Urolithins: A Prospective Alternative against Brain Aging

Brain aging and neurodegenerative diseases like Alzheimer’s and Parkinson’s are growing global health concerns, with oxidative stress, inflammation, and mitochondrial dysfunction playing key roles in cognitive decline. In their study, Urolithins: A Prospective Alternative against Brain Aging, An et al. explore how urolithins—gut-derived metabolites of ellagitannins and ellagic acid found in foods like pomegranates and walnuts—may offer neuroprotective benefits. These compounds have been shown to cross the blood-brain barrier, reduce oxidative stress, suppress neuroinflammation, enhance mitochondrial function, and prevent the buildup of toxic proteins associated with neurodegenerative diseases. The study reviews both preclinical and emerging clinical evidence, suggesting that urolithins may serve as functional food components, potential therapeutic agents, or biomarkers for cognitive health. However, further human trials are needed to fully understand their long-term effects and clinical applications in brain aging prevention.

As people live longer, brain-related conditions like Alzheimer’s disease (AD), Parkinson’s disease (PD), and mild cognitive impairment (MCI) are becoming more common. Scientists predict that by 2050, over 130 million people worldwide will be affected by dementia. Brain aging is influenced by several factors, including oxidative stress, chronic inflammation, mitochondrial dysfunction, and toxic protein buildup. These processes can damage neurons, leading to cognitive decline and increasing the risk of neurodegenerative diseases.

One of the most exciting discoveries in recent years is the gut-brain connection—how gut bacteria influence brain health. The gut microbiome produces bioactive compounds that can impact inflammation, brain signaling, and neuroprotection. A key group of these compounds is urolithins (Uros), which are metabolites derived from ellagitannins and ellagic acid, found in foods such as pomegranates, walnuts, berries, aged wine, and certain medicinal plants. However, the ability to produce Uros varies between individuals. The study states, “Only 40% of elderly people (>60) can produce meaningful levels of Uros from dietary precursors”, which suggests that aging reduces the body’s ability to convert dietary polyphenols into beneficial metabolites.

Researchers are particularly interested in Uros because they can cross the blood-brain barrier (BBB ), allowing them to directly influence brain function. This study reviews existing research on Uros and brain health, focusing on their potential role in slowing brain aging, improving memory and learning, and preventing neurodegenerative diseases.

This study is a scientific review, meaning it analyzes findings from previously published research rather than conducting new experiments. The researchers examined how Uros are formed in the body, how they affect brain cells and function, and their potential role in neurodegenerative diseases. They reviewed animal studies to determine Uros' impact on memory, cognition, and neuroinflammation, and they also analyzed human trials to assess whether consuming Uro-rich foods, such as pomegranates and walnuts or taking Uro supplements could improve brain health. By compiling this evidence, the study identifies both the therapeutic potential of Uros and gaps in research that need further investigation.

The brain consumes a large amount of oxygen, making it highly susceptible to oxidative stress. When reactive oxygen species (ROS) accumulate, they damage proteins, lipids, and DNA, contributing to neurodegenerative diseases. The study explains, “Damage to neural cells occurs when ROS production overwhelms the antioxidant defense mechanisms.” Uros, particularly UroA and UroB, have been shown to neutralize ROS and support natural antioxidant defenses.

In cell studies, Uros protected neurons from oxidative damage and apoptosis. The study highlights, “UroA significantly increased PKA/CREB/BDNF neurotrophic signaling pathway in H2O2-treated SH-SY5Y cells, suggesting its protective role against oxidative stress.” Additionally, Uros enhance the activity of key antioxidant enzymes, such as superoxide dismutase (SOD) and catalase (CAT), helping the brain maintain its defense against oxidative damage. In animal models, Uro supplementation improved cognitive function and reduced oxidative damage, suggesting that these compounds may help counteract age-related brain decline.

Chronic inflammation in the brain is a major contributor to neurodegenerative diseases. Overactive immune cells, such as microglia and astrocytes, release pro-inflammatory cytokines, which can lead to nerve cell damage, cognitive decline, and an increased risk of Alzheimer’s and Parkinson’s disease. The study notes that Uros can block key inflammatory pathways, reducing the expression of pro-inflammatory molecules like TNF-α, IL-1β, and IL-6.

In lab studies, UroA and UroB significantly decreased neuroinflammation in microglia exposed to lipopolysaccharide (LPS), a compound that triggers immune responses. The study states, “UroB significantly inhibited lipoteichoic acid (LTA)- and polyinosinic-polycytidylic acid (poly(I:C))-induced inflammation in BV2 cells.” This suggests that Uros’ anti-inflammatory effects are not limited to a single type of immune activation. In animal models, Uro supplementation reduced inflammation, improved memory, and protected neurons from damage in aged mice and Alzheimer’s models.

Mitochondria are essential for energy production in brain cells, but they become less efficient with age, leading to brain fog, memory problems, and neurodegeneration. One of the most promising effects of Uros is their ability to activate mitophagy, a process that removes damaged mitochondria and replaces them with new, healthy ones.

The study highlights, “Mitophagy deficiency and subsequent mitochondrial dysfunctions are early and pivotal events in brain aging and neurodegenerative diseases, and mitophagy induction seems to be a crucial mechanism in the effects of Uros.” In both cell and animal studies, Uros increased the levels of PINK1 and Parkin, proteins involved in mitochondrial quality control. Additionally, human trials found that UroA supplements improved mitochondrial function and muscle endurance in older adults, suggesting broader benefits beyond brain health.

A key feature of Alzheimer’s disease is the accumulation of amyloid-beta (Aβ) plaques and tau tangles, which interfere with brain cell communication and memory formation. The study explains, “UroA significantly inhibited DYRK1A activity, reducing tau phosphorylation and improving memory in 3×Tg AD mice.” This suggests that Uros may prevent or slow Alzheimer’s disease progression by reducing toxic protein buildup.

In animal models, UroA treatment reduced Aβ levels, improved cognitive function, and protected neurons from damage. Similarly, in Parkinson’s disease models, UroA helped clear toxic proteins, reduce neuroinflammation, and enhance motor function, making it a potential therapeutic candidate for multiple brain disorders.

The gut microbiome plays a crucial role in brain health, and Uros may serve as biomarkers for cognitive decline risk. The study states, “Microbial-derived metabolites of polyphenols can be used as biomarkers to predict the risk of neurodegenerative diseases.” Individuals with higher Uro levels tend to have better gut and brain health, while those with low Uro production may be at greater risk for cognitive impairment and neurodegeneration.

The findings suggest that Uros could be a safe and natural solution for brain aging and neurodegeneration, but several questions remain. Since not everyone produces Uros efficiently, should direct Uro supplements be developed? More human trials are needed to confirm long-term benefits and establish Uros as potential therapeutic agents. Additionally, Uros might serve as biomarkers for brain health, allowing doctors to assess cognitive decline risk based on gut microbiome composition.

The gut-brain connection is a rapidly growing field, and urolithins may play a crucial role in protecting against brain aging. Their antioxidant, anti-inflammatory, and mitochondrial-boosting properties make them strong candidates for preventing Alzheimer’s, Parkinson’s, and cognitive decline. While more human research is needed, early findings are promising. In the future, Uros could lead to personalized nutrition strategies, innovative supplements, and new medical treatments to support healthy brain aging.