A recent study published in Biological Psychiatry highlights the potential of Urolithin A, a natural compound, in effectively reversing high-anxiety behavior in rats. The core mechanism behind this effect lies in Urolithin A’s ability to repair mitochondrial function in key neurons of the brain’s nucleus accumbens, restoring mitochondrial autophagy and synaptic plasticity, ultimately alleviating anxiety symptoms at their root.
A New Approach to Anxiety Relief
Have you ever felt like your brain is a smartphone running low on battery, constantly alert with anxiety but unable to find the charger? Scientists have recently discovered that the issue might lie deep within the tiny "batteries" of our cells—mitochondria. Now, an exciting new study suggests that a mysterious substance called Urolithin A could be the key to restoring these “batteries” and recharging an anxious brain.
Anxiety is a state of mental and physical tension that manifests as persistent worry, nervousness, restlessness, or difficulty concentrating, and it can lead to symptoms such as rapid heartbeat, shallow breathing, gastrointestinal discomfort, and insomnia. Anxiety disorders can vary in severity, and chronic anxiety is a significant mental health burden. Mitochondria, as central regulators of energy metabolism and cellular homeostasis, are crucial for the health and function of neurons.
A recent study published in Biological Psychiatry reveals that Urolithin A can repair mitochondrial function in the brains of rats, reversing high-anxiety behaviors.
Figure from ScienceDirect
1. How Does Urolithin A Reverse Anxiety?
In this study, researchers evaluated the anxiety-like behavior of rats and investigated the effects of long-term oral supplementation of Urolithin A (UA, 25 mg/kg/day) on high-anxiety (HA) rats. The HA rats were randomly divided into two groups: one group received UA supplementation (HA-UA), and the other maintained a control diet, while low-anxiety (LA) rats also received the same control diet. The study lasted for two months, and anxiety behaviors were assessed using multiple tasks. The results showed that UA significantly reduced anxiety-like behavior in both male and female high-anxiety rats, with no significant impact on the normal behavior of low-anxiety rats.
Figure 1. Distinct behavioral phenotypes observed in rats with divergent trait anxiety are normalized by UA.
The researchers focused on the nucleus accumbens (NAc), a critical region for anxiety regulation, where mitochondrial dysfunction in medium spiny neurons (MSNs) is associated with anxiety phenotypes. The findings indicated that mitochondrial and synaptic pathways were severely disrupted in the NAc MSNs of HA rats.
Single-nucleus RNA sequencing of NAc tissue from all three groups revealed that compared to normal rats, HA rats exhibited significantly reduced mitochondrial autophagy. This suggests that UA treatment could effectively restore mitochondrial autophagy levels across all subtypes. In D1-MSN B neurons, although the differences between the HA and LA groups were not statistically significant, UA still significantly upregulated mitochondrial autophagy.
Figure 2. UA treatment normalizes mitochondrial molecular phenotypes in the NAc of HA rats (F)
Further transcriptomic analysis revealed that UA not only corrected the abnormal gene expression related to mitochondrial dynamics, autophagy, and energy metabolism but also partially restored the normal levels of synaptic plasticity-related genes. This finding suggests that restoring mitochondrial homeostasis could be a key mechanism underlying UA’s anti-anxiety effects.
2. Urolithin A: A "New Star" in Anti-Aging
Urolithin A is a compound metabolized by the gut microbiota from ellagic acid or ellagitannins found in foods. It is known to enhance mitochondrial health and offers neuroprotective benefits.
In 2016, researchers at Washington University found that Urolithin A promotes mitochondrial autophagy and extends the lifespan of Caenorhabditis elegans by 45%. A 2019 human clinical trial showed Urolithin A’s anti-aging effects. Additionally, studies have shown that Urolithin A can reverse ovarian aging.
From a global regulatory perspective, only the United States currently permits Urolithin A for use in foods, as the FDA has granted it GRAS (Generally Recognized as Safe) status. This means it can be used as an ingredient in food products like protein shakes, meal replacements, instant oatmeal, nutritional protein bars, and milk beverages.
In the European Union, Urolithin A was submitted for novel food approval by Amazentis in 2018, but it has not yet received formal authorization and is not yet freely available for use in the EU market.
In Japan, while Urolithin A has not yet been approved for functional labeling, its metabolic precursor, ellagic acid, is widely used in functional foods.
In China, Urolithin A has only been approved for cosmetic use and has not yet been approved for use in dietary supplements or as a new food ingredient.
3. Other Anti-Anxiety Ingredients Worth Noting
As society accelerates and work-life pressures continue to rise, emotional health issues have become a significant factor in influencing public mental and physical well-being. The prevalence of negative emotions like depression and anxiety has steadily increased, and emotional management and mental relaxation have become core topics in the health and wellness industry.
In response, functional ingredients with potential anxiety-relieving or mood-regulating effects have already been market-tested and are in active use. These ingredients are recognized for their safety, functional mechanisms, and regulatory compliance. Additionally, consumer preferences for mood supplements vary by region.
Ingredients of interest include GABA, South African Sceletium tortuosum, L-theanine, magnesium L-threonate, hypericin, Portulaca oleracea, Gastrodia elata, Poria cocos, jujube, Rhodiola rosea, lemon balm, holy basil extract, tremella polysaccharides, valerian extract, chamomile extract, and Roma leaf extract, among others.
Conclusion
This study reveals a clear pathway from cellular energy dysfunction to complex anxiety behaviors, positioning Urolithin A (UA) as a potential intervention that can precisely repair this pathway. The study shows that UA does not merely act as a sedative; instead, it targets the brain’s nucleus accumbens, a key anxiety hub, and repairs mitochondrial dysfunction in critical neurons.
By rebooting mitochondrial autophagy, optimizing energy metabolism, and restoring synaptic plasticity, UA reverses high-anxiety behavior at its core, without significantly affecting normal emotional states. This discovery not only deepens our understanding of the neurobiology of anxiety—anchoring it in objective cellular dysfunction—but also lays a strong foundation for developing next-generation anti-anxiety strategies that target mitochondria with precision, showing great translational potential.
References:
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Urolithin A Abolishes High Anxiety and Rescues the Associated Mitochondria-Related Transcriptomic Signatures and Synaptic Function.