This Exercise-Induced Peptide May Offset Age-Related Decline

Here's what new research on humans and mice reveals about MOTS-c.

Posted Jan 21, 2021

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A recently discovered exercise-induced peptide called MOTS-c shows promise for addressing age-related physical decline, boosting physical performance across the lifespan, improving metabolism, and maintaining skeletal muscle functions.

Previous research (Lee et al., 2015) conducted at the University of Southern California's Lee Laboratory found that MOTS-c, a mitochondrial-derived peptide (MDP), targets muscles, regulates metabolism and metabolic homeostasis, mediates mitochondrial regulation of insulin, and protects against age- and diet-dependent insulin resistance and obesity.

The latest MOTS-c research (Reynolds et al., 2021) in humans and mice conducted by members of USC's Lee Lab suggests that this peptide may offset age-dependent frailty and improve healthspans. These findings were published on Jan. 20 in Nature Communications.

Four takeaways from the Lee Laboratory's latest MOTS-c study: 

  1. Endogenous MOTS-c levels increase upon exercise in humans
  2. MOTS-c treatment improves physical performance in young mice
  3. MOTS-c treatment enhances physical capacity in old mice
  4. Late-life MOTS-c treatment improves mouse healthspan

"Mitochondria are known as the cell's energy source, but they are also hubs that coordinate and fine-tune metabolism by actively communicating to the rest of the body," senior author Changhan David Lee, professor at the USC's School of Gerontology and Lee Lab founder/principal investigator, said in a news release. "As we age, that communication network seems to break down, but our study suggests you can restore that network or rejuvenate an older mouse, so it is as fit as a younger one."

"The older mice were the human equivalent of 65 and above; once treated [with MOTS-c], they doubled their running capacity on the treadmill," Lee added. "They were even able to outrun their middle-aged, untreated cohorts."

The first arm of this study focused on how treating mice with MOTS-c via injection improved physical performance, exercise capacity, and overall fitness. "Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 months), middle-aged (12 months), and old (22 months) mice," the authors state.

All mice that received the MOTS-c treatment performed better than age-matched, untreated mice at physical challenges such as running quickly on an accelerating treadmill or balancing on a rotating rod during the rotarod performance test.

Interestingly, mice treated with MOTS-c three times a week while also consuming a high-fat diet experienced less weight gain and showed significant physical improvements in comparison to untreated counterparts.

When the researchers gave the oldest mice in their study a late-life MOTS-c treatment (three times a week), these mice showed improved grip strength, longer stride lengths, and faster walking speeds. "The results from MOTS-c treatment in mice are extremely promising for future translation into humans," Lee said. "Especially the fact that such results were obtained even with treatment starting at older ages."

In the second arm of this study, the researchers focused on how short, high-intensity bouts of exercise on a stationary bicycle induced endogenous MOTS-c expression in human skeletal muscles and blood plasma. Human samples were collected before, during, and after a vigorous stationary-bike workout, as well as four hours of post-exercise rest.

Analysis of the human samples showed that in muscle cells, MOTS-c levels "increased nearly 12-fold after exercise and remained partially elevated after a four-hour rest." Blood plasma MOTS-c levels increased by approximately 50 percent during and immediately after exercise but returned to baseline after the four-hour rest period. "These findings suggest that exercise induces the expression of mitochondrial-encoded regulatory peptides in humans," the authors write.

"Indicators of physical decline in humans, such as reduced stride length or walking capacity, are strongly linked to mortality and morbidity," Lee concluded. "Interventions targeting age-related decline and frailty that are applied later in life would be more translationally feasible compared to lifelong treatments."

It's too early to know if MOTS-c treatments in humans will prove to be a "fountain of youth"; more research is needed. That said, for any Dorian Gray wannabes seeking "youth that never fades," having empirical evidence that vigorous workouts trigger the production of an age-defying peptide can serve as a source of motivation to stay active.


Joseph C. Reynolds, Rochelle W. Lai, Jonathan S. T. Woodhead, James H. Joly, Cameron J. Mitchell, David Cameron-Smith, Ryan Lu, Pinchas Cohen, Nicholas A. Graham, Bérénice A. Benayoun, Troy L. Merry & Changhan Lee. "MOTS-c Is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Physical Decline and Muscle Homeostasis." Nature Communications (First published: January 20, 2021) DOI: 10.1038/s41467-020-20790-0

Changhan Lee, Kyung Hwa Kim, Pinchas Cohen. "MOTS-c: A Novel Mitochondrial-Derived Peptide Regulating Muscle and Fat Metabolism." Free Radical Biology and Medicine (First published: May 20, 2016) DOI: 10.1016/j.freeradbiomed.2016.05.015

Changhan Lee, Jennifer Zeng, Brian G. Drew, Tamer Sallam, Alejandro Martin-Montalvo, Junxiang Wan, Su-Jeong Kim, Hemal Mehta, Andrea L. Hevener, Rafael de Cabo, Pinchas Cohen. "The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance." Cell Metabolism (First published: March 03, 2015) DOI: 10.1016/j.cmet.2015.02.009