• A small cohort of older adults (65 to 90 years) received oral supplementation with 1000 mg of urolithin A daily.
  • Supplemented participants significantly improved muscle endurance for leg and hand skeletal muscles.
  • Urolithin A improved mitochondrial health biomarkers in participants’ blood.

To move, breathe, and have our hearts beat, we need healthy muscles supplied with plenty of energy generated by mitochondria – the cell’s power generators. But with age, mitochondria begin to fail, leaving our muscles with less energy and, ultimately, driving muscle weakness and frailty.

Data from a clinical study (NCT03283462) shows that long-term supplementation with urolithin A – a natural gut microbe-derived metabolite – in older adults (65-90 years) improved muscle endurance and mitochondrial health. In a study published in JAMA Network Open, oral supplementation with 1000 mg of urolithin A daily for four months improved the number of muscle contractions until fatigue and the blood plasma levels of biomarkers of mitochondrial health. The findings from this clinical study, funded by the Swiss life science company and urolithin A manufacturer Amazentis, indicate that urolithin A was safe and well-tolerated as well as beneficial for muscle endurance and mitochondrial health in older adults.

The researchers propose that urolithin A may also be a promising approach to counteracting age-associated muscle decline. “This is relevant both to people with chronic diseases and people who want to be more active later in life,” said the lead author, David Marcinek, a professor of radiology at the University of Washington School of Medicine.

(Liu et al., 2022 | JAMA Network Open) Urolithin A supplementation improves walking endurance in older adults. The average increase from baseline in the 6-minute walk distance was 60.8 meters in the urolithin A group and 42.5 meters in the placebo group. However, it is essential to note that these differences were not statistically significant.

Running on Mitochondrial Health

To fuel not only our muscles but essentially all cell functions, we need our mitochondria to convert food into adenosine triphosphate (ATP). In skeletal muscle, the decline in mitochondrial efficiency and capacity for creating ATP is associated with decreased performance and increased fatigue. With age, a progressive reduction in the cell’s ability to eliminate its dysfunctional mitochondria by a selective autophagy process named mitophagy contributes to poor mitochondrial quality. Therefore, restoring levels of mitophagy is an approach to improving mitochondrial function. 

“Mitochondria are like batteries that power the cells in your body,” said Marcinek. “But over time, they break down. The process of mitophagy recognizes this failure and proactively tears down the mitochondria, reducing it to elemental components that a cell can reuse. But with aging, mitophagy becomes less efficient, and your body accumulates this pool of failing mitochondria. It’s one way that muscles become less functional as we age.”

Urolithin A Improves Muscle and Mitochondrial Health in Older Adults

Liu and colleagues conducted this double-blind, placebo-controlled randomized clinical trial in adults aged 65 to 90 at a medical center and a cancer research center in Seattle, Washington, from March 1, 2018, to July 30, 2020. The researchers chose a supplementation period of 4 months, with efficacy readouts at 2 and 4 months, because it is the earliest point at which improvements in muscle function endpoints can be observed.

To get a readout of the effect of urolithin A on muscle endurance, Liu and colleagues investigated whether oral administration of urolithin A improved the 6-minute walk distance and muscle endurance in hand and leg muscles. Testing these two muscle groups in this trial served to isolate the effects on skeletal muscle by minimizing the potential confounding effects of changes in cardiovascular or lung function that could influence whole-body performance measures, such as the 6-minute walk distance.

This clinical study demonstrated that long-term supplementation with urolithin A substantially enhanced skeletal muscle-specific endurance. However, the University of Washington researchers did not find significant improvements in the 6-minute walk distance and maximal ATP production in hand muscles were not significant for urolithin A. Despite the absence of a significant effect on the 6-minute walk distance, the observation that urolithin A supplementation significantly improved muscle endurance in both the hand and leg skeletal muscle is important. That’s because these results demonstrate a direct functional effect on muscle performance in the absence of exercise training in two functionally and anatomically diverse skeletal muscles.

“Even though we did not observe an effect of the supplement in whole-body function (via six-minute measure and ATP production),” Marcinek said, “these results are still exciting because they demonstrate that just taking a supplement for a short duration actually improved muscle endurance. Fatigue resistance got better in the absence of exercise.”

(Liu et al., 2022 | JAMA Network Open) Urolithin A supplementation significantly improved muscle endurance in both the hand and leg skeletal muscle. To assess the effect of urolithin A supplementation on muscle endurance, Liu and colleagues measured the ability to maintain repeated voluntary contractions to 70% of maximum voluntary contraction – flexing until fatigue using a custom-built exercise apparatus – in muscles of the leg (FDI) and hand (TA). At the 2-month visit, urolithin A supplementation significantly improved endurance in both muscles. At the 4-month visit, endurance in the urolithin A group continued to improve, but a parallel increase in the placebo group led to no significant treatment effect.

Liu and colleagues also investigated the effect of urolithin A on mitochondrial health. Supplementation of urolithin A improved the metabolic markers of mitochondrial function in the older participants. For example, clinicians use acylcarnitine levels to test for inherited disorders of fatty acid and branch chain amino acid metabolism. Patients with this type of metabolic disorder accumulate acylcarnitines. Similarly, clinicians test levels of ceramides – sticky, greasy molecules that help maintain cell membranes and perform other critical life-sustaining tasks – that can wreak havoc on the cardiovascular system, promoting plaque accumulation in arterial walls. Here, urolithin A significantly decreased, albeit minimally, the levels of acylcarnitines and ceramides in older participants, which points to an improvement in metabolic health.

“I think these changes suggest that the treatment affects the metabolic condition of people. Even though it didn’t affect the maximum ATP production, it improved test subjects’ general metabolism,” Marcinek said.

Finally, the University of Washington researchers also looked at how urolithin A affected inflammation, a known driver of aging and age-related diseases. To do so, Liu and colleagues used the C-reactive protein (CRP) test, which can be used to detect or monitor significant inflammation in acute conditions. High CRP levels can also indicate that there’s inflammation in the heart’s arteries, which can mean a higher risk of a heart attack. Similar to the effect on acylcarnitines and ceramides, urolithin A significantly reduced CRP levels compared to baseline in the same treatment group.

This trial suggests that urolithin A may be a promising approach to counteract age-associated muscle decline. Dr. Marcinek thinks that urolithin A supplementation may be most helpful in people who cannot get the exercise they want due to poor muscle health or disease. Marcinek said, “Just getting them over that point where exercise is possible – a walk around the block or climbing some stairs – might help a person build their own health.”