26 June 2013

The relationship between circadian rhythms and aging

The SIRT1 gene regulates the circadian clock in a young body better than in an old one

NanoNewsNet based on MIT materials: The link between circadian rhythms and agingThe structure of a person's sleep and wakefulness is largely determined by the internal circadian clock, in most cases obeying the 24-hour cycle of day and night.

The circadian clock controls many functions of the body, in particular, metabolism, and participates in the regulation of body temperature.

Studies conducted on night shift workers have revealed an increased predisposition to diabetes, and animal experiments have shown that circadian rhythm disorders are associated with the development of diabetes and obesity.

A new study conducted at the Massachusetts Institute of Technology (MIT) has shown that the SIRT1 gene, which is known to delay the development of age-related diseases, plays a key role in the management of circadian rhythms. Scientists have found that in normal mice, there is an age-related extinction of the circadian function of this gene, but an increase in the levels of the sirtuin–1 protein – a product of SIRT1 expression - in the brain can prevent this extinction. Conversely, the loss of SIRT1 function disrupts circadian regulation in young mice, mimicking what happens with normal aging.

The data obtained at MIT suggest that drugs that increase the activity of SIRT1 in humans can have a significant positive effect on health, says MIT biology professor Leonard Guarente, senior author of an article about this study published in the journal Cell (Hung-Chun Chang, Leonard Guarente. SIRT1 Mediates Central Circadian Control in the SCN by a Mechanism that Decays with Aging).

In his opinion, "if during the aging process we could maintain the activity of SIRT1 as high as possible, we could slow down aging at the level of the central clock of the brain, and the health benefits would be determined by their influence."

In humans and animals, circadian rhythms follow an approximately 24-hour cycle controlled by a circadian rhythm control center called the suprachiasmatic nucleus located in the hypothalamus.

"Almost everything that happens at the physiological level is organized according to the circadian cycle," explains Professor Guarente. "Therefore, recently the idea has been developing that maintaining the correct circadian cycle is very important for health. If it is violated, you have to pay for the loss of health and, possibly, accelerated aging."

The sirtuin 1 protein is the main regulator of the cellular response to stress, coordinating the work of a number of hormonal networks, proteins and genes. Ultimately, its function is to preserve the cell's health and life. Last year, Professor Guarente – he was the first to link SIRT1 with aging more than 15 years ago – received data that maintaining the correct circadian cycle correlates with a longer life expectancy in mice. The scientist was interested in what role SIRT1 plays in this phenomenon, which, as is known, increases the life expectancy of many biological species.

To investigate the role of SIRT1 in controlling circadian rhythms, Guarente and his colleagues created genetically modified mice in whose brains different amounts of sirtuin 1 protein were synthesized. In one group of mice, normal levels of sirtuin-1 were preserved, in the other, sirtuin–1 was not synthesized at all; in two more groups, protein expression was increased – two and ten times compared to the norm.

In mice with reduced levels of sirtuin-1, the circadian cycle was slightly longer (23.9 hours) than in normal mice (23.6 hours), and in mice with 10 times increased protein levels, it was slightly shorter (23.1 hours).

In mice with normal levels of sirtuin-1, the results of previous studies were confirmed: when the 12-hour cycle of light and dark change was violated, young animals adjusted their circadian rhythms much faster than older ones. However, experiments have shown for the first time that the aging process is not accompanied by the extinction of the circadian rhythm control function if the levels of sirtuin-1 in the brain of animals are elevated.

In addition, the researchers found that SIRT1 exercises this control by regulating the activity of the genes BMAL1 and CLOCK – the two main "guardians" of the central circadian clock.

Diagram from the article in Cell – VMAccording to Professor Guarente, more and more evidence is accumulating that the ability to adequately respond to serious or minor violations of the light/dark cycle is important for maintaining a healthy metabolism.

"Essentially, we experience mini-jet lag every day because the light cycle is constantly changing. The most important thing for us is the ability to adapt smoothly to these shocks," Guarente believes. "Many studies on mice show that while young mice do it perfectly, older animals have problems. The same thing may well happen to a person."

If this is the case, then it is possible to treat or prevent age–related diseases by strengthening the circadian function of SIRT1 - either by delivering its activators to the brain, or by using drugs that enhance some other component of control over circadian rhythms, the scientist believes.

"I think we need to study every aspect of the brain's circadian clock machinery, and any interventions that can support these mechanisms in the aging process should benefit," he says. "One entry point may be SIRT1, because we have shown that in mice, the genetic preservation of its activity helps maintain its circadian function."

Several SIRT1 activators are currently being tested as drugs against diabetes, inflammation and other diseases, but they are not designed to overcome the blood-brain barrier and most likely will not be able to reach the central nervous system. However, it is possible to develop such SIRT1 activators that can penetrate into the brain, Guarente believes.

Roman Kondratov, associate professor of biology at Cleveland State University, believes that Professor Guarente's latest study raises several interesting questions related to the possibility of delaying or reversing age-related changes in the brain by "rejuvenating" the main circadian clock with SIRT1 activators.

"The importance of this study is that it has both purely scientific and applied significance, taking into account the fact that pharmacological modulators of SIRT1 are now being actively studied," says the researcher.

Currently, Professor Guarente's laboratory is studying the relationship between health, circadian function of SIRT1 and diet. Scientists suggest that a high-fat diet breaks the circadian clock, but this breakdown can be countered by an increase in gene activity.

Portal "Eternal youth" http://vechnayamolodost.ru26.06.2013

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