MOTS-c
Mitochondrial peptide, regulator of energy metabolism
After exercise, the level of MOTS-c in the blood rises about 12-fold in humans.
Encoded by mitochondrial DNA, not by the nucleus, this sixteen-amino-acid peptide was discovered in 2015 at the University of Southern California. It activates AMPK, the energy sensor that exercise also activates: the cell takes up more glucose and uses more fat, hence its name of “exercise mimetic.”
It is studied for endurance and insulin sensitivity: when administered, it improved physical capacity at every age studied, even late in life (Reynolds, Nature Communications, 2021), and it prevented the insulin resistance linked to a high-fat diet (Lee, Cell Metabolism, 2015).
- Half-life
- Short in the blood; the effect works through AMPK activation and gene expression, which persist well after.
- Route
- Subcutaneous injection.
Technical sheet
- Family
- Mitochondrial peptide, regulator of energy metabolism
- Half-life
- Short in the blood; the effect works through AMPK activation and gene expression, which persist well after.
- Route
- Subcutaneous injection.
- Time to effect
- Energy and recovery from exertion in two to four weeks; insulin sensitivity and body composition over several months, alongside physical activity.
- Level of evidence
- Laboratory research
Chemical identity
- Form
- Synthetic peptide, values for the base form
- CAS No.
- 1627580-64-6
Salt form: as stated on the lot's certificate of analysis.
A peptide encoded by mitochondrial DNA
MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is encoded by the mitochondria's own DNA, not by the nucleus.
It is one of the first identified “mitochondrial-derived peptides”: a signal that adjusts the cell's metabolism, and through the blood that of other organs, to the energy available.
AMPK, the sensor activated by exercise
MOTS-c activates AMPK, the cell's energy sensor, the one exertion also activates: by slowing the folate cycle, it builds up AICAR, which turns it on. The cell then takes up more glucose, uses more fat, and manufactures new mitochondria, as with exercise.
Moving into the nucleus
Under metabolic stress (fasting, exercise, excess sugar), MOTS-c moves into the nucleus and regulates antioxidant defense genes there, notably through the NRF2 pathway (Kim et al., 2018).
Studied effects and observed timelines
Endurance: when administered, it improved physical capacity at every age studied (Reynolds, 2021)
Two to four weeks
Glucose and fat use: it activates AMPK, which increases glucose uptake
A few weeks to a few months
Body composition: in the study that discovered it, it prevented fat gain on a high-fat diet
Several months
What you may feel
- Reaction at the injection site.
- Mild fatigue or dizziness in the first few days for some users.
Stop and consult if
- Faintness, sweating, or tremors suggesting low blood sugar, especially in someone being treated for diabetes.
When to abstain
- Pregnancy or breastfeeding.
- Diabetes under treatment, without your prescriber's input.
- Active cancer or a recent history of it.
- Minors.
Anti-doping : Prohibited in and out of competition by the World Anti-Doping Agency (metabolic modulators, AMPK activators, S4.4).
The effects to watch for, and how to reduce them
This sheet is educational. It replaces neither a diagnosis nor follow-up: for any medical condition, pregnancy, breastfeeding or current medication, talk to a health professional.
- SS-31MOTS-c directs the metabolism, SS-31 protects the machinery that carries it out: two angles on the same mitochondria.
- NAD+NAD+ fuels the reactions AMPK restarts.
To avoid
- Blood-sugar-lowering treatments without supervision: the effects can add up.
Discovered in 2015 by Pinchas Cohen's team (University of Southern California), MOTS-c has a solid mechanistic basis: a direct effect on AMPK, and prevention of insulin resistance and fat gain in laboratory studies. In humans, the first clinical signal comes from an analogue (CB4211).
2015 · Lee et al., Cell Metabolism
Discovery of the peptide; cells and an experimental model of a high-fat diet
MOTS-c activates AMPK, improves insulin sensitivity, and prevents diet-related fat gain and insulin resistance.
2021 · Reynolds et al., Nature Communications
Human volunteers under exertion, muscle biopsies, and an experimental model of endurance
MOTS-c levels rise in muscle and blood after exercise in humans; when administered, it improves endurance capacity and delays age-related physical decline in the model studied.
2021 · CohBar, phase 1a/1b trial of CB4211 (a MOTS-c analogue)
65 healthy adults (phase 1a), then 20 adults with obesity and fatty liver disease (phase 1b)
Good tolerability, with a reported decrease in glucose and liver enzymes compared with placebo. Results announced by the company, not published in a peer-reviewed journal, and obtained with an analogue, not with MOTS-c itself.
Does it replace exercise?
No. It reproduces some of the signals of exercise inside the cell: AMPK activation, glucose uptake, fat use, the making of new mitochondria. Strength, bone density and heart capacity are built through training.
Why does the level fall with age?
It falls with mitochondrial function, and a 2024 meta-analysis (seven studies) finds it lower in diabetes. That is what steered research toward metabolic aging and insulin resistance.
What sets MOTS-c apart?
It is encoded by mitochondrial DNA, not by the nucleus: one of the first peptides of this kind identified.
It activates AMPK, which regulates the use of sugar and fat, and under metabolic stress it moves into the nucleus to regulate antioxidant defense genes there (Kim et al., 2018).
A genetic variant of MOTS-c is also associated with longevity (Fuku, 2015).
Glossary (5)
- Mitochondria
- The cell's energy powerhouse; it has its own DNA, inherited from the mother.
- AMPK
- AMP-activated protein kinase: the sensor that detects an energy shortfall and restarts its production.
- Insulin sensitivity
- The cells' ability to respond to insulin and take up glucose; when it declines, it's called resistance.
- Exercise mimetic
- A substance that triggers some of the adaptations exercise brings about.
- Folate cycle
- A series of reactions that recycles the chemical groups needed for DNA and methylation.