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Inhibition of neurons in the brain prolonged the life of worms and mice

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American biologists have extended the life of nematodes and mice by suppressing the activity of neurons in the brain. Excitation of neurons, on the contrary, brought death closer even in long-living mutants. Apparently, this mechanism also works for people – at least for long-livers, unlike younger people, the work of genes that are associated with the transmission of an exciting signal is suppressed in neurons. The REST protein, which is now called one of the targets for prolonging life, is responsible for this suppression.

Calorie restriction is the most reliable way to extend the life of almost any animal. At the same time, the body secretes less insulin or its analogues, and the main metabolism stimulator, the TOR protein, stops functioning in the cells. As a result, the cells switch to a more economical mode: they produce less protein, store less food for future use and spend fewer resources “for nothing”, which in total allows them to wear out more slowly, and the body as a whole – to live longer.

It is also known that the activity of the nervous system can be associated with life expectancy. For example, nematodes lacking their sense of smell live longer than healthy individuals – probably because in the absence of a smell of food they produce less insulin. Insensitivity to pain also prolongs life – perhaps this explains the phenomenon of longevity of a naked mole-rat.

Joseph Zullo (Joseph Zullo) and Derek Drake (Derek Drake) with colleagues from Harvard University tried to establish a connection between metabolic changes, nervous system activity and life expectancy. They pushed off three databases – ROSMAP, CommonMind Consortium (CMC) and Gibbs – which collected the results of RNA sequencing in brain cells in people of different ages. By comparing the number of different RNAs (that is, in fact, the activity of the corresponding genes) in long-livers (older than 85 years) and older people (up to 80 years), the researchers found that the former suppressed the work of genes associated with neuronal excitation. The genes that are responsible for the processes of inhibition of neurons, worked for both centenarians and elderly people in approximately the same way.

Scientists have suggested that muffled neuronal activity may be associated with longevity and tested this hypothesis on  C. elegans nematodes. In the worms, the calcium channel was blocked to reduce the excitability of the cells, and the animals lived 25 per cent longer than the control group. The effect manifested itself even when it began to block excitability in elderly animals. This means that the effect cannot be explained by calorie restriction – adult nematodes already eat little.

The researchers then drew a line of transgenic nematodes, the neurons of which carried a chlorine channel. He reacted to the addition of histamine and suppressed the functioning of the nerve cells on which it was located. Scientists initially slowed down the work of the nervous system as a whole and recorded the extension of the life of the worms. And then they launched the channel selectively in glutaminergic and cholinergic neurons, which are responsible for the transmission of excitation. The effect turned out to be the same – therefore, it is the exciting neurons that shorten the life of the worms with their excessive activity.

In a previous study, this research team showed that REST gene expression is growing in an ageing human brain. It works as a repressor, that is, suppresses the work of genes. Now researchers have confirmed that in the same set of genes, which are more often suppressed in long-livers than in older people, sequences for binding to REST are often found. They suggested that it was he who was responsible for suppressing the excitement in the brain of long livers.

Scientists have developed a line of transgenic mice in which the REST gene could be turned off. They injected fluorodeoxyglucose into the animal organism, which glows upon cleavage, and measured the luminosity in the brain. It turned out that in older mice with REST off, the brain absorbed more glucose, that is, it worked more actively.

Nematodes also have a REST ortholog  – the spr-4 gene. Researchers enhanced its expression artificially and found that in this case, the excitation in the neurons of the worms decreases, and the life expectancy increases. Since REST in mice was associated with energy absorption, scientists began experimenting with the activity of the insulin pathway. It turned out that if you activate the insulin signalling in worms with increased expression of spr-4, then this negates the whole effect of prolonging life. And vice versa: if you suppress the work of spr-4, then turning off the insulin alarm does not prolong life.

Researchers have concluded that neuronal excitation and metabolism are inextricably linked: intense glucose uptake leads to nerve cell hyperactivity. And, apparently, this partially explains the effect of calorie restriction on life expectancy.

According to STAT, the publication process took scientists about two years – it took so long to provide additional data and to convince reviewers that the experiments were honest. Researchers and gerontologists themselves, who are not associated with this group, call the results amazing and counter-intuitive – because in people it is brain activity that is considered a sign of “healthy old age” and longevity. Nevertheless, at the cellular level, the prerequisites for this discovery have been known for a long time – both the fact that economical metabolism contributes to a long life, and that some types of nerve signalling are suppressed in long-lived mutants.

Researchers note that there is no talk of specific applications of their results in humans yet. However, it is not excluded that the REST protein in the human brain can become a promising target for anti-ageing therapy.

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