13th February, 2021, Dr Chee L Khoo
One of the signs of getting old is that you are increasingly drawn to articles about efforts to reduce the effects of aging on health and age-related conditions. The positive effects of direct urolithin A (UA) administration in health, aging, and age-related conditions have been identified in several recent studies. UA is a gut microbiome derived natural compound that only 40% of people can naturally convert from dietary precursors at meaningful levels. Quick, tell me more. Where can I source more of UA? Is there a scientific basis to the beneficial effects of UA?
UA is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA). ETs have a very low bioavailability and are either directly eliminated in the stool or converted into more bioavailable derivates. ETs are hydrolysed into EA by gut bacterial enzymes called tannases. Further enzymatic reactions transform EA into urolithins. UA and urolithin B (UB) are the most abundant final products and UA is the most conserved and widely studied urolithin across species. ET is quite ubiquitous in nature, including edible plants such as as pomegranates, strawberries, raspberries, and walnuts.
Interestingly, the conversion of ETs and EA to UA does not occur in all individuals. The process is variable and takes place in only approximately 40% of the human elderly population. Being a ‘UA producer’ requires an appropriate gut microbiome and varies with age, health status, and dietary intake. Efforts have been made to identify the bacterium, or bacteria, responsible for UA conversion. Although some species have been proposed based on ex vivo studies in faeces [1,2], the UA-producing bacteria in the human gut are still unknown [3].
The most consistent effect of UA on humans have been the improvement on mitochondrial health. UA is shown to clear the body of dysfunctional mitochondria, a process called mitophagy. Mitophagy improves the quality of the cellular mitochondria pool and is tightly linked to the generation of new organelles, leading to improved mitochondrial respiratory capacity [4]. As we age, mitophagy becomes less effective. Perhaps, if we can restore mitophagy, we could slow down aging.
Preclinical (i.e. animal) studies show positive impacts of UA on natural aging and diseases related to aging. In worms feed pomegranate, UA extends lifespan by 45%, while its precursor EA has no effect [5]. UA also prevented age-related muscle decline [5], as indicated by improved integrity of muscle fibers, increased mobility, and higher rates of pharyngeal pumping in old, UA-treated worms [5]. Similarly, mice showed enhanced skeletal muscle strength in the prevention study and better aerobic performance in both prevention and intervention mode.
In mice experiments, mice treated with UA showed a reduced infarct size and a partial preservation of ejection fraction. In mice models of Alzheimer’s Dementia (AD), UA improved memory in response to stimuli, increased learning, increased memory retention and neuronal survival. There are numerous studies showing benefits in animal models of multiple sclerosis, inflammatory bowel disease and spinal and joint degeneration.
What about benefits of UA in humans?
Association studies
In association studies, plasma and urine urolithins were measured in subjects after consumption of food rich in ET and EA. Subjects who were able to produce UA following the consumption of the foods were classified as urolithin metabotype A (UM-A) and those who were not able to produce any urolithin were classified as urolithin metabotype B (UM-B).
UM-A individuals had a BMI in the normal range (19-25 kg/m2), better gut health, lower baseline values of serum CVD biomarkers (6,7). These individuals already had good health and UA supplements did not improve those values. On the other hand, UM-B individuals had higher baseline risk values which improved with UA supplements (8).
Further, higher plasma UA levels were also positively associated with improved endothelial function [9] and were observed in individuals who consumed a Mediterranean diet [10], a plant-based diet high in unsaturated fat [11]. Conversely, the proportion of metabotype A profiles declined with age in subjects from 20 to 50 years of age [12].
These studies indicate associations but cannot directly identify UA’s health benefits in humans but they indicate that UA is the key metabolite of ETs and EA and that the ability to produce it is a sign of general health. The fact that UA levels decline with age is a concern that must be investigated further.
Intervention studies
In a most recent randomised clinical trial of 66 older adults, those who received supplementation with 1000 mg of urolithin A had a significant improvement in muscle endurance (number of muscle contractions until fatigue) for both hand and leg skeletal muscles compared with those who used placebo (13). Plasma levels of several acylcarnitines, ceramides (biomarkers of mitochondrial health), and C-reactive protein were decreased after urolithin A supplementation.
This trial suggests that urolithin A may be a promising approach to counteract age-associated muscle decline. Future study is needed to confirm the role of urolithin A supplementation in healthy aging.
References:
- Selma, M.V. et al. (2014) Gordonibacter urolithinfaciens sp. nov., a urolithin-producing bacterium isolated from the human gut. Int. J. Syst. Evol. Microbiol. 64, 2346–2352
- Selma, M.V. et al. (2014) Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species. Food Funct. 5, 1779–1784
- Cortés-Martín, A. et al. (2020) Where to look into the puzzle of polyphenols and health? The postbiotics and gut microbiota associated with human metabotypes. Mol. Nutr. Food Res. 64, 1900952
- Ploumi, C. et al. (2017) Mitochondrial biogenesis and clearance: a balancing act. FEBS J. 284, 183–195
- Ryu, D. et al. (2016) Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888
- Selma, M.V. et al. (2016) The human gut microbial ecology associated with overweight and obesity determines ellagic acid metabolism. Food Funct. 7, 1769–1774
- Romo-Vaquero, M. et al. (2019) Deciphering the human gut microbiome of urolithin metabotypes: association with enterotypes and potential cardiometabolic health implications. Mol. Nutr. Food Res. 63, e1800958
- González-Sarrías, A. et al. (2017) Clustering according to urolithin metabotype explains the interindividual variability in the improvement of cardiovascular risk biomarkers in overweight-obese individuals consuming pomegranate: a randomized clinical trial. Mol. Nutr. Food Res. 61, 1600830
- Istas, G. et al. (2018) Plasma urolithin metabolites correlate with improvements in endothelial function after red raspberry consumption: a double-blind randomized controlled trial. Arch. Biochem. Biophys. 651, 43–51
- Meslier, V. et al. (2020) Mediterranean diet intervention in overweight and obese subjects lowers plasma cholesterol and causes changes in the gut microbiome and metabolome independently of energy intake. Gut 69, 1258–1268
- Davis, C. et al. (2015) Definition of the Mediterranean diet; a literature review. Nutrients 7, 9139–9153
- Cortés-Martín, A. et al. (2018) The gut microbiota urolithin metabotypes revisited: the human metabolism of ellagic acid is mainly determined by aging. Food Funct. 9, 4100–4106
- Liu S, D’Amico D, Shankland E, et al. Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2022;5(1):e2144279. doi:10.1001/jamanetworkopen.2021.44279