Urolithin A Unveiled: Exploring Its Potential for Longevity

Urolithin A has attracted interest from longevity enthusiasts for its potential to optimize mitochondrial efficiency. These powerhouses of the cell must be maintained for optimal health by producing new mitochondria and recycling the old mitochondria. This process involves complex pathways of gene regulation that can malfunction with aging. It is thought that urolithin A supplementation could optimize mitochondrial efficiency, but how much science is there to support this notion, and how safe is it?

The growing interest in longevity has prompted research on a wide variety of supplements to decelerate the aging process. Much of the research has focused on the mitochondria. These complex, sausage-shaped structures are the power plants of human cells and are found in nearly every cell of the human body. Some cells, such as muscle and nerve cells, which require more energy, have thousands of mitochondria.

In addition to energy supply, the mitochondria serve other critical functions, such as storing calcium ions, which are needed for blood clotting and muscle contraction. Mitochondria also contain enzymes needed to produce heme, which is required for red blood cells to transport oxygen. In addition to driving all these life-sustaining functions, mitochondria are responsible for triggering cell death (autophagy) and the recycling of older, dysfunctional mitochondria (mitophagy).

The process of mitophagy is important to maintaining mitochondrial function. Removing and recycling damaged mitochondria produces new, fully functional mitochondria. If this process of mitophagy is impaired, cell health can be negatively affected, leading to age-related chronic diseases, such as Parkinson’s disease, Alzheimer's, cardiac disorders, osteoarthritis, and cancer.

Understanding urolithin A

Urolithin A (UA) is an important postbiotic produced by your gut microbiome that influences mitochondrial function. Foods that contain the polyphenols needed to produce urolithin A include walnuts, strawberries, pomegranates, and raspberries. Some studies suggest that only a fraction (perhaps 15–40%) of older adults can produce UA reliably from a regular diet.

Animal studies, often on mice, have suggested that urolithin A can promote optimal mitochondrial function, and recent clinical studies on humans suggest that supplementation can improve mitochondrial health and muscle function in older individuals. Urolithin A appears to promote the recycling of mitochondria by triggering a pathway that first causes the degradation of older mitochondria and then stimulates the production of new, healthy mitochondria.

Potential benefits for longevity

In addition to supporting mitochondrial turnover, urolithin A supplementation in animal models such as worms and mice shows promising effects in reducing inflammation, supporting nerve growth and memory, spinal disc and joint tissue repair, muscle strength and endurance, intestinal lining integrity, and kidney function.

Is there science behind urolithin A?

The first randomized clinical trial of urolithin A was a two-part study that evaluated various doses of the supplement. Part one of the study was a single dose at 250 mg, 500 mg, 1,000 mg, or 2,000 mg among 24 healthy middle-aged participants (aged 50). In part two of the study, 36 participants were randomly assigned to 28 days of a daily supplement at 250 mg, 500 mg, or 1,000 mg. The results revealed that urolithin A was absorbed and detectable in the blood and muscle tissue.

Another randomized placebo-controlled trial, ATLAS, took the testing a step further by randomizing 88 overweight, middle-aged (40–64) participants to three equal groups: placebo, 500 mg, or 1,000 mg per day over four months. No significant differences were found between the three groups for the pre-specified primary endpoint: peak power output. However, hamstring strength improved in both the 500 mg and 1,000 mg groups, and hand grip strength, aerobic capacity, and walking distance each improved in the 1,000 mg group compared to placebo.

Additional tests were conducted to evaluate whether urolithin A supplementation supports mitophagy and muscle metabolism. These tests focused on measuring acylcarnitines in the blood to evaluate mitochondrial efficiency. The 500 mg group experienced reductions in the acylcarnitines, which are linked to increased mitochondrial efficiency, while no changes were detected in the 1,000 mg group.

Measures of inflammation, such as C-reactive protein (CRP) and pro-inflammatory cytokines, were evaluated to detect whether urolithin A offers any anti-inflammatory potential. The 1,000 mg dose showed a statistically significant reduction in CRP and reductions in some of the pro-inflammatory cytokines. Because the inflammatory markers were already low at baseline in this population, Urolithin A showed a mild anti-inflammatory effect.

Overall, the ATLAS trial found that long-term dosing was safe and well tolerated and that leg muscle strength and mitochondrial health improved in the 500 mg group while leg muscle strength and aerobic capacity increased in the 1,000 mg group. However, the pre-defined outcome of interest (peak power output) did not differ between the placebo and treatment groups.

A study among 66 older adults (65–90), again over four months, compared a placebo to 1,000 mg daily supplementation of urolithin A. This study did not find any difference in the 6-minute walk test or cell energy production (ATP) but did find improvements in muscle endurance and plasma biomarkers.

When considering a supplement, it is important to remember that these dietary products are not regulated by the Food and Drug Administration (FDA). Manufacturers need only advise the FDA that they are releasing the product. Consumers can check the FDA website for updates and advisories on reported issues, but there is no government oversight for effectiveness or quality control.

The FDA released a Generally Recognized as Safe (GRAS) notice in 2018 for typical use at 250 mg up to 1,000 mg. While there is no recommended dosage, urolithin A is available for purchase in a wide array of dosages, including at least the following: 500 mg, 700 mg, 800 mg, 1,000 mg, and 2,000 mg.

What are the possible side effects and safety precautions?

Although the ATLAS study sample sizes were small, careful investigation of the supplemental information on adverse events suggests a possible dose-response relationship with headaches. In other words, the 1,000 mg group had a higher frequency of headaches than the 500 mg group or placebo group, but this difference did not reach statistical significance. According to the study investigators, other adverse events were likely associated with the muscle biopsies performed to measure mitochondrial gene expression.

Individuals who are taking medications should always check with their primary care clinician before starting a supplement. Your clinician will want you to keep a list of all the supplements you are taking (and the date you started taking them) so that if any new symptoms arise, you will have an idea of when you started the supplement that you can compare to the onset of new symptoms.

How to incorporate urolithin A into my longevity strategy

The best longevity strategy incorporates good sleep, nutrition, movement, relationships, exposure to sunlight and the outdoors, and good oral and gut health. Taking a longevity supplement is not likely to correct for deficiencies in these other areas. However, if taking a supplement gets you excited about focusing on your health in a new way, then it may be worth considering.

For instance, would learning about urolithin A rejuvenate your appreciation for the gut microbiota producing important postbiotics? Given that the safety profile seems reasonable at the lowest dose tested (500 mg), there may be a net benefit with short-term use. Lower doses (e.g., 250 mg) are available commercially as well. On the other hand, many of the benefits noted, such as strength and endurance, can be gained with old-fashioned conditioning programs that have no downsides. Consider what has worked well for you in the past and find ways to build on those wins.

Conclusion

Overall, the current research suggests that supplementation with urolithin A among older and middle-aged adults seems to be safe, but the proper dosing is uncertain, and the real-world benefits are difficult to measure because improvements are not dramatic. Some benefits were detected at the 500 mg dose, but some adverse events were also observed. The cautious consumer might consider starting with the lowest dose available and keep an eye on unusual cardiovascular or neurological symptoms. Set some goals for your strength and endurance, and start a program that builds up gradually.

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