MOTS-c: Old Mice Ran Twice as Long

At 22 months old, the mice had reached an age when physical performance was already declining. Researchers gave one group a peptide called MOTS-c for two weeks, then tested how long the animals could keep running on a treadmill.

The treated old mice ran twice as long as untreated old mice. They also outperformed a comparison group of untreated, middle-aged mice.

That result appeared in a 2021 Nature Communications paper. It gives MOTS-c a concrete reason to attract attention: a measured change in what an old animal could do. The same team also examined muscle and blood samples from people after a hard cycling session, looking for a connection between this peptide and exercise.

MOTS-c, episode 6 of 30 Peptides. The endurance result in this issue comes from mice; the human experiment measured the body's own peptide after exercise.

Mitochondria help cells turn fuel into usable energy. Muscle cells depend on them during exercise, when the demand for energy rises. These structures also have a small set of their own genetic instructions, separate from the DNA stored in the cell's nucleus.

MOTS-c is encoded in that mitochondrial DNA. It is a short peptide, made from 16 amino acids, the building blocks that also form larger proteins.

The location of its genetic instructions makes it unusual. The researchers were studying whether a signal encoded by mitochondria could help the rest of the cell respond when fuel demand changed. That would give mitochondria a role in controlling how cells adapt to physical effort.

A useful place to look was skeletal muscle, the tissue that moves your limbs. Muscle has to keep supplying energy while a run gets harder. It must also handle the strain that comes with sustained activity. The study examined both jobs, from the movement of whole animals down to the response of cells in a dish.

The treadmill test measured how long the animals could keep moving as the pace increased.

The old-mouse experiment used male mice aged 22 months. There were 19 animals in the control group and 18 in the MOTS-c group. Researchers also tested middle-aged mice, about 12 months old, with ten animals in each treatment group.

The mice received daily treatment for two weeks before the treadmill test. As the test continued, the belt moved through progressively faster stages. An animal that stayed on longer eventually had to keep up with a harder pace.

Old mice given MOTS-c ran for 2 times as long and covered 2.16 times the distance of old controls. The distance gain was slightly larger because the mice that continued running reached faster stages. About 17% of the treated old mice reached the final, fastest stage. None of the old control mice did.

Those results describe endurance during a graded test. They do not tell us that every physical ability changed by the same amount. In young mice elsewhere in the paper, MOTS-c improved running performance without improving grip strength. Maze tests also failed to show a learning or memory benefit.

That difference helps define the finding. A peptide can change how long a muscle sustains work while leaving another task unchanged. The next experiments asked what happened to fuel use and the muscle's response to stress.

Muscle draws energy from different fuels, including carbohydrate and fat. Researchers can estimate the mixture an animal uses by measuring the oxygen it consumes and the carbon dioxide it produces. The ratio between those gases changes with the fuel being used.

In this study, old control mice showed a different daily fuel-use pattern from middle-aged mice. During the daytime, when mice generally rest more, the older animals continued relying more heavily on carbohydrate. After MOTS-c treatment, their pattern looked more like that of the middle-aged group.

The researchers described this as an improvement in metabolic flexibility: the ability to adjust fuel use as conditions change. They also examined muscle collected after exercise and found changes in pathways that process sugars and amino acids.

This offers a possible explanation for the treadmill result. A muscle facing rising demand needs to adjust its metabolism. The fuel-use measurements suggest that MOTS-c affected that adjustment in old mice. They do not establish one single pathway as the cause of the extra running time.

There was another part of the response to investigate. Hard work places demands on the proteins that keep a cell functioning. Those proteins need to retain the shapes that allow them to do their jobs, even as conditions become more stressful.

To study that response directly, the team used mouse muscle precursor cells grown in a dish. They reduced the glucose and serum in the cells' growth medium, creating a shortage of nutrients and other support. Cells exposed to MOTS-c survived these conditions better than controls.

The researchers then followed a fluorescently labeled version of the peptide. It entered the nucleus, the compartment that holds most of the cell's DNA. They also measured changes in gene activity, including genes involved in maintaining proteins under stress.

One regulator drew particular attention: HSF1, a protein that helps switch on parts of the cell's stress response. Some of the genes it controls help other proteins fold and function properly.

The team reduced HSF1 inside the cells and repeated the nutrient-stress experiment. That removed the protective effect associated with MOTS-c. HSF1 therefore appeared necessary for protection under those laboratory conditions.

That result connects the peptide to a system that helps cells cope when nutrients become scarce. The experiment was carried out in cultured mouse cells, so it explains a possible route for the animal findings without proving the whole chain from an injection to a longer run.

The next part of the paper moved to people and asked a different question: does the body change its own MOTS-c levels during exercise?

Ten healthy, sedentary young men took part in the human experiment. Their average age was about 25. Each completed a hard session on a stationary bicycle: ten one-minute efforts at peak cycling power, with 75 seconds of recovery between efforts.

Researchers took blood samples during and after the session. They also collected muscle samples before exercise, afterward, and after four hours of rest.

MOTS-c in muscle rose 11.9-fold immediately after exercise. It remained above the starting level four hours later. In circulation, the change was smaller: about 1.6-fold during exercise and 1.5-fold afterward. Blood levels returned to baseline by four hours.

The men received no MOTS-c treatment. Their measurements show that exercise was followed by a change in the body's own peptide. The treadmill experiment tested what happened when mice received additional MOTS-c. These are complementary experiments, but the human arm does not establish that administering the peptide improves human endurance.

That is the main gap in the paper. Ten young men also cannot tell us how this response behaves across women, older adults, or people with disease. Two authors disclosed financial ties to a company developing mitochondrial peptides. The published methods and results are what allow readers to examine the work directly.

The molecule being tested in animals also responds to physical effort in people. A human treatment study would need to measure whether adding MOTS-c changes performance, alongside its effects on health.

The researchers also followed aging mice on a longer treatment schedule. After an initial period of daily treatment, the older animals continued receiving MOTS-c three times a week. At around 30 months, they were too old for the earlier running test, so the team assessed simpler movements.

Treated mice performed better on a 60-second walking test. Their stride length and grip strength were also better than those of controls. These outcomes describe physical abilities that remained measurable very late in the animals' lives.

The overall survival comparison was not statistically significant. This paper therefore does not establish that MOTS-c extends lifespan. Its strongest aging result concerns physical function: old animals could sustain more movement, and several late-life measures improved.

That focus on function is useful when you follow longevity research. Choose an ability you care about preserving and give it a repeatable measure. You might record the time for a familiar walk, using the same route and a similar level of effort. Keep a note of conditions that could change the result, such as an illness or unusually hot weather.

A record like that gives you a way to describe your own progress. It also makes research easier to evaluate, because you can look for studies that measure the ability you care about. A change in a blood marker may help explain an effect; a walking or endurance test tells you what the participant could do.

For MOTS-c, that functional result is unusually clear in old mice: after two weeks, the treated group ran twice as long. Understanding whether people can gain a similar benefit requires a human treatment experiment that asks the same question directly.

Reply with the physical ability you most want to preserve as you get older. I’ll use those answers to focus future issues on outcomes that matter outside the lab.

Next is Semax, a peptide studied for its effects on the brain. New issues arrive Monday, Wednesday, and Friday.

1. Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications, 2021;12:470. Open-access full paper. 2. Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 2015;21:443–454. Background on the peptide's discovery and sequence.

For entertainment and education only. Not medical advice. Talk to your doctor before starting anything.