Targeting aging with urolithin A in humans: A systematic review

Aging leads to a decline in mitochondrial function, muscle strength, and increased inflammation, all of which contribute to various age-related diseases. In their study, Kuerec et al., Targeting Aging with Urolithin A in Humans: A Systematic Review, the authors explore whether Urolithin A (UA), a gut-derived metabolite, can counteract these effects. Since not everyone can naturally produce UA, supplementation has been studied as a way to enhance mitochondrial health, reduce inflammation, and support muscle function. This systematic review examines five clinical trials involving 250 healthy adults, analyzing the effects of UA supplementation (ranging from 10 to 1000 mg per day over 28 days to 4 months) on mitochondrial efficiency, inflammation markers, muscle performance, and overall metabolic health. The findings suggest that while UA positively influences mitochondrial gene expression and muscle endurance, it does not significantly increase ATP production or alter overall body composition, highlighting the need for further long-term research to confirm its anti-aging potential.

Aging affects nearly every system in the body, leading to muscle loss, slower metabolism, and increased inflammation, all of which contribute to age-related diseases. Scientists are actively exploring compounds that might help slow these processes, and Urolithin A (UA) has emerged as a promising candidate.

UA is a metabolite produced in the gut when certain foods—like pomegranates, walnuts, and raspberries—are digested. However, not everyone can naturally produce UA, as it depends on the presence of specific gut bacteria. According to the study, "approximately 40% of adults demonstrated the ability to generate UA 24 hours after consuming one glass of pomegranate juice." Since natural production varies between individuals, researchers found that "direct supplementation with 500 mg UA resulted in more than six times higher plasma levels of UA than one glass of pomegranate juice intake." This suggests that UA supplementation provides a more reliable and effective way to increase UA levels in the body.

Animal and lab studies have suggested that UA may support mitochondrial health, reduce inflammation, and improve muscle strength. This systematic review examines five clinical studies evaluating UA’s effects on mitochondrial function, inflammation, muscle performance, gut microbiome composition, and human cardiovascular health.

To determine the effectiveness of UA, researchers followed a strict selection process when analyzing the available studies:

• Study Selection: Five clinical studies with 250 healthy adults were included. These studies specifically tested UA supplementation rather than dietary sources like pomegranate juice.
• Dosage and Duration: Participants received between 10 mg and 1000 mg of UA daily for periods ranging from 28 days to 4 months.
• Health Markers Analyzed: Researchers measured mitochondrial function, inflammation levels, muscle strength, endurance, gut microbiome diversity, cardiovascular function, and potential side effects.
• Risk of Bias Assessment: The Cochrane risk-of-bias tool was used to evaluate the quality and reliability of the studies.

The study ensured that only direct UA supplementation was analyzed, stating that "UA was administrated directly (not as a precursor form),” meaning any indirect sources of UA (such as ellagic acid from food) were excluded.

Mitochondria, often called the powerhouses of the cell, produce adenosine triphosphate (ATP), the body's primary energy source, but their efficiency declines with age, leading to fatigue, muscle weakness, and metabolic slowdowns. Scientists investigated whether UA supplementation could enhance mitochondrial function and counteract this decline.

The study found that UA increased the expression of mitochondrial genes related to fatty acid oxidation and autophagy, stating that “UA (500 or 1000 mg/day for 28 days) significantly enriched gene ontology (GO) Mitochondrial Matrix and GO Mitochondrion in the vastus lateralis.” However, despite these genetic-level changes, UA did not significantly boost ATP production, as the study noted that "treatment with UA (1000 mg/day for 4 weeks) did not affect the change in maximal ATP production from baseline to 4 months." This suggests that while UA may improve mitochondrial function at a genetic level, it does not directly enhance energy output in the short term.

Chronic inflammation is a key factor in aging-related diseases such as heart disease, diabetes, and neurodegenerative disorders. The study found that UA supplementation had a dose-dependent anti-inflammatory effect, meaning higher doses resulted in greater reductions in inflammation markers.

At 500 mg/day for 4 months, UA significantly lowered interleukin-1 beta (IL-1β), with researchers reporting that “four months of 500 mg UA significantly decreased the levels of IL-1β.” A higher dose of 1000 mg/day for 4 months further reduced levels of C-reactive protein (CRP), interferon-gamma (INF-γ), and tumor necrosis factor-alpha (TNF-α), as the study stated that “a higher dose of UA (1000 mg/day for 4 months) led to significant decreases in CRP, INF-γ, and TNF-α levels compared to placebo.” These findings suggest that UA may help reduce inflammation as people age, particularly at higher doses.

Muscle loss (sarcopenia) is a major concern with aging, leading to weaker mobility and an increased risk of falls. Scientists tested whether UA could enhance muscle strength and endurance in middle-aged and older adults.

• Hamstring and knee flexion strength significantly improved in participants who took UA for 4 months, with the study reporting that “UA (500 or 1000 mg/day for 4 months) significantly increased muscle strength expressed as average peak torque in the hamstring muscle and the maximum torque during knee flexion.”
• Muscular endurance (the ability to sustain activity) increased in some cases, but the effects were inconsistent.
• Handgrip strength, a key indicator of total muscle function, remained unchanged, as researchers stated that “UA (500 mg/day for 4 months) did not affect handgrip strength.”

These findings suggest that UA may improve lower body strength, but its effects on overall muscle function remain uncertain.

The study reported no serious adverse effects from UA supplementation. Some participants experienced mild symptoms like headaches and muscle pain, but these were not directly linked to UA. Researchers confirmed that “there were no serious adverse events attributed directly to UA reported in any of the studies.”

UA is a promising compound for healthy aging, particularly for reducing inflammation and supporting muscle strength. While it enhances mitochondrial function at a genetic level, the study found that "UA did not affect mitochondrial maximal adenosine triphosphate production, biogenesis, or dynamics," meaning its effects may be more subtle than previously thought.

If you’re considering UA supplementation, remember it is not a magic bullet for aging. Instead, it may be useful when combined with exercise and a balanced diet. More long-term research is needed to determine whether UA can significantly slow aging and improve overall longevity, but for now, it remains a promising supplement for maintaining muscle strength and reducing inflammation.