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MITOPHAGY AND THE HEALTHY MITOCHONDRIA
A few years ago Johan Auwerx, a physician, biologist and professor at the Swiss Federal Institute of Technology in Lausanne (EPFL), and researchers from Amazentis wondered if compromised mitochondria could lead to muscle weakening, a symptom of biological aging. They compared mitochondrial function in two groups of people over 60—healthy, active people and ‘prefrail’ people, whose muscle function had already declined. Using a benign radioactive tracer to measure how well the participants’ muscle mitochondria used ATP, they found that ‘prefrail’ people had lower muscle mitochondrial activity.
If sluggish mitochondria do drive aging, then generating new and healthy mitochondria might rejuvenate tissue, the researchers reasoned. And in fact when mice produce new mitochondria, it seems to ease some of the effects of aging, though how this works is not well understood.
Cells also recycle faulty mitochondria. To study this process, called mitophagy, Finkel’s team genetically engineered mice to make their mitochondria produce a fluorescent protein. They then dissected different tissues from the animals, and observed cells recycling the fluorescent mitochondria. “Young animals have very high rates of mitophagy in the brain, and older animals have very low rates of mitophagy,” he says.
TOWARD REJUVENATED MITOCHONDRIA
Such results suggest that boosting mitophagy may produce a healthier population of mitochondria overall, which might help turn back the clock in aging tissue. To test this hypothesis, Amazentis researchers and Auwerx have focused their investigations on urolithin A. In the 2016 Nature Medicine study, the team fed urolithin A to aging roundworms called C. elegans. The compound activated mitophagy, the worms lived 50% longer, and several lines of evidence suggested that mitophagy was essential for life extension. When the researchers fed mice the same compound, the animals exhibited a 57% increase in endurance (as measured by time spent on a running wheel) compared to a placebo.
Since then the researchers have run several clinical trials to test how urolithin A supplements affect humans. In a phase I clinical trial reported in 2019 in Nature Metabolism, they showed that urolithin A was safe for human consumption and that it increased expression of mitochondrial genes in muscle.
According to Anurag Singh, the chief medical officer at Amazentis, a supplement with a precise, clinically tested dose of urolithin A is needed. The metabolite is formed by gut microbiota when precursor compounds, called ellagitannins—commonly found in foods like pomegranates, berries and walnuts—are consumed.
But the diversity of gut microbiomes varies from person to person. In a recent clinical trial published in the European Journal of Clinical Nutrition, Auwerx and the Amazentis team tested 100 people and reported that only about 40 percent of them could naturally produce significant levels of urolithin A from diet alone. The trial also showed that the company’s urolithin A supplement supplied as much of the compound as six glasses of pomegranate juice. Meanwhile, a separate clinical trial that tested whether urolithin A improves muscle health and muscle strength in healthy adults has concluded, but has not been published.