Reduction in Calories Good For the Brain

20 Oct 2016 --- A reduction in dietary caloric intake can help the brain avoid the death of neurons that is associated with neurodegenerative conditions, according to a new study published in Aging Cell by scientists at the Center for Research on Redox Processes in Biomedicine (Redoxoma).

The results of in vitro and in vivo experiments suggested that a 40% reduction in calories increases mitochondrial calcium retention in situations where intracellular calcium levels are pathologically high.

"More than promoting the advantages of eating frugally, we aim to understand the mechanisms that make not overconsuming calories better for health,” said Ignacio Amigo, lead author of the article.

“This can point to new targets for the development of drugs against various diseases.”

According to Amigo, calcium participates in the process of communication between neurons. However, Alzheimer's disease and other neurological disorders can cause an excessive influx of calcium ions into brain cells due to overactivation of neuronal glutamate receptors. This condition, known as excitotoxicity, can damage and even kill neurons.

To verify the effect of caloric restriction on excitotoxicity, Redoxoma's scientists compared two groups of mice and rats.

Control animals were given food and water ad libitum for 14 weeks and were overweight at the end of the experiment. The other group received a 40% caloric restriction (CR) diet for the same period.

“We calculated the daily amount of calories consumed on average by the control group and offered the other group 40% less,” Amigo explained. “They didn't become underweight and remained healthy, although we supplemented their diet with vitamins and minerals to avoid malnutrition due to the restricted amount of food.”

In the first test, the animals were injected with kainic acid, a glutamate analogue with a similar effect in terms of inducing neuronal calcium influx, albeit more persistent. In rodents, it can cause brain damage, seizures and neuronal cell death due to overactivation of glutamate receptors in the hippocampus. It is used in the laboratory to mimic epilepsy.

“We administered a small dose to avoid killing the animal. Even so, kainic acid caused seizures in the control group. It had no effect on the CR group,” Amigo said.

Because previous research had shown that increasing mitochondrial calcium uptake can afford protection against excitotoxicity, he continued, “We decided to verify in vitro whether this was the case in our model. We isolated brain mitochondria from rats and again compared those fed ad libitum with those on a 40% CR diet. As we added calcium to the medium, we observed higher levels of mitochondrial calcium uptake in the CR group.”

The next step was to see what happened when the mitochondria isolated from each group were treated with cyclosporin, a drug known to increase calcium retention.

While calcium uptake did indeed increase in the mitochondria from the control group, it remained unchanged in the CR group, eliminating the difference observed in the previous test.

“Cyclosporin's target in mitochondria is well known,” Amigo said. “The drug inhibits the action of a protein called cyclophilin D, leading to increased mitochondrial calcium retention.”

In this case, however, cyclophilin D levels were found to be the same in both groups. The researchers therefore decided to measure the levels of other proteins that might be interfering with cyclophilin D's action in the organism.

“We discovered that caloric restriction induces an increase in levels of a protein called SIRT3, which is capable of modifying the structure of cyclophilin D. It removes an acetyl group from the molecule in a process known as deacetylation, and this inhibits cyclophilin D, so that the mitochondria retain more calcium and become insensitive to cyclosporin,” Amigo said.

According to the scientists, these results suggest an enhanced capacity to manage cerebral oxidative stress, a condition that contributes to the onset of several degenerative diseases.

The researchers hope the proteins with activity affected by nutritional intervention in this recent study are potential targets to be explored for treatment of diseases in which excitotoxicity causes loss of neurons.