Over the last 10 years, MIT biologist Leonard Guarente and other researchers have demonstrated that very-low-calorie diets provoke a comprehensive physiological response, which promotes survival due to a set of proteins called sirtuins. A new report by Guarente published online in Cell has now demonstrated that sirtuins may also have a key part in the psychological response to dietary restriction.
Guarente’s study revealed that mice become much more anxious when sirtuins are elevated in the brain which happens when their food intake is cut. In two large genetic studies of humans the researchers discovered that mutations that boost sirtuin production are generally linked to higher rates of anxiety and panic disorder. They hypothesize that this anxiety could be an evolutionary adaptation, which makes animals as well as humans more cautious when they have to search more widely for scarce food.
Guarente, Novartis Professor of Biology at MIT comments:
“It makes sense, because behavior effects would be as adaptive, and as selected by evolution, as physiological effects. I don’t think it’s surprising that behavior really falls under the umbrella of natural selection.”
The researchers indicate that it could be possible to treat anxiety with drugs that inhibit sirtuins. However, they also warn to be cautious when treating patients with sirtuin activating drugs. Some of these drugs are currently undergoing clinical trials for metabolic diseases like diabetes and although these drugs cannot enter the brain, some researchers investigate into the potential of using inhibitors to treat neurological disorders like Alzheimer’s disease. Doctors may have to look for anxiety as a potential side effect should these drugs be developed and approved.
The majority of experimental studies were conducted in Guarente’s laboratory at MIT, whilst genetic studies were primarily performed by collaborators at the Virginia Commonwealth University and the University of Lausanne in Switzerland. Lead author of the report is Sergiy Libert is a postdoc in Guarente’s lab.
Guarente was the first scientist to discover that sirtuins prolong lifespan in yeast. The discovery was made about 20 years ago and since then, it has been demonstrated that sirtuins have similar effects in worms, mice and other animals. Sirtuins coordinate a variety of hormonal networks, regulatory proteins and other genes, and basically keep cells alive and healthy. They are commonly activated in response to stress factors like starvation or inflammation.
Guarente says: “We always wondered whether there might a psychological component that goes along with this.”
In their new study, Guarente and his team examined two groups of mice, one group had elevated levels of the SIRT1 protein in their brains and the other group (control group) did not. The researchers decided to examine the psychological consequence of these alterations for which they placed the mice on a raised circular platform with four quadrants, two of which were protected by a wall and the other two were unprotected.
Guarente explains: “Normal 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.”
The researchers observed that the mice in the elevated SIRT1 protein group spent a lot more time closer to the walls compared to the mice in the control group, which suggests that the elevated SIRT1 group were more anxious than those lacking sirtuin protein, who were much more adventurous.
After a subsequent investigation into the cellular mechanism of the team’s observation, they discovered that sirtuins help to control levels of the neurotransmitter serotonin, which is long known to be vital for mood regulation.
Guarente comments: “We 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.”
Anxiety and depression are usually caused due to low serotonin levels. The researchers discovered that sirtuins activate monamine oxidase (MAO), which reduces serotonin levels. MAO, also known as MAO inhibitor is an enzyme that breaks down serotonin and is the target of many antidepressant drugs.
When examining the mice for depression, the researchers detected similar effects to anxiety, but according to Guarente, “in mice, the measures for depression are not as robust, so it’s a little bit harder to assess.”
Guarente’s team decided to collaborate with researchers at the University of Lausanne who had detected that mutations in the SIRT1 gene in humans are linked to anxiety, panic disorder and social phobia. Both teams examined the molecular consequences of some of those SIRT1 mutations, and established that they led to sirtuin over activity, whilst another group of collaborators at Virginia Commonwealth University discovered a strong relationship between one of those SIRT1 mutations and the risk of panic disorder. This indicates that individuals on very-low-calorie diets are also likely to feel more anxious as their brains produce more sirtuins. Guarente comments that he is unaware of any corresponding investigations.
Recent studies indicate that sirtuin activators could be beneficial for the treatment of neurological disorders like Alzheimer’s and Parkinson’s but these drugs would need to possess the ability to cross the blood-brain-barrier, which inhibits most molecules circulating in the bloodstream from entering the brain.
Guarente says that drugs like this could produce anxiety side effects yet would still be worth pursuing.
He concludes:
“What we want to do is we want to learn as much as we can about the biology of sirtuins, to inform the use of sirtuin drugs to treat diseases. The more we know about the biology, the better position we’ll be in to know how to use the drugs, how to dose them and how to anticipate any possible side effects. I think most people would be willing to trade a therapeutic for a debilitating disease like Alzheimer’s for an increase in anxiety, which could be treated secondarily with a selective serotonin reuptake inhibitor such as Prozac.”
Written by Petra Rattue