A study led by EPFL shows that Urolithin A, a natural compound, can abolish high anxiety in rats by repairing mitochondrial function in their brain cells, specifically in the nucleus accumbens. The findings open a new avenue for approaches to help reduce anxiety.
Anxiety disorders affects millions of people worldwide, with about 14% experiencing an anxiety disorder in any given year. These conditions are often disabling, and current treatments don't work well enoughbecause they focus on managing symptoms rather than address the disorder's biological causes. Compounding the problem, anxiety medications can also have side effects or cause dependency problems while often blunting normal emotions.
In recent years, studies by the group of Professor Carmen Sandi at EPFL's Laboratory of Behavioral Genetics have pointed to a link between anxiety and the brain's mitochondria, the cell's energy suppliers which are vital for fuelling cells and helping them work correctly. Problems with mitochondrial function have turned up in both animals and people with anxiety, but only a few studies have explored whether "fixing" them could actually lower anxiety.
Sandi has now led a new study that shows that restoring mitochondria to health could be the key to reducing anxiety. The study, with David Mallet and Dogukan Ülgen as first co-authors and in collaboration with Amazentis and Columbia University, explored the anxiety-reducing effects of Urolithin A, a molecule produced by gut bacteria and already known to support mitochondrial health.
A systematic approach
"Previous studies tried to restore mitochondrial function genetically directly in the brain with viral injections, this is the first one that focuses on a systemic approach," says Sandi. Focusing on the nucleus accumbens, a brain area involved in anxiety and emotion, the researchers studied the effects of Urolithin A on rats, looking at their behavior and what was happening inside their brain cells.
The team gave the only clinically validated, highly pure, proprietary Urolithin A supplement, ("Mitopure®,") to two rodent models of high anxiety: The first was a group of outbred rats, which showed typical individual differences in anxiety across the population. The second group of rats were selectively bred for heightened stress reactivity and, thus, with a genetic predisposition towards high anxiety. The researchers also used rats with low anxiety as the control group.
The researchers then mixed Urolithin A into the animals' food at a dose similar to previous studies (25 mg/kg/day). They then tracked changes in anxiety-related behavior over two months and used single-nucleus RNA sequencing to check the levels of gene expression inside "medium spiny neurons" in the rats' nucleus accumbens, a brain region central to anxiety regulation. They also used electrophysiology and imaging to see how the structure and function of those neurons changed.
"A robust anxiolytic effect"
The results were striking: Urolithin A completely reversed high-anxiety behaviors in the anxious rats ("a robust anxiolytic effect") while leaving normal rats unaffected. At the cellular level, they found that Urolithin A repaired disruptions in mitochondrial gene networks, including the restoration of healthy activity in cell pathways that are responsible for producing energy and keeping cells in good shape.
They also found that the molecular machinery involved in mitophagy, which is the process by which cells clear out damaged mitochondria, was consistently out of balance in the anxious rats but was corrected by the treatment with Urolithin A.
The diet containing Urolithin A also repaired the structure and function of the rats' neurons, restoring the small connections (their "spines") that are needed for brain circuits to work properly. Levels of a protein called Mitofusin 2, which keeps mitochondria healthy and has previously been tied to regulate anxiety behaviors, also returned to normal.
Towards clinical trials
More importantly, all these molecular and cellular changes lined up with improvements seen in the rats' anxiety. Interestingly Urolithin A had no obvious effect on the low-anxious rats, indicating that it works specifically where brain circuits are disturbed.
The work confirms in two rat models that mitochondrial problems drive anxiety. By directly targeting and repairing this dysfunction, Urolithin A supplementation could eschew some of the side effects seen with current drugs and pave the way for more precise nutritional interventions for anxiety. Because Urolithin A has already been shown to be safe in humans, the study's findings could be rapidly translated into clinical trials. "This is what we're aiming to do next," says Sandi.
Other contributors
- Amazentis S.A.
- Columbia University
