# MOTS-c

The Mitochondrial-Derived "Exercise Mimetic" Peptide: A Revolutionary Discovery in Metabolic Health and Longevity Science

Evidence-Based Scientific Guide | Updated December 2024

#### Key Takeaways

- Mitochondrial-derived: MOTS-c is encoded within mitochondrial DNA - the first peptide discovered from this source
- Exercise mimetic: Activates metabolic pathways similar to physical exercise
- AMPK activation: Potently activates the master metabolic regulator
- Insulin sensitivity: Dramatically improves glucose metabolism in studies
- Longevity signal: Levels naturally decline with age; centenarians show preserved levels

## What is MOTS-c?

MOTS-c (Mitochondrial Open reading frame of the Twelve S rRNA type-c) is a groundbreaking discovery in peptide biology. Identified in 2015 by Dr. Pinchas Cohen's laboratory at the University of Southern California, MOTS-c is a 16-amino acid peptide encoded within the mitochondrial genome - making it the first identified mitochondrial-derived peptide (MDP) with hormone-like signaling properties.

This discovery fundamentally changed our understanding of mitochondria. Previously viewed primarily as cellular "powerhouses" for energy production, mitochondria are now recognized as sophisticated signaling organelles that communicate with the rest of the body through peptides like MOTS-c.

16
Amino Acids
2015
Year Discovered
1st
Mitochondrial Hormone
AMPK
Primary Target

## The Science: How MOTS-c Works

MOTS-c operates through multiple interconnected mechanisms that explain its profound effects on metabolism, exercise capacity, and longevity.

#### AMPK Activation

MOTS-c potently activates AMP-activated protein kinase, the master metabolic switch that:

- Increases glucose uptake
- Enhances fatty acid oxidation
- Stimulates mitochondrial biogenesis
- Activates autophagy

#### Folate-Methionine Cycle

MOTS-c modulates the folate cycle, affecting:

- One-carbon metabolism
- Methylation reactions
- Nucleotide synthesis
- Epigenetic regulation

### The Exercise Connection

One of the most exciting aspects of MOTS-c is its role as an "exercise mimetic" - a compound that can simulate some of the metabolic benefits of physical exercise.

#### Exercise Increases MOTS-c Levels

Research has demonstrated that:

- Acute exercise significantly elevates circulating MOTS-c levels
- Skeletal muscle releases MOTS-c during contraction
- Exercise-induced MOTS-c may mediate some metabolic benefits of training
- This positions MOTS-c as a key "exerkine" - a signaling molecule released during exercise

### Nuclear Translocation

A fascinating aspect of MOTS-c biology is its ability to translocate to the cell nucleus under metabolic stress conditions. Once in the nucleus, MOTS-c:

- Interacts with transcription factors
- Regulates gene expression related to metabolism
- Activates antioxidant response elements (ARE)
- Promotes adaptive stress responses

## Metabolic Benefits: The Research

The metabolic effects of MOTS-c have been demonstrated across multiple preclinical studies and early human research.

### Glucose Metabolism and Insulin Sensitivity

#### Key Study: Lee et al., Cell Metabolism 2015

In the landmark paper that introduced MOTS-c to the world, researchers demonstrated:

- MOTS-c administration prevented age-dependent and high-fat diet-induced insulin resistance
- Improved glucose tolerance in obese mice
- Enhanced insulin sensitivity in muscle tissue
- Reduced weight gain despite high-fat diet consumption

### Obesity and Weight Management

MOTS-c has shown remarkable effects on body composition:

- Reduced fat accumulation: Animals treated with MOTS-c showed significantly less fat gain on high-fat diets
- Increased energy expenditure: Enhanced metabolic rate and thermogenesis
- Preserved muscle mass: Protective effects against muscle wasting
- Metabolic flexibility: Improved ability to switch between fuel sources

### Physical Performance Enhancement

#### Exercise Capacity Studies

Research has shown MOTS-c can enhance physical performance:

- Improved endurance capacity in aged mice
- Enhanced running time to exhaustion
- Better maintenance of muscle function during aging
- Faster recovery from metabolic stress

## MOTS-c and Aging

Perhaps most intriguingly, MOTS-c appears to play a central role in the aging process itself.

### Age-Related Decline

Circulating MOTS-c levels naturally decline with age:

- Significant reductions observed in plasma MOTS-c by middle age
- Correlates with declining metabolic function
- May contribute to age-related insulin resistance
- Parallels the decline in mitochondrial function with aging

#### Centenarian Studies

Remarkably, research on exceptional longevity has revealed:

- Centenarians maintain higher MOTS-c levels than age-matched controls
- Certain genetic variants associated with longevity affect MOTS-c expression
- Japanese centenarians show preserved mitochondrial-derived peptide levels
- Suggests MOTS-c may be a key factor in exceptional longevity

### Reversing Age-Related Decline

Animal studies have demonstrated that MOTS-c administration can reverse aspects of metabolic aging:

- Restored glucose homeostasis in aged animals
- Improved physical function and capacity
- Enhanced stress resistance
- Reduced markers of cellular aging

## MOTS-c vs. Other Metabolic Interventions

### Comparison with Metformin

Both MOTS-c and metformin activate AMPK, but through different mechanisms:

- Metformin: Inhibits mitochondrial Complex I, indirectly activating AMPK
- MOTS-c: Directly activates AMPK through the folate cycle pathway
- Both may have complementary effects on metabolism
- MOTS-c represents endogenous signaling; metformin is a pharmaceutical intervention

### Synergy with Exercise

MOTS-c is not meant to replace exercise but potentially to:

- Enhance exercise benefits when combined with training
- Provide some metabolic benefits for those who cannot exercise due to injury or illness
- Help maintain metabolic health during periods of reduced activity
- Support recovery and adaptation from training

## Current Research Status

#### Research Phase Notice

MOTS-c is currently in the research and investigational phase. While preclinical data is highly promising, human clinical trials are ongoing and regulatory approval has not been granted for therapeutic use. The information provided is for educational purposes about emerging science.

### Ongoing Clinical Research

Current human studies are investigating:

- Safety and tolerability profiles in humans
- Optimal dosing and administration routes
- Effects on glucose metabolism in prediabetic individuals
- Impact on exercise performance and recovery
- Biomarker changes related to metabolic health

### Future Therapeutic Applications

MOTS-c research may lead to treatments for:

- Type 2 Diabetes: Novel mechanism for improving insulin sensitivity
- Obesity: Metabolic enhancement without stimulant effects
- Sarcopenia: Age-related muscle loss
- Frailty: Improving physical function in elderly
- Metabolic Syndrome: Comprehensive metabolic improvement

## The Biological Significance

The discovery of MOTS-c has broader implications for our understanding of biology:

### Mitochondrial Communication

MOTS-c represents a paradigm shift in understanding mitochondrial function:

- Mitochondria are now recognized as signaling organelles, not just energy producers
- The mitochondrial genome encodes regulatory peptides previously unknown
- Mito-nuclear communication is bidirectional and complex
- Other mitochondrial-derived peptides (Humanin, SHLP family) are being discovered

### Evolutionary Perspective

MOTS-c is highly conserved across species, suggesting ancient and critical functions:

- Present in all mammals studied
- Conserved amino acid sequence suggests strong evolutionary pressure
- May have evolved as a stress response mechanism
- Links mitochondrial function to whole-body metabolism

## How to Support Natural MOTS-c Levels

While exogenous MOTS-c remains investigational, you can support natural levels through:

### Exercise

- Regular aerobic exercise: Increases MOTS-c release from muscle
- High-intensity intervals: May produce greater MOTS-c elevations
- Resistance training: Supports overall mitochondrial health
- Consistency: Regular exercise maintains elevated baseline levels

### Mitochondrial Support

- Cold exposure: May stimulate mitochondrial biogenesis
- Fasting/Time-restricted eating: Activates AMPK and mitochondrial pathways
- Quality sleep: Essential for mitochondrial repair and function
- Avoid metabolic toxins: Limit alcohol, processed foods, environmental toxins

## Key Scientists and Institutions

#### Research Leaders

- Dr. Pinchas Cohen - University of Southern California: Pioneer of mitochondrial-derived peptide research, discovered MOTS-c
- Dr. Changhan David Lee - USC Leonard Davis School: Lead researcher on MOTS-c mechanisms and aging
- USC Leonard Davis School of Gerontology - Leading institution for MOTS-c research

## The Bottom Line

MOTS-c represents one of the most exciting discoveries in metabolic and longevity science of the past decade. As a mitochondrial-derived peptide that functions as an exercise mimetic and longevity signal, it offers unprecedented insights into the molecular mechanisms of aging and metabolism.

While therapeutic applications remain in development, understanding MOTS-c biology reinforces the importance of:

- Regular physical exercise as the most effective way to naturally elevate MOTS-c
- Protecting mitochondrial health through lifestyle factors
- The interconnection between metabolic health and longevity
- The promise of emerging peptide therapies for age-related conditions

#### Summary

- What: A 16-amino acid peptide encoded in mitochondrial DNA
- Function: Metabolic regulator and exercise mimetic
- Mechanism: AMPK activation, folate cycle modulation, nuclear signaling
- Longevity Link: Declines with age; preserved in centenarians
- Status: Investigational - active human research ongoing
- Natural Boost: Exercise, particularly high-intensity and endurance training

## References and Further Reading

- Lee C, et al. "The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance." Cell Metabolism, 2015
- Lee C, et al. "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis." Nature Communications, 2021
- Kim SJ, et al. "The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity." Physiological Reports, 2019
- Zempo H, et al. "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c." Aging, 2021
- Cohen P, et al. "Mitochondrial-derived peptides and metabolic regulation." Annual Review of Physiology, 2020