Comparison
MOTS-c vs Spermidine
Side-by-side of MOTS-c and Spermidine. Every row below is pulled from the compound schema and will update as our data grows. For deeper reads, follow through to each compound page.
MOTS-c
MOTS-c peptide is a 16-amino-acid mitochondrial-derived peptide. Preclinical signals for insulin sensitivity, exercise capacity, dosage notes.
Spermidine
Spermidine supplement benefits cover autophagy induction, longevity signals, and cognition. Wheat germ extract data, doses, and human trials reviewed.
Effects at a glance
MOTS-c
- •16-amino-acid peptide encoded in mitochondrial DNA (12S rRNA region); discovered 2015
- •Activates AMPK in skeletal muscle and liver; improves insulin sensitivity in rodent models
- •Circulating endogenous levels decline with age, motivating the longevity-restoration hypothesis
- •CohBar's MOTS-c analog CB4211 discontinued after phase 1b NASH readout did not meet endpoints
- •Anecdotal protocols use 5 to 10 mg subcutaneously 2 to 3 times weekly
- •Not on the WADA Prohibited List as of 2026; future scrutiny likely given exercise-mimetic mechanism
Spermidine
- •Endogenous polyamine that induces autophagy via EP300 acetyltransferase inhibition and TFEB activation
- •Concentrated in wheat germ, soybeans, aged cheese, and mushrooms; ~10 to 15 mg/day in Mediterranean diets
- •Eisenberg 2016 reported dietary spermidine extended mouse lifespan and improved cardiac function
- •Wirth 2018 pilot (n=28) reported cognitive signal at 0.9 mg/day in older adults at risk for dementia
- •Larger Wirth 2019 follow-up (n=85) did not replicate the memory benefit at 12 months
- •Generally regarded as safe at supplemental doses; food-source position is reassuring
Side-by-side
| Attribute | MOTS-c | Spermidine |
|---|---|---|
| Category | peptide | supplement |
| Also known as | Mitochondrial Open Reading Frame of the Twelve S rRNA-c, MOTSc | spermidine trihydrochloride, wheat-germ-extract spermidine |
| Half-life (hr) ↗ | 0.5 | 6 |
| Typical dose (mg) ↗ | 5 | 1.2 |
| Dosing frequency | 2-3x weekly | daily, typically morning with food |
| Routes | subcutaneous | oral |
| Onset (hr) | 1 | 2 |
| Peak (hr) | 4 | 4 |
| Molecular weight | 1880.18 | 145.25 |
| Molecular formula | C82H132N22O25S2 | C7H19N3 |
| Mechanism | Mitochondrial-derived peptide that activates AMPK in skeletal muscle and liver, improves insulin sensitivity, and translocates to the nucleus under metabolic stress to modulate nuclear gene expression in retrograde mitochondrial signaling. | Induces macroautophagy via inhibition of EP300 histone acetyltransferase and activation of TFEB-mediated lysosomal biogenesis. Substrate for hypusination of eIF5A, required for translation of mitochondrial respiration proteins. |
| Legal status | Not FDA approved; research-use-only grey market; not currently on WADA Prohibited List | OTC dietary supplement (wheat-germ extract has GRAS status in US) |
| WADA status | unknown | allowed |
| DEA / Rx | Not scheduled (research chemical) | OTC supplement (not scheduled) |
| Pregnancy | Insufficient data; not recommended | Insufficient data; not routinely recommended at supplemental doses |
| CAS | 1627580-64-6 | 124-20-9 |
| PubChem CID | 139599184 | 1102 |
| Wikidata | Q24832108 | Q411089 |
Safety profile
MOTS-c
Common side effects
- injection-site irritation
- transient fatigue
- headache (anecdotal)
Contraindications
- pregnancy
- lactation
- active malignancy (theoretical)
- severe hypoglycemia risk on concurrent insulin or sulfonylurea
Interactions
- insulin: additive insulin sensitization may increase hypoglycemia risk(moderate)
- metformin: both activate AMPK; theoretical additive metabolic effect, no controlled data(minor)
- sulfonylureas: increased hypoglycemia risk via additive insulin sensitization(moderate)
Spermidine
Common side effects
- mild GI upset (rare)
- headache (rare)
Contraindications
- wheat-germ allergy or celiac disease (for wheat-germ-extract products)
- active cancer (theoretical)
- pregnancy and lactation (insufficient data)
Interactions
- DFMO (difluoromethylornithine): competing polyamine metabolism; do not combine without oncology guidance(moderate)
Which Should You Take?
Spermidine comes out ahead for most readers on the criteria we weight: 2 catalogued goals, OTC dietary supplement, oral dosing, with a Tier-A outcome catalogued. MOTS-c is the right call when one of the conditionals below applies.
- → If your priority is metabolic health and glucose control, pick MOTS-c.
- → If your priority is mitochondrial function, pick MOTS-c.
- → If your priority is focus or working memory, pick Spermidine.
Edge case: If you want to avoid research-only / gray-market sourcing, Spermidine is the more accessible choice.
Default choice: Spermidine. Lower friction to source, a Tier-A evidence outcome catalogued, and broader goal coverage. Reach for MOTS-c only if your priority sits squarely in the goals it owns above.
This verdict is generated from each compound's schema (goals, legal status, evidence outcomes, dosing route). It updates automatically as our compound data evolves; the deeper read sits on each individual compound page.
Common questions
What is the difference between MOTS-c and Spermidine?
MOTS-c and Spermidine differ in category (peptide vs supplement), mechanism, and typical dosing. See the side-by-side table for full details.
Which has a longer half-life, MOTS-c or Spermidine?
MOTS-c half-life is 0.5 hours; Spermidine half-life is 6 hours.
Can you stack MOTS-c with Spermidine?
Stack compatibility depends on mechanism overlap, legal status, and individual response. Check each compound page for specific interactions and contraindications before combining.
Go deeper