Human life is governed by a circadian rhythm (around 24 hours) that is controlled by a tiny biological clock located in the brain. Based on the light stimuli that enter through the retina, this molecular device synchronizes and tells the time to the rest of the organism so that it acts accordingly. Night is not the same as day, neither for the eyes, nor for the liver, skin or pancreas. The peripheral clocks, located in organs and tissues, receive this beat from the central chronometer and are regulated to start one or other functions, depending on the time. Like a kind of orchestra in tune, all those molecular instruments that manage circadian rhythms communicate, interact and work, in turn, with autonomy necessary to make the body function. This is how the gears of life work.
If those clocks that mark the rhythm of existence did not exist, aging would accelerate. It was seen in mice: in functional studies, when animals were generated without these molecular timers, they aged prematurely and died much earlier, as if a human died at 40 years of age. In practice, the mice had all their genes, the ability to express them correctly and perform the functions they usually perform, but without those circadian clocks, they did not know what was the best time to perform those functions and the entire vital infrastructure ended up collapsing further. sooner rather than later.
These tiny chronometers are key to survival, but their modus operandi remains, to a large extent, a mystery: the scientific community knows of their importance in the vital process, but is still trying to unravel how exactly these communication networks are configured between one another. and others. A couple of investigations published this Thursday in magazines Science and Cell Stem Cell, and led by the Spaniards Salvador Aznar-Benitah, head of the Aging and Metabolism Program at the Barcelona Biomedical Research Institute (IRB), and Pura Muñoz-Cánoves, researcher at the multinational Altos Lab, have taken a step forward in the knowledge of These interactions between molecular clocks and, in experiments with arrhythmic mice, have proven that a lack of coordination between the central chronometer of the brain and the one that regulates time in the muscle accelerates the aging of muscle tissue. Reestablishing these communication networks, however, allows the function of this area to be recovered and its activity to be preserved.
It is the first time that they have successfully tested in animal models a hypothesis that they have been developing for more than a decade: the idea was that, to maintain circadian rhythms, there are probably a native rhythm in each tissue, independent of communication with the rest of the organism, and then there is another process of interaction with the clocks of other organs to synchronize functions. “It makes a lot of sense that if our circadian rhythm prepares us for food, the tongue, intestine, pancreas and liver are all synchronized to know that they are going to have to start metabolizing food. Imagine the fuss if the liver is prepared at two in the morning and the stomach at one in the afternoon,” Aznar-Benitah reflects.
In the study published in Science, the researchers designed an arrhythmic animal model—with deficiencies in the central clock, the peripheral muscle clock, or both—to be able to dissect which circadian functions were performed independently by the tissue and which depended on communication with other clocks. “The deregulation of our clock is one of the clear characteristics that happens to all of us as we age. What we saw during aging is that the clock machinery, the basic one, the one that tells the tissue that it is this time or that time, that does not change; Therefore, if we wanted to find possible therapeutic ways to keep the clock in a young state in the old organism, we had to understand what happens to the clock. And what it is telling us is that a large part of what happens to the clock is not that the machinery does not work well, but that the synchronization with other tissues, both peripheral and central, are what are modified. And we had to understand in which part of the functions the tissue does not need communication and in which part of the functions it does need it and with whom,” explains the scientist.
The experiment showed that in some daily functions, muscle tissue does not need to synchronize with anyone. “If you have an animal that does not have the clock except in the muscle cells, that muscle is capable of maintaining between 10% and 15% of its functions temporarily,” explains Aznar-Benitah. And that has a sense of strict survival, the scientist reflects: “What is basic, remains. And we think that there is an evolutionary advantage in that, because if all the functions of all the tissues were linked to one communication, if a person has an infection in the liver, a domino effect would be generated: the liver fails and everything else would fail. The fact that these functions have been separated from the need to communicate and synchronize with others means that, even if a person has a heart problem, the skin maintains its ability to have a barrier,” he exemplifies.
The research also revealed that there are another 30% or 35% of muscle tissue functions that depend on the central clock. “Between the 15% independent functions and the 35% that depend on brain interaction, we have already mapped half of the tissue functions. There are another 50% of functions that we know are circadian, but we have not yet identified with whom the muscle has to communicate for this function to occur when it has to occur,” admits the researcher.
Calorie restriction to strengthen communications
The study confirms, in any case, that the coordination between the molecular clocks of the tissues is “crucial” to maintain the general health of the organism. In fact, experiments to reestablish communications between these body timers improved the condition of muscle tissue. One mechanism studied was to subject mice to temporary caloric restriction—they only ate during the active dark phase (night feeding)—and they discovered that this practice “could partially replace the central clock and improve the autonomy of the muscle clock.” Circadian restoration through caloric restriction mitigated muscle loss, impaired metabolic functions, and decreased muscle strength in old mice. “Eating like this strengthens the communication” between the brain clock and the muscle clock in mice, says Aznar-Benitah, although he clarifies that these findings cannot yet be extrapolated to humans—nor can the impact of practices such as calorie restriction. —.
The researcher points out that both this study and the one published in Cell Stem Cell, which focuses on studying the communication between the brain clock and the skin clock, are one more step in understanding how these precise molecular devices work. But they still have no practical application. In fact, he predicts, we will have to analyze fabric by fabric to see what the autonomous role of each watch is and how its coordination with other chronometers influences. “I don’t believe that communication between the brain and peripheral tissue is always going to slow down aging. There will be tissues that functionally depend much more on this communication, whil
e others will depend much more on other peripheral tissues. But we have to test that one by one. What we do know is that in tissues and organs that we have been studying for a long time, such as liver, muscle, skin, there is a clear benefit of reestablishing communication between the peripheral tissue and the central clock,” he explains.
In the skin, for example, time is key: the internal clock of this tissue knows that the best time to promote cell division of stem cells and regenerate the skin is when it is not in contact with ultraviolet light: these rays They are mutagenic and dividing DNA at a time when cells are exposed to ultraviolet light would imply accumulating many mutations and errors, with the potential dangers that this entails. “Also, as these cells are dividing, the mutations [que adquieren por exposición a los rayos ultravioletas] they would be expanding to the daughter cells, which would inherit that mutation. What the circadian rhythm does is separate these processes: it tells the skin cells not to divide while there is a peak of ultraviolet light,” says Aznar-Benitah. Her study published in Cell Stem Cell, who analyzed this separation between DNA division and exposure to ultraviolet light, revealed that, if these communication networks between the central clock and the molecular timer in the epidermis are broken, cell division occurs at the same time as ultraviolet exposure. “Only when you have proper communication is it separated.”
A “federation” of watches, not a “dictatorship”
Juan Antonio Madrid, professor of Physiology and director of the Chronobiology and Sleep Laboratory at the University of Murcia, calls the research “beautiful and elegant because it describes many interactions and answers many questions” through “very interesting genetic engineering work.” “, he says: “It is true that it is in mice, but it is interesting because it reveals to us how the body’s circadian system is not a hierarchical system, like a dictatorship, where the brain’s clock rules. “They are more like a watch federation where everyone contributes.” Madrid’s intuition has also long been shifting towards that idea of a more federative organization and not so much a kind of clocks “slaves” to a central clock. “The muscle clock has the ability to decide which orders from the central clock it accepts and which it filters or does not take into account,” he explains.
The translation to real life will take time to see, but all this knowledge will have applications, assures Madrid: “Arrhythmic animals, from which we take away their clocks, age very quickly and die prematurely. And they have seen that if only the brain clock is reactivated, they do not recover their health; If they reactivate only the muscle clock, they are not in an optimal situation either; But when they reset the muscle clock and calorie restriction, even if the brain clock does not work, the mice regain metabolic health. As we age, clocks attenuate their signal. But if lifestyle habits, for example in nutrition, having regular eating habits and fasting for about 12 hours at night, favor the maintenance of health. That may compensate for the loss of the watches. And those signals or synchronizers are good in all tissues.”
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