Urolithin A Supports Muscle Strength and Exercise Performance in Middle-Aged Adults

Many people work out in their middle age for its immediate effects, but the real benefits are ones you can’t see right away. While a gradual decline in muscle mass and strength with aging is natural, exercise dictates the trajectory. But staying in shape takes willingness and dedication. Although a muscle anti-aging pill hasn’t yet been discovered, there’s plenty of ongoing research identifying compounds that mitigate muscle decline.  

A recent clinical trial (NCT03464500) shows that middle-aged adults taking a postbiotic—a compound created when gut bacteria metabolize food—called Urolithin A for four months show improvements in muscle aging. In this study, adults taking Urolithin A had, on average, increases of 12% in muscle strength. The participants who supplemented also had better aerobic endurance as well as reduced inflammation, which can play a major role in aging. Urolithin A supplementation, which is thought to work by boosting NAD+ levels, was also tied to changes in compound levels that indicate higher cell metabolism and energy output. 

The fact that Urolithin A treatment improved the outcomes related to physical performance in the absence of any exercise regimen is an important finding for the field. “The improvement in strength and exercise-performance occurred in the absence of any changes to participants exercise routine,” said co-author Johan Auwerx, MD, PhD, Ecole Polytechnique Fédérale de Lausanne (EPFL) professor. “These results are exciting because this is the first in human demonstration that Urolithin A repairs the mitochondria via mitophagy and can translate to meaningful physiological benefits.”

Mitophagy In Aging and Disease 

Urolithin A is a known activator of mitophagy, the cell’s recycling process for clearing out damaged structures important for generating energy (mitochondria). For some time, researchers have been looking at targeting mitophagy to activate the recycling of faulty mitochondria during aging as a strategy to mitigate muscle decline.

Mitochondrial dysfunction is a hallmark of aging and is intricately linked to age-related deterioration of skeletal muscle. Studies associate impaired mitochondrial function with slow walking speed, muscle fatigue, and loss of strength. Improving mitochondrial health is, therefore, a viable strategy to improve muscle health.

Exercise has been shown to activate mitophagy, i.e., the removal and recycling of dysfunctional mitochondria, and to promote mitochondrial biogenesis. To date, nutritional interventions have focused on stimulating anabolic pathways via protein supplementation. Stimulating mitophagy to reverse mitochondrial dysfunction linked to aging represents a novel nutritional approach to address age-associated muscle and cellular health declines.

What Is Urolithin A?

Urolithin A is a gut-microbiome-derived postbiotic metabolite of compounds in foods such as pomegranate, berries, and walnuts. Administration of Urolithin A has been shown to induce mitophagy and improve mitochondrial function in lab models of aging but not in middle-aged people. At the body function level, Urolithin A improved muscle function in nematodes, young rodents, and old mice.

From a clinical translational perspective, Urolithin A is safe and bioavailable in humans to enhance mitochondrial gene expression in the skeletal muscle and improve cellular health after a 4-week oral administration in sedentary older adults. A recent clinical trial in older adults also demonstrated improvements in muscle endurance with long-term Urolithin A intake.

Urolithin A Supports Middle-Aged Muscle 

The current study, backed by the Swiss life science company Amazentis, was designed as a proof-of-concept investigation of the efficacy of long-term oral supplementation with 500 or 1,000 mg of Urolithin A in middle-aged adults. At the recommendation of experts who have run clinical trials related to muscle function, Rinsch and colleagues selected a 4-month intervention period as the minimum period to start detecting an impact on physical performance and muscle function.

The study population consisted of untrained adults between 40 and 64 years of age who were overweight (high BMI) and had average physical endurance. Chris Rinsch, CEO and Co-Founder of Amazentis, and colleagues set these criteria because it is known that metabolic impairments linked to overweight or obese status lead to mitochondrial dysfunction and accelerated muscle aging.

Among several positive and clinically meaningful results observed in the current study, the most striking was the impact on leg muscle strength. Rinsch and colleagues observed significantly improved lower-body muscle strength in the hamstring skeletal muscle at both doses of Urolithin A. Maintaining lower-body strength and endurance is essential for healthy aging. Multiple aging studies have documented the relationships between muscle-strength improvements in walking ability and exercise capacity.

Unlike muscle strength, which improved with both doses of Urolithin A, the results showed that only the higher dose of Urolithin A led to clinically relevant improvements in measures of physical performance and aerobic endurance. This could indicate a dose-response effect with Urolithin A and suggest that whole-body measures may require more prolonged supplementation. It is noteworthy that the group administered the high dose of Urolithin A (1,000 mg) showed performance increases that reflect a clinically meaningful difference in mobility. 

Urolithin A Supports Muscle Mitochondria Health

A hallmark of muscle health is the ability to remove and recycle damaged cell components. Mitophagy is the process by which cells remove dysfunctional mitochondria and, in turn, regenerate functional organelles. Both mitophagy and mitochondrial biogenesis decline with aging and in age-related diseases.

Urolithin A has been shown to induce markers of mitophagy and mitochondrial function in pre-clinical models of aging. In this trial, Urolithin A activated gene sets related to mitochondria and muscle contraction. Rinsch and colleagues also analyzed, for the first time, the impact of Urolithin A in skeletal muscle at the protein level, revealing an effect on mitophagy markers and function.

Additionally, circulating acylcarnitines—compounds that play an essential role in regulating the balance of intracellular sugar and lipid metabolism—are increased during aging and in conditions associated with mitochondrial dysfunction while being lowered by long-term exercise. The current study showed that Urolithin A supplementation reduced plasma acylcarnitines after long-term administration, albeit only at the 500 mg Urolithin A dose. These data suggest that the impact of Urolithin A on acylcarnitines might be a function of the length of intervention and dosing.

Together with its benefit on mitochondrial health, Urolithin A also reduced plasma biomarkers of inflammation. The reduction of the C-reactive protein by Urolithin A is particularly relevant, as circulating C-reactive protein concentration is positively associated with an increased risk of unhealthy aging and poorer immune health. These biomarker data indicate how Urolithin A supplementation offers a potential dual benefit for muscle health by improving mitochondrial function and reducing inflamm-aging—age-related chronic inflammation.

“This study further validates the role of mitochondrial health as an important pillar of vitality and shows Mitopure is a first-in-class nutrient that meaningfully impacts muscle health. We are proud to offer this proprietary form of Urolithin A in our Timeline® brand and inside Nestlé Health Science products,” said Rinsch. “We remain committed to pioneering clinically validated products that optimize cellular health with the mission of keeping millions of people healthier for longer.”

“Mitochondrial decline is a key hallmark of aging and poor metabolic health. This study is an important milestone and shows that Urolithin A could be a gamechanger in our field,” said Dr. Eric Verdin, president and chief executive officer of the Buck Institute for Research on Aging—who recently joined the Amazentis scientific advisory board.

References:

Singh A, D'Amico D, Andreux PA, et al. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Rep Med. 2022;3(5):100633. doi:10.1016/j.xcrm.2022.100633