• Elderly, overweight mice treated with BAM15 — a compound called a mitochondrial uncoupler — have increased muscle mass and improved muscle function.
  • BAM15 treatment leads to the removal of damaged mitochondria and the generation of healthy mitochondria.
  • This improvement is tied to the reduced “inflammaging,” or age-related inflammation, linked to muscle loss.

In the United States, one-third of adults over 65 are obese. This excessive body fat exacerbates the age-related loss of skeletal muscle mass and function, known as sarcopenia, by accelerating fat accumulation and lowering physical activity. Adults with sarcopenic obesity are at high risk for long-term disability, worsened quality of life, and death, representing a serious public health concern. So, interventions that prevent, delay, or reverse the causes and consequences of sarcopenic obesity may reduce morbidity and enhance lifespan in older adults. 

Research published in March 2022 by Dantas and colleagues from the Pennington Biomedical Research Center in Louisiana provides the first evidence that the mitochondrial targeting compound BAM15 prevents sarcopenic obesity in aged mice. Published in the Journal of Cachexia, Sarcopenia, and Muscle, the researchers found that treatment BAM15, which was originally identified in 2006 by Merck, improves muscle mass and function, increases mitochondrial synthesis and quality control, and reduces muscle cell stress and death-related signaling in 80-week old mice, which is roughly equivalent to humans age 60-65. These findings show that mitochondrial uncoupling by agents like BAM15 may mitigate the age-related decline in muscle mass and function by adaptations that confer protection against sarcopenic obesity.

(Dantas et al., 2022 | Journal of Cachexia, Sarcopenia, and Muscle) Mitochondrial uncoupling preserves skeletal muscle mass and function in aged mice. (From left to right) 80-week old obese mice treated with BAM15 for ten weeks showed increased lean mass, fiber cross-sectional area (fCSA), grip strength, and spontaneous physical movement over seven days.

BAM15 Mediates Sarcopenic Obesity in Aged Mice

Mitochondria are the primary site of energy production and thus highly influence muscle function. Aging is associated with several mitochondrial derangements and is exacerbated by obesity. “Loss of muscle mass is typically not a concern in younger adults with obesity. However, as people age, that changes. Older adults with sarcopenic obesity suffer accelerated muscle loss. They become less active. As a result, they are at high risk for falls, stroke, heart disease, poorer quality of life, and premature death,” said Christopher Axelrod, MS, Director of Pennington Biomedical Research Center’s Integrated Physiology and Molecular Medicine Laboratory.

Interestingly, targeting mitochondria with compounds called “uncouplers” confers lifespan extension in rodents and insects. However, the effects of mitochondrial uncouplers in sarcopenic obesity had been minimally explored. In this study, Dantas and colleagues treated 80-week old and overweight mice with the mitochondrial uncoupler BAM15 for ten weeks, which conferred protection against sarcopenic obesity in aged mice. BAM15 treatment prevented diet-induced obesity while effectively protecting against the loss of muscle mass and function with additional improvements in overall metabolic health.

(Dantas et al., 2022 | Journal of Cachexia, Sarcopenia, and Muscle) Mitochondrial uncoupling prevents diet-induced obesity and improves glucose tolerance in aged mice. (From left to right) 80-week old obese mice treated with BAM15 for ten weeks showed bodyweight reduction, no change in average food intake, and major decreases in groin and genital fat tissue (iWAT and gWAT) weight and total fat mass.

“Typically, when you lose weight, you also lose muscle, and in some circumstances, you can lose a lot of it,” Axelrod said. “In this study, the aged mice increased their muscle mass by an average of 8 percent, their strength by 40 percent, while they lost more than 20 percent of their fat.” BAM15 is distinguished from other uncouplers by its ability to maintain lean mass after weight reduction. The lack of compensatory food intake in mice fed BAM15 is psychologically important because the reward center in the brain is intimately connected with food consumption; therefore, targeting metabolic efficiency with mitochondrial uncoupling may not be associated with the same psychological risk profile as dieting or using pharmacological agents that target satiety.

Mitochondrial Uncouplers in Clinical Trials

Recent years have seen a resurgence of interest in mitochondrial uncouplers as human medicines. For example, the FDA recently granted IND approval for the chemical uncoupler 2,4-dinitrophenol (DNP) to re-enter the clinic as a potential therapeutic for patients with Huntington’s disease. But DNP was in the news for all of the wrong reasons though for causing a combination of abnormal heartbeat, sweating, breathing, and high temperature eventually leading to death. Niclosamide and nitazoxanide are FDA-approved anti-parasitic drugs discovered to have mitochondrial uncoupling activity. Nitazoxanide is not known to have anti-obesity effects, but it is currently in phase 2 clinical trials for scarring in patients with advanced nonalcoholic fatty liver disease (NAFLD). Niclosamide has been studied in obese mouse models where it slowed fat mass gain and decreased lean mass gain when administered in a diet-induced obesity prevention model.

This study shows that BAM15 and other mitochondrial uncouplers may have huge implications for treating aging. “These data highlight that mitochondrial uncouplers may play an important role in improving health span – the time a person enjoys good health – in advanced age,” said Pennington Biomedical Executive Director John Kirwan, Ph.D. “Extending health span is even more important than extending lifespan. Suppose you could add 20 or 30 years to a person’s life. What would be the point if their quality of life was awful?”