Low-calorie diets are a known benefit for the overall health of the body, but the exact mechanisms underlying this effect remain elusive. Now, a study published in the journal Aging Cell, has shown that low-calorie intake increases neurons’ capacity to neutralize excessive levels of calcium, which contribute to neuronal damage in several diseases, including Alzheimer’s disease.
The study, “Caloric Restriction Increases Brain Mitochondrial Calcium Retention Capacity And Protects Against Excitotoxicity” was conducted by a research group in Brazil.
“More than promoting the advantages of eating frugally, we aim to understand the mechanisms that make not overconsuming calories better for health,” Ignacio Amigo, PhD, lead author of the study, said in a press release. “This can point to new targets for the development of drugs against various diseases.”
Calcium is one of the most powerful messengers within neurons and, for this reason, its concentration levels must remain highly regulated. When neurons communicate, certain groups of proteins are activated, such as the glutamate receptors. Neurons become activated by calcium entry through these receptors, which will initiate several molecular pathways important for neuronal function and survival. When communication is over, however, cells store calcium in certain compartments, such as the mitochondria (the cell’s powerhouse), thus allowing calcium levels to return to baseline, waiting for the next signals.
In Alzheimer’s disease and other brain disorders, however, neuronal communication is poorly regulated, causing increased activation of the glutamate receptors and, consequently, excessive amounts of calcium enter brain cells. This damaging process is called excitotoxicity, and may result in neuronal death.
Researchers used mice and rats to investigate the association between low-calorie intake and excitotoxicity. Control animals were given free access to food and water for 14 weeks. By then, these animals were overweight. The other group received a diet with 40% fewer calories supplemented with vitamins and minerals to avoid malnutrition, for the same period. These animals did not lose weight and were healthy by the end of the 14 weeks.
The animals were then given kainic acid, a drug that activates glutamate receptors to induce calcium entry in neurons.
“We administered a small dose to avoid killing the animal,” said Amigo. “Even so, kainic acid caused seizures in the control group. It had no effect on the [caloric restriction] group.”
Because mitochondria are one of the cell’s compartments to store calcium, researchers wondered whether there would be differences between mitochondria from the caloric restriction group and those of the fat animals. Indeed, they observed the first group presented mitochondria that were more able to store higher levels of calcium.
The team also noted that cyclosporine, a drug that increases calcium retention in the mitochondria, had effect only on mitochondria from fat animals, with no change in mitochondria from the caloric restriction group. Thus, the drug and low-calorie intake had the same effect; they increased the mitochondria’s capacity to store elevated levels of calcium.
But how? Both factors stimulate the production of a protein called SIRT3, which activates certain chemical reactions that make mitochondria retain more calcium. In mitochondria from the dietary group, these reactions were activated already, explaining why cyclosporine had no effect.
However, the advantages of low-calorie intake do not only increase the brain’s capacity to buffer excessive calcium levels. It also leads to the activation of several proteins of the antioxidant system, another advantage to avoid the development of neurological diseases.
According to Amigo, these proteins whose activity is improved by nutritional intervention may become future targets for the treatment of diseases in which neuronal loss due to excitotoxicity is implicated.
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