MOTS-c

MOTS-c ("mitochondrial open reading frame of the 12S rRNA-c") is a short peptide of 16 amino acids. Unlike almost all human proteins, its code sits in the small DNA inside mitochondria, the cell's energy-producing structures, rather than in the cell nucleus. It belongs to a small family of "mitochondrial-derived peptides" that also includes humanin. The body makes it naturally, and it can be measured in blood and muscle.

It was first described in 2015 by a team at the University of Southern California led by Changhan Lee and Pinchas Cohen (Lee 2015). Most later work comes from the same network (Kong 2023). Some of these researchers have declared consulting roles and shares in the biotech company CohBar, Inc., which is worth keeping in mind when reading the results.

Research on giving MOTS-c is in cells and mice. In people, published studies only measure natural MOTS-c levels in groups such as older adults, people with diabetes or people who exercise. We could not find any published trial in which people were given MOTS-c. When FDA reviewed it for compounding, it said it had not identified any human exposure data for products containing it.

• Type: natural peptide, 16 amino acids, encoded in mitochondrial DNA.
• Studied for: insulin sensitivity, weight gain on high-fat diets, exercise capacity and ageing.
• Strongest evidence: mouse studies. Human studies are observational and do not involve giving the peptide.
• Legal status: not approved as a medicine in the US.

At a glance: 8 studies report a dose (4 in people, 3 in animals, 1 in cells).

Doses used in human studies

• Zempo H 2021: No peptide given to people (genetic study). Mouse arm: 7.5 mg/kg twice daily by intraperitoneal injection for 21 days (from the full text)

Every study

The proposed mechanisms come from cell and mouse studies, mostly from one research network:

• AMPK activation: by slowing the folate cycle and purine synthesis, MOTS-c raised levels of a molecule (AICAR) that switches on AMPK; treated mice also took up more glucose into muscle in response to insulin (Lee 2015). AMPK was also needed for its effect on fat cells in another group's study (Lu 2019).
• Signals to the nucleus: under metabolic stress it entered the nucleus and worked with the transcription factor NRF2 to change gene activity (Kim 2018).
• Sequence matters: changing a single amino acid (K14Q) weakened its insulin-sensitising effect in cells and mice (Zempo 2021).

1. Wash your hands and work on a clean, uncluttered surface. Let a refrigerated vial reach room temperature so the stopper is easier to pierce.
2. Wipe the rubber stopper of the peptide vial and of the bacteriostatic water with a fresh alcohol swab, and let them air-dry.
3. Draw the chosen volume of bacteriostatic water into a sterile syringe. With 2 mL, a 10 mg vial ends up at 5,000 mcg/mL, or 50 mcg per U-100 unit.
4. Insert the needle through the stopper and let the water run slowly down the inside wall of the vial, not straight onto the powder.
5. Swirl or roll the vial gently until the powder dissolves. Do not shake it: foaming can damage some peptides.
6. Check the solution against the light. It should be clear; cloudiness or particles mean something is wrong with the vial or the water.
7. Write the date and the volume of water on the label. Every unit calculation later depends on that volume.
8. Store the reconstituted MOTS-c vial in the refrigerator, away from light.

• A U-100 insulin syringe holds 1 mL in 100 units, so each unit is 0.01 mL. The marks measure volume, not peptide.
• Syringes come in 0.3 mL (30 units), 0.5 mL (50 units) and 1 mL (100 units) sizes. The smaller ones have finer marks and are easier to read for small volumes.
• Read the volume at the top edge of the plunger's rubber seal, at eye level.
• Tap out air bubbles before reading: a bubble takes up volume and makes the reading wrong.
• Use a new sterile syringe and needle every time, and dispose of them in a sharps container.

• The peptide vial, with its certificate of analysis (COA) for that batch. See how to read a COA.
• Bacteriostatic water (water with 0.9% benzyl alcohol), which keeps a multi-use vial from growing bacteria. Sterile water has no preservative.
• Sterile syringes to add the water, and U-100 insulin syringes to measure.
• Alcohol swabs for the stoppers.
• A sharps container for used needles.
• A label or marker to write the date and the volume of water on the vial.

Side effects and safety in people are unknown, because no published trial has given MOTS-c to humans. In its compounding review, FDA said products containing it may carry a risk of immune reactions and impurity problems, and that it had not identified any human exposure data.

• Product quality: MOTS-c sold online is not checked by any regulator for identity, purity, dose or sterility.
• Immune reactions: FDA noted a possible risk of immunogenicity (the body reacting against the peptide) for some routes of administration.
• Unknown long-term effects: the animal studies lasted weeks to months, or used intermittent dosing in old mice. Effects of repeated use in people have not been studied.
• Injection risks: any injected product that is not sterile can cause infection or abscesses.

Before mixing

• Freeze-dried (lyophilised) peptide is the most stable form. It is usually kept refrigerated, or frozen for long storage, sealed and away from light.
• Heat, moisture and light speed up degradation. Keep the vial in its box and avoid leaving it in a car or by a window.

After mixing

• Keep the reconstituted vial refrigerated and away from light. Do not freeze it again: freezing and thawing a solution can break the peptide down.
• How long a mixed vial stays good depends on the peptide and the diluent, and for most research peptides there is no published stability data. Follow the supplier's guidance and discard any vial that turns cloudy.
• Pierce the stopper as few times as possible, and always with a new sterile needle after wiping it with alcohol.
• Write the volume of water on the label (for example "2 mL"). Without it, the unit calculations cannot be checked later.