Synchronizing the body’s circadian clock can prevent aging | Health and wellness

Human life is governed by a circadian rhythm (about 24 hours), which is controlled by a tiny biological clock located in the brain. Based on light stimuli coming through the retina, this molecular device synchronizes and tells the rest of the body time to act accordingly. Night is not the same as day, neither for the eyes, nor for the liver, skin or pancreas. Peripheral clocks located in organs and tissues receive this rhythm from the central chronometer and are adjusted to trigger certain functions depending on the time. Like a sort of tuned orchestra, all the molecular instruments that control circadian rhythms communicate, interact and operate, in turn, with the autonomy necessary for the body to function. This is how the mechanisms of life work.

If those clocks that mark the rhythm of existence did not exist, aging would accelerate. This was seen in mice: in functional studies, when the animals were created without these molecular timers, they aged prematurely and died much earlier, as if a person died at 40 years old. In practice, mice had all their genes, the ability to express them correctly, and perform the functions they normally perform, but without this circadian clock, they did not know what time was best to perform these functions, and all the vital infrastructure eventually failed building. sooner or later it will collapse further.

These tiny timekeepers are key to survival, but how they work remains largely a mystery: the scientific community knows of their importance in the life process, but is still trying to unravel exactly how these communication networks are wired together. . and others. A couple of investigations published this Thursday in magazines The science And Cell Stem cell, led by the Spaniards Salvador Aznar-Benita, head of the aging and metabolism program at the Barcelona Institute of Biomedical Research (IRB), and Pura Muñoz-Cánoves, a researcher at the multinational Altos laboratory, took a step forward in understanding these interactions between molecular clocks and in experiments on arrhythmic mice have proven that a lack of coordination between the brain’s central chronometer and the one that regulates time in the muscles accelerates the aging of muscle tissue. However, restoring these communication networks allows the function of this area to be restored and its activity to remain active.

For the first time, they successfully tested in animal models a hypothesis that they had been developing for more than ten years: the idea was that to maintain circadian rhythms in each tissue, there is likely to be an autochthonous rhythm, independent of communication with the rest of the body, and then another process of interaction with clocks of other organs to synchronize functions. “It makes a lot of sense that if our circadian rhythm is preparing us for food, the tongue, intestines, pancreas and liver are synchronized to know that they have to start digesting the food. Imagine the fuss if the liver is cooked at two in the morning and the stomach at one in the afternoon,” Aznar-Benitah reflects.

In a study published in The scienceThe researchers developed an arrhythmic animal model—deficient in the central clock, the peripheral muscle clock, or both—to be able to analyze which circadian functions are carried out by tissues independently and which depend on connections to other clocks. “The deregulation of our clocks is one of the obvious things that happens to all of us as we age. During aging, we saw that the clock mechanism, the basic one, the one that tells the tissues that now is this time or that time, does not change; So if we wanted to find possible therapeutic ways to keep the clock young in an old body, we needed to understand what was happening to the clock. And what this tells us is that most of what happens to the clock is not because the mechanisms are not working well, but because the synchronization with other tissues, both peripheral and central, is changing. And we needed to understand in what part of the functions the tissue does not need communication, and in what part of the functions it does need it and with whom,” explains the scientist.

The experiment showed that in some everyday functions of muscle tissue there is no need to synchronize with anyone. “If you have an animal that doesn’t have a clock except for muscle cells, that muscle is able to temporarily support 10% to 15% of its function,” explains Aznar-Benitah. And this creates a sense of strict survival, the scientist reflects: “What is basic remains. And we think there is an evolutionary advantage to this, because if all the functions of all tissues were connected to one connection, if a person had an infection in the liver, there would be a domino effect: the liver would fail and everything else would fail. The fact that these functions are separate from the need to communicate and synchronize with others means that even if a person has heart problems, the skin retains its ability to create a barrier,” he gives an example.

The study also found that another 30–35% of muscle function is dependent on the central clock. “Between 15% independent functions and 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 determined who the muscle must interact with in order for that function to occur when it needs to occur,” admits the researcher.

Calorie restriction to strengthen communication

Either way, the study confirms that coordination between tissue molecular clocks is “crucial” for maintaining overall body health. In fact, experiments to restore communication between these body timers have improved the condition of muscle tissue. One mechanism studied was to subject mice to temporary calorie restriction—they only ate during the active dark phase (night feeding)—and they found that this practice “can partially replace the central clock and improve muscle clock autonomy.” Restoring circadian rhythms through calorie restriction reduced muscle loss, metabolic dysfunction, and decline in muscle strength in aged mice. “This diet enhances the connection” between the brain and muscle clocks in mice, Aznar-Benitah says, although he notes that these results cannot yet be extrapolated to humans, nor can the effects of practices such as calorie restriction.

The researcher notes that both this study and the study published in cell stem cell, which focuses on studying the connection between the brain clock and the skin clock is another step towards understanding how these precise molecular devices work. But they have no practical application yet. In fact, he predicts, we will have to analyze tissue by tissue to see what the autonomous role of each watch is and how its coordination with other timekeepers is affected. “I don’t believe that communication between the brain and peripheral tissues will always slow down aging. There will be tissues that are functionally dependent to a much greater extent on this connection, while others will be more dependent on other peripheral tissues. But we have to check it one by one. What we do know is that in the tissues and organs that we have been studying for a long time, such as the liver, muscle, skin, there is a clear benefit from restoring communication between peripheral tissue and the central clock,” he explains.

In skin, for example, time plays a key role: the internal clock of this tissue knows that the best time to stimulate cell division of stem cells and skin regeneration is when it is not in contact with ultraviolet light: these rays are mutagenic and DNA division occurs at that time When cells are exposed to ultraviolet light, there will be an accumulation of many mutations and errors with the potential dangers that this entails. “In addition, as these cells divide, the mutations (they acquire due to exposure to ultraviolet rays) will spread to the daughter cells, which will inherit the mutation. The circadian rhythm separates these processes: it tells skin cells not to divide while there is a peak in ultraviolet radiation,” says Aznar-Benitah. His research, published in Cell Stem cell, who analyzed this separation between DNA division and exposure to ultraviolet light, found that if these communication networks between the central clock and the molecular timer in the epidermis are disrupted, cell division occurs simultaneously with exposure to ultraviolet light. “It is only when you have the right communication that it is shared.”

“Federation” of watches, not a “dictatorship”

Juan Antonio Madrid, professor of physiology and director of the Laboratory of Chronobiology and Sleep at the University of Murcia, calls the study “beautiful and elegant because it describes many interactions and answers many questions” through “very interesting genetic engineering work,” he said. says: “It is true that this is observed in mice, but it is interesting because it shows us that the body’s circadian system is not a hierarchical dictatorship-like system where the brain clock rules. “They are more like a watch federation where everyone contributes.” Madrid’s intuition has also long been moving towards the idea of ​​a more federal organization, rather than a kind of clock “slave” 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 ignores,” he explains.

It will take time to translate into real life, but all this knowledge will be put to use, Madrid assures: “Arrhythmic animals from whom we take away their clocks age very quickly and die prematurely. And they saw that if they just activated the brain clock, they would not restore their health; If they only reactivate the muscle clock, they are also not in an optimal situation; But when they reset the muscle clock and restrict calories, even if the brain clock isn’t working, the mice regain metabolic health. With age, the clock weakens its signal. But if lifestyle habits such as nutrition, eating regularly and fasting for about 12 hours at night help maintain health. This can compensate for lost hours. And these signals or synchronizers are good in all tissues.”

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