Thanks to public health measures and modern medicine, people are living longer than they ever have. By 2050, projections suggest the population over 65 years of age will double in size. For the most part, longer life is an enormous benefit to society, but it also means that an increasing percentage of the population is poised to experience the tell-tale symptoms of aging, such as weakening muscles, faltering memories and slowing metabolism.

Of the many ways to address individual aging, a compound called urolithin-A has sparked interest from a number of researchers. For more than a decade, scientists at the life science company Amazentis and the Swiss Federal Institute of Technology in Lausanne have been investigating the compound, and Amazentis now produces a supplement that contains it. Urolithin A is naturally produced by gut microbes in certain individuals when they metabolize a precursor compound found in pomegranates, berries and walnuts, and it has been associated with mitochondrial health.

In a 2016 study published in Nature Medicine, these researchers showed that urolithin A significantly extended the lifespan of worms, and modestly improved muscle strength and significantly increased endurance in mice. For the last five years they have focused on understanding the compound’s potential benefits for humans, with mitochondria and muscle health as the focus. In 2019, they reported phase I clinical trial results in Nature Metabolism that indicated that urolithin A is safe for human consumption. They have recently run a trial to explore the connection between mitochondrial health and muscle strength.


Free radicals and oxidative stress

The best-known theory of biological aging emerged in the 1950s. Denham Harman, a biochemist at the University of California, Berkeley, proposed that as cells metabolize nutrients and consume oxygen, they produce compounds called reactive oxygen species as a byproduct. Harman hypothesized that these compounds, which chemists call free radicals, react with cellular components, causing damage that over time leads to aging. In the 1970s he expanded on this theory, proposing that mitochondria are the source of the free radicals.

As Harman’s free-radical theory of aging took hold, it fueled research into cancer, Alzheimer’s and many other diseases. It even crept into popular awareness, driving current recommendations for foods like blueberries, green tea, red wine and pomegranates that are high in natural antioxidants.

But free radicals alone have not been able to explain all the effects of aging. For example, even though the naked mole rat has a longer lifespan than other rodents, it also has very high levels of oxidative stress. So, back in the labs, researchers began moving on.


Mitochondrial DNA and inflammaging

Biologists soon uncovered new connections between mitochondria and aging—connections that draw on mitochondria’s unusual origins. Some 1.4 billion years ago, somewhere in Earth’s primitive oceans, a eukaryotic cell is believed to have engulfed an oxygen-respiring bacterium, which over generations became mitochondria. Though fully integrated cellular organelles, the mitochondria never entirely lost their primordial genome, known today as mitochondrial DNA (mtDNA). Today mtDNA produces 13 key mitochondrial proteins.

As mitochondria age, they change shape and become less active.  Eventually they fail and release mtDNA. Because mitochondria began as a foreign organism, researchers suspect that this released mtDNA triggers an immune response. Several studies suggest that in aging organisms this leads to persistent inflammation—a phenomenon dubbed ‘inflammaging’ that can contribute to a variety of age-related diseases.

mtDNA itself also changes with age. As a person gets older, their mitochondrial genome accumulates mutations and deletions faster than the genes in the cell’s nucleus. These mutations have been linked to symptoms of aging. For example, mice with a defective DNA-replication enzyme called mtDNA polymerase have more mutations in their mitochondria DNA (mtDNA) than an average mouse. They also develop gray fur and osteoporosis, and they die young.

That said, such links may correlate with aging rather than drive it, says Toren Finkel, who directs the Aging Institute at the University of Pittsburgh Medical Center. “Mitochondrial dysfunction probably results from other problems in the mitochondria, not necessarily its DNA.”

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.

Improvements in mitophagy might also improve muscle function in younger people, according to Louise Burke and John Hawley, sports nutrition researchers at the Mary MacKillop Institute for Health Research at the Australian Catholic University. In collaboration with Amazentis, they are measuring the effect of urolithin A performance of elite endurance athletes and taking muscle biopsies to measure mitochondrial changes. “In many sporting events, athletes will compete in several events to get the gold medal,” Burke says, adding that improved mitophagy might enable athletes to recover more quickly after a race, then perform at full strength within a couple of days.

Nutrition, including supplements, “is not going to replace exercise or your lifestyle,” Hawley cautions, because exercise is well known to improve muscle function by inducing the formation of new mitochondria. Still, maintaining stable numbers of well-functioning mitochondria could help people stave off the effects of aging for a little while longer.

To learn more about the connection between mitophagy and aging, visit this dedicated resource produced by Timeline Nutrition, a subsidiary of Amazentis.