20 December 2011

How a low-calorie Diet Slows down Brain Aging

The diet of dullness
A mechanism has been discovered that improves brain function in case of malnutrition

Ivan Kulikov, Newspaper.RuA low-calorie diet triggers a molecular mechanism that slows down the degradation of nerve cells and aging of the brain.

The "rejuvenating" effect is fixed with a decrease in the level of calories consumed by a third of the daily, Italian biologists have found.

The key link in the molecular scenario that slows down the degradation of neurons is the CREB1 protein from the class of protein transcription factors, that is, proteins that control the transfer (transcription) of information from DNA to matrix RNA – an intermediate working "blueprint" for the synthesis of proteins on ribosomes.

CREB proteins, which turn on and off the synthesis of neuropeptides (important enzymes regulating synaptic connections between neurons – endorphin, vasopressin, etc.) and neurotrophin (neuron growth factor), have long been of interest to biologists studying the molecular mechanisms of basic neurofunctions – memory, consolidation of emotions, ability to learning, that is, functions that ensure the plasticity of the brain, its ability to adapt, responding to signals coming from the external environment.

Thus, a lot of experimental data has been accumulated showing that with a deficiency of CREB, "long" synaptic connections between neurons are blocked (which is logical, since CREB regulates the synthesis of long-lived neuropeptides), while the construction of "short" ones is not affected.

Mice in which this protein was turned off showed normal results in tests of RAM and poor in exercises requiring the use of long-term memory. There was also an increased level of CREB expression in the amygdala (the part of the brain responsible for processing and remembering basic emotions – fear and pleasure) of normal mice after training.

CREB performs regulatory functions by attaching to certain DNA sites, and is a signal-dependent transcription factor, that is, it requires an external signal for activation. The role of such a signal is performed by a cyclic adenosine monophosphate molecule (cAMP, or cAMP, hence the abbreviation CREB – cAMP response element-binding, or "cAMP-dependent transcription factor"). The cAMP molecule (a secondary intermediary that transmits a signal inside the cell when the primary signaling molecule, for example, a neurotransmitter protein molecule, cannot penetrate the cell membrane) is a derivative of adenosine triphosphate, or ATP - the "energy angel", a nucleotide that plays an important role in the metabolism of matter and energy within all living systems.

It is logical to assume that changes in metabolic processes observed, for example, with a deficiency of nutrients, can affect the regulatory function of CREB and, through the synthesis of neuropeptides and other neuroenzymes, the basic functions of the brain as a whole, including regeneration and ensuring the stable functioning of neurons.

A group of biologists working under the leadership of Giovambattista Pani from the Faculty of General Pathology and Medicine of the Catholic University of the Sacred Heart (Italy) undertook to investigate this issue, whose article "The role of neuronal cAMP-dependent transcription factor in the brain's response to calorie deficiency" It is due to be published this week in the Proceedings of the National Academy of Sciences. (A summary of the results of the work – Eating less keeps the brain young – can be read on the Medical Xpress – VM website.)

In a series of experiments on mice with knockout CREB and healthy animals from the control group, the Italians managed to establish that a low-calorie diet plays the role of a "trigger" that activates a certain cAMP-dependent transcription factor encoded by the CREB1 gene.

In addition, it was found that CREB1 is responsible for the synthesis of specific proteins that contribute to the normal functioning of the brain and prevent age-related degradation of nerve cells. A low-calorie diet is understood when animals received 70% of the normal daily amount of calories. As shown by numerous experiments, which were also described by "Gazeta.En", it is this kind of moderate fasting that prolongs the life of not only mammals, but also less developed animals, such as flies, worms and even yeast.

The fact that fasting prevents the aging of the brain and, thus, the development of age–related dementias - Alzheimer's, Parkinson's and many others, has been known to science for a long time, but the molecular mechanism of this dependence remained unclear.

It looks like it's starting to clear up a little bit now: as shown by molecular (using fluorescent marker proteins) and cellular analysis (measuring the level of long-term neuronal potentiation critical for memory function), the brains of healthy dieting mice produced CREB1 more actively than the brains of healthy mice in the control group, and in cognitive tests these animals showed consistently better results and that interestingly, there was a lower level of intraspecific aggression than mice with CREB turned off, which showed all the symptoms typical of old or overeating animals.

The positive effect of malnutrition, according to the authors, is also explained by the fact that, as shown by the same experiments, the activation of CREB1 (a transcription factor working in the body of higher animals and humans), forced by a deficiency of nutrients, triggers the synthesis of sirtuins – a class of proteins on which the density of DNA packing in the chromatin of eukaryotic nuclei – molecular a container containing DNA, RNA and histone proteins that are also involved in transcription. An excess of sirtuins "loosens" the histone packaging of DNA, contributing to both cell division and repair of damaged DNA, that is, in other words, regulates aging processes and stress resistance, as well as the generosity of grant donors who have been sponsoring a real "sirtuin boom" in molecular biology for the past ten years.

It is the sirtuin-expressing function of CREB1, as the Italians suggest, that is behind the "rejuvenating" effect that a low-calorie diet has on the mammalian brain.

If the healing effect produced on the brain by moderate fasting can be considered firmly established and partially deciphered (it is still unclear why and how nutrient deficiency stimulates CREB expression), then the prospects for drug correction of age-related brain changes still look vague. So, there are reasonable suspicions that artificial activation of sirtuins can stimulate neoplasms: for example, prostate cancer has been found that sirtuin is expressed faster in cancer cells than in normal tissues.

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