A new study led by Massachusetts Institute of Technology (MIT) biologist Leonard Guarente, who over 15 years ago discovered the lifespan-extending effects of a set of proteins called sirtuins, and who since has shown they play a key biological role in promoting survival in response to very-low-calorie diets, has found that they also play a key role in the psychological response to calorie restriction.
Working with mice, he and his colleagues showed that when brain levels of sirtuins are high, which is what happens when diet is restricted, the animals become much more anxious. The researchers hope their findings will help inform the development of drugs that target sirtuins, such as some currently being explored for the treatment of Alzheimer’s and other neurological diseases.
They write about their findings in the 8 December online issue of the journal Cell.
As well as the effect in mice, the team found that sirtuin-boosting gene variants in humans often coincide with higher rates of anxiety and panic disorder. They suggest the findings mean that anxiety is an evolutionary adaptation that makes us, and other animals, be more cautious when faced with having to search more widely when food is scarce.
In a media statement, Guarente, the Novartis Professor of Biology at MIT, which is situated in Cambridge, Massachusetts, in the US, said this idea makes sense because “behavior effects would be as adaptive, and as selected by evolution, as physiological effects.”
He said we should not be surprised to find that behavior also comes under the umbrella of natural selection.
For the study, the researchers examined two groups of mice: one with abnormally high levels of sirtuins in their brains, and the other with none. When faced with a challenge where they have to go out into an unprotected region, the mice with very high levels of sirtuins in their brains spent much more time sticking close to the walls, suggesting they were more anxious, while the mice without any sirtuins in their brains were far more adventurous and ventured out into the uprotected region more readily.
When they looked at the cellular mechanisms behind this, they found that sirtuins appear to influence levels of serotonin, the neurotransmitter that plays a key role in regulating mood. Low serotonin levels usually result in anxiety and depression.
“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,” said Guarente.
Guarente and colleagues found that the sirtuins were reducing serotonin by activating monamine oxidase (MAO), an enzyme that breaks down the serotonin. This is the same path that antidepressants known as MAO inhibitors use: they target MAO to stop it reducing serotonin.
As well as showing signs of anxiety, the mice appeared to show signs of depression, but Guarente said “in mice, the measures for depression are not as robust, so it’s a little bit harder to assess.”
In another phase of the study, the team at Guarente’s lab collaborated with researchers at the University of Lausanne in Switzerland, who had previously identified that mutations in the human sirtuin gene were linked to anxiety, panic disorder and social phobia. Working together, the two teams found that these same mutations led to sirtuin overactivity. Meanwhile, another group of collaborators based at Virginia Commonwealth University discovered a strong link between one particular mutation and raised risk of panic disorder.
These findings would indicate that being on very low calorie diets would make people feel more anxious, since this causes the brain to produce more sirtuins. However, Guarente said he was not aware of any research on this.
Recent studies have looked at the possibility of raising sirtuin levels as a way to treat Alzheimer’s, Parkinson’s and other neurological disorders. Drugs that target this would have to pass the blood-brain barrier, which normally stops most molecules in the bloodstream from getting into the brain. We would have to be careful with such drugs, in that anxiety could be a side effect, but this should not stop us investigating them, said Guarente.
Instead, we should learn as much as we can about the biology of sirtuins, he explained, so that we can use sirtuin drugs effectively.
“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,” said Guarente.
“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,” he added.
Written by Catharine Paddock PhD