Three old mice, see how they run

USC’s ‘exercise protein’ doubles running capacity and extends healthy lifespans in older mice

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Three old mice, see how they run

LOS ANGELES—A new study by researchers at the University of Southern California (USC) Leonard Davis School of Gerontology found that treating mice with a powerful human hormone or ‘energy protein’ improved the physical performance and fitness of older mice—to the point that they beat younger mice in stamina and endurance on the treadmill. The findings, first published online Jan. 20 in Nature Communications, present new possibilities for addressing age-related physical decline as we age.

The research reveals a detailed look at how the mitochondrial genome encodes instructions for regulating physical capacity, performance, and metabolism during aging—and may be able to increase healthy lifespan.

“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,” says Changhan David Lee, assistant professor at the Leonard Davis School and corresponding author of the study. “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.”

A major key in the study was the role of MOTS-c, one of several recently identified hormones known to mimic the effects of exercise. 

However, MOTS-c is unique because it is encoded in the small genome of mitochondria rather than the larger genome in a cell’s nucleus, which opens up a whole new genome to target for new interventions, according to Lee, who, along with Pinchas Cohen—professor of gerontology, medicine and biological sciences and dean of the USC Leonard Davis School—first described the evolutionarily conserved protein and its effects on metabolism in 2015.

“Because of its mitochondrial origin, we initially thought that MOTS-c would have metabolic function,” Lee explains. “In 2015, we published the identification of MOTS-c (as a new gene) and its role in metabolism – (i) regulation of glucose metabolism, (ii) preventing diet-induced obesity, insulin resistance, fatty liver, and (iii) reversal of age-dependent insulin resistance in skeletal muscle. At that time, we also introduced the idea that the overall function of MOTS-c was to promote homeostasis (i.e. increased resilience). We reported that MOTS-c responds to cellular stress. 

“MOTSc moves into the nucleus and activates an adaptive stress response program. This was paradigm-shifting because our cells operate based on two co-evolved genomes (i.e. a big genome in the nucleus and small bacteria-like genome in the mitochondria). But the nuclear genome was long considered the control center of a cell, whereas the mitochondrial genome was thought to only encode for structural proteins of the energy producing machinery (i.e. the electron transport chain).”

MOTS-c functions in the part of the brain that regulates metabolism, known as the hypothalamus, and more specifically in specialized neurons known as POMC neurons. As such, according to Lee, “exercise induces a coordinated MOTS-c response in the metabolic center of the brain and peripheral metabolic tissues, including muscle and fat.” 

“The results from MOTS-c treatment in mice are extremely promising for future translation into humans,” Lee tells DDN. “We have several lines of studies involving mice. The ultimate goal of these studies is to better understand the biology of aging and age-related diseases (e.g. cancer, diabetes, immunity). There is still much to be unraveled regarding MOTS-c, including detailed mechanisms of action and potential therapeutic applications. We are currently investigating how MOTS-c integrates with known longevity pathways that can be modulated by exercise and diet. We hope this will further unveil important details on how MOTS-c could reverse declining physical capacity with age or in diseased conditions.”

“Aging is the major risk factor for most non-communicable chronic diseases. We hope that MOTSc, and other mitochondrial-derived peptides (MDPs), can promote cellular fitness and delay the onset of multiple chronic diseases, such as cancer and diabetes, by slowing down the common risk factor that is aging, he adds, with the ultimate goal being to “increase a healthy lifespan and compress the time spent with diseases/disability later in life.”

For the current Nature Communications study, the research team tested how injections of MOTS-c affected mice of different ages by measuring physical capacity and performance in young (2 months), middle-aged (12 months), and old (22 months) mice. 

When the mice were presented with physical challenges—including maintaining balance on a rotating rod and running on an accelerating treadmill—mice of all ages who had received MOTS-c treatment fared significantly better than untreated mice of the same age.

Even groups of mice that had been fed a high-fat diet showed marked physical improvement after MOTS-c treatment and less weight gain than untreated mice, the study found. These findings echo previous research on MOTS-c treatment in mice, which also found that it reversed diet-induced obesity and diet- and age-dependent insulin resistance.

Additionally, treating the oldest mice nearing the end of their lives with MOTS-c resulted in marked physical improvements, the researchers reported. This late-life treatment improved grip strength, gait (measured by stride length) and physical performance, which was assessed with a walking test (running was not possible at this age).

“The older mice were the human equivalent of 65 and above and once treated, they doubled their running capacity on the treadmill,” Lee says. “They were even able to outrun their middle-aged, untreated cohorts.”

To measure the effects of exercise on MOTS-c levels in people, researchers collected skeletal muscle tissue and plasma from 10 sedentary, healthy young male volunteers who exercised on a stationary bicycle. Samples were collected before, during and after the exercise, as well as following a four-hour rest.

In muscle cells, levels of MOTS-c significantly increased nearly 12-fold after exercise and remained partially elevated after a four-hour rest, while MOTS-c levels in blood plasma also increased by approximately 50 percent during and after exercise and then returned to baseline after the rest period. The findings suggest that the exercise itself induced the expression of the mitochondrial-encoded regulatory peptides.

The expression of MOTS-c during exercise in humans and the results from the studies in mice lend support to the idea that aging is regulated by genes in both the mitochondrial and nuclear genomes. While further research on MOTS-c is needed, the data indicates that MOTS-c treatment could increase health span, or the portion of the life span spent in good health, and address frailty and other age-related conditions, Lee says.

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

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