R&D News: Anxiety could potentially be treated with drugs that inhibit sirtuins
When sirtuins are elevated in the brain, as occurs when food intake is cut, mice become much more anxious. Furthermore, in two large genetic studies of humans, the study team found that mutations that boost production of sirtuins are commonly associated with higher rates of anxiety and panic disorder.
The researchers believe that this anxiety may be an evolutionary adaption that makes animals - including humans - more cautious under the stressful condition of having to forage more widely for scarce food.
â€œIt makes sense, because behavior effects would be as adaptive, and as selected by evolution, as physiological effects. I donâ€™t think itâ€™s surprising that behavior really falls under the umbrella of natural selection,â€ says Mr Guarente.
The research suggests that anxiety could potentially be treated with drugs that inhibit sirtuins. On the other hand, it also raises a caution when treating patients with drugs that activate sirtuins, several of which are now in clinical trials for metabolic diseases, including diabetes. Those drugs canâ€™t enter the brain, but some researchers are exploring the possibility of using sirtuin inhibitors to treat neurological disorders such as Alzheimerâ€™s disease. If such drugs were developed and approved, doctors might need to watch for anxiety as a possible side effect.
About 20 years ago, Mr Guarente has discovered that sirtuins prolong lifespan in yeast; since then, they have been shown to have similar effects in worms, mice and other animals.
In the new Cell study, Mr Guarente and his colleagues examined two groups of mice: some with elevated levels of the SIRT1 protein in their brains and some with none. To test the psychological consequences of these alterations, the mice were placed on a circular raised platform with two quadrants protected by a wall, and two unprotected quadrants.
â€œNormal mice will spend a considerable amount of time venturing out into the unprotected region, and super-anxious mice tend to stay in the protected area,â€ Mr Guarente says.
The researchers found that the mice with abnormally high sirtuin levels spent much more time closer to the walls, suggesting they were more anxious. But mice lacking sirtuin protein were much more adventuresome.
The team then investigated the cellular mechanism behind this phenomenon, finding that sirtuins help control levels of the neurotransmitter serotonin, long known to be critical for mood regulation.
â€œWe were very surprised to see that, but it also made it relatively easy for us to figure out the mechanism by which sirtuins were regulating mood,â€ Mr Guarente says.
Low serotonin levels usually produce anxiety and depression. The researchers found that sirtuins reduce serotonin levels by activating monamine oxidase, or MAO, an enzyme that breaks down serotonin. (MAO is the target of many antidepressant drugs, known as MAO inhibitors.)
The researchers also tested the mice for depression and found effects similar to anxiety, but â€œin mice, the measures for depression are not as robust, so itâ€™s a little bit harder to assess,â€ Mr Guarente says.
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