dose | Research indicates dosing remains experimental. Mouse studies used 5 mg/kg IV, three times weekly. | Research indicates 5-10 mg administered 3-5 times per week via subcutaneous injection. |
| Timing | No established timing protocol. | Morning administration preferred. Can be dosed pre-workout for enhanced exercise performance. |
| Cycle Duration | Mouse studies used intermittent dosing (3x/week for several weeks). Human protocols not established. | 8-16 week cycles. |
| Evidence Level | animal_plus_anecdotal | Emerging (strong preclinical) |
FOXO4-DRI is a D-retro-inverso peptide that selectively targets the FOXO4-p53 protein-protein interaction in senescent cells. In senescence, FOXO4 binds p53's disordered transactivation domain (TAD2) in the nucleus, preventing p53 from translocating to mitochondria where it would trigger apoptosis. FOXO4-DRI competitively disrupts this interaction, causing nuclear exclusion of p53 and its redirection to mitochondria, selectively inducing apoptosis in senescent cells while sparing healthy cells. The D-retro-inverso configuration provides protease resistance.
Research indicates dosing remains experimental. Mouse studies used 5 mg/kg IV, three times weekly.
No established timing protocol.
Mouse studies used intermittent dosing (3x/week for several weeks). Human protocols not established.
MOTS-c is a 16-amino acid mitochondrial-derived peptide encoded by the 12S rRNA gene of the mitochondrial genome. It primarily acts through the folate-AICAR-AMPK pathway: by regulating the folate cycle and de novo purine biosynthesis, it increases AICAR accumulation, which phosphorylates and activates AMPK. This enhances glucose uptake in skeletal muscle, improves insulin sensitivity, and mimics exercise-mediated physiological responses. Skeletal muscle MOTS-c levels increase 11.9-fold in response to acute exercise in young men.
Research indicates 5-10 mg administered 3-5 times per week via subcutaneous injection.
Morning administration preferred. Can be dosed pre-workout for enhanced exercise performance.
8-16 week cycles.
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