Sleep and Aging I

The "clock in the brain" and the influence of genes on the rhythm of life

Svetlana Yastrebova, Biomolecule

A new week, a new day, a new year. The time of life is divided into fragments of different duration, and all these fragments are repeated. Every few hours we are hungry. We go to bed every night. Every four weeks, a woman's body produces an egg. Most of the processes that occur with our body are cyclical, and some cycles are tied to others. And although the aging of the body cannot be called a periodic process (after all, no one is getting younger!), its course directly depends on the biorhythms of a person, in particular, on the cycle of sleep and wakefulness. The evidence for this is at the level of behavior, and at the level of individual organs, cells and genes.

The pineal gland produces the "sleep hormone" melatonin at night, and sunlight slows down its formation. Melatonin is the main regulator of circadian rhythms that control a person's daily routine. Drawing by Sophie Jacopin.

The clock in the brain

The most noticeable and one of the most important biorhythms in human life is circadian, also known as circadian (from the words circa – about, approximately and dias – day). A simpler name for circadian rhythms is sleep and wakefulness rhythms*. It's because of them that we can't work for days (and I would like to!)**. Of course, circadian rhythms have a reverse, bright side: there is a suspicion that a regular change of sleep and wakefulness helps organisms not to age for some time * **.

* – As practice shows, the mechanisms of changing sleep and wakefulness can be explained even to children – ""Wake up!" – "Go to sleep..." – "Wake up!" – "Go to sleep..." – "Wake up!“» [1].

** – A similarity of the "sleep gene" was found in drosophila, which is described in the article "Sleepless nights of drosophila" [2]. Theoretically, this may lead to the fact that the need for sleep can be controlled, but it is unlikely that we will ever see it.

*** – There is an assumption that initially (many millions of years ago) circadian rhythms helped organisms not to die from oxygen, which at that moment in the atmosphere became abnormally much for the then inhabitants of the planet – "The prototype of the biological clock" [3].

At least, it is known for certain that the brain structures that ensure the operation of the "internal clock" in humans and mice show clear signs of degeneration with age. These structures include the suprachiasmatic nucleus (SCN) of the hypothalamus and the blue spot (locus coeruleus, LC) – the region of the brain stem. The suprachiasmatic nucleus is the main regulator that controls the work of other parts of the brain and internal organs (Fig. 1). It spreads its influence to the blue spot, and then, in turn, sends signals to the cerebral cortex, which, as we know, directs directed attention. Human productivity also depends on the efficiency of the cortex.

Figure 1. The effect of the suprachiasmatic nucleus of the hypothalamus on the work of various cells of the body. The functioning of cells of all types of tissues obeys the central rhythm, which is set by the suprachiasmatic nucleus of the hypothalamus. It "monitors" that signals from the nervous and endocrine systems come to the cells at the same time – in fact, synchronizes them. By the way, the same can be done outside the body: by growing several samples of various human tissues in cultures, these cultures can be synchronized if the SCN signals are imitated. This synchronization of the activity of cultures of different cell types of the same person is shown in the graphs. Drawing from the journal website.frontiersin.org.

In the course of studies of postmortem brain slices of healthy elderly people, it turned out that SCN neurons degenerate with age. The LC structure is also changing. In addition, the activity of the frontal lobes of the cortex decreases significantly with age (and the degree of decrease in this activity directly affects intelligence), as shown in fMRI studies [4]. All this leads to the fact that over time, acute peaks of activity during wakefulness disappear in people. That is, the elderly, of course, are awake, but their attentiveness and speed of thinking are not as good as before. Probably, the reason for this is the gradual deterioration of the brain's sleep and wakefulness regulators.

In the elderly, compared with the young, sleep efficiency is reduced. This may be associated with senile drowsiness, which occurs even when a person has definitely had enough sleep. Apparently, the age-related decline in sleep quality is not caused by any specific pathologies, it's just part of the usual aging process. However, whether aging itself is so inevitable is a question.

In addition, old people suffer worse from having to skip sleep. This was shown by experiments in which 12 men aged 21-31 years and 11 men aged 61-70 years did not sleep for 40 hours (Fig. 2). In the elderly, the subjective feeling of drowsiness was stronger than in the young, and attention fell more noticeably due to lack of sleep [5].

Another experiment with the same duration was conducted in 2005 [6]. Its results are also shown in Figure 2 (gray-shaded areas). In it, two groups of male participants (again elderly and young) had to sleep for 75 minutes for 40 hours, then stay awake for 150 minutes, besides doing it according to a schedule. Such an artificial regime was supposed to reveal how much sleep is more effective in people of one age group than in subjects from another group. It is not difficult to guess that the young during the experiment and after it felt better than the elderly, because they slept better.

Figure 2. Subjective perception of sleep and wakefulness quality in young and elderly men during a 40-hour sleep deprivation experiment [5], as well as sleep efficiency during an experiment with multiple sleep episodes [6]. The elderly begin to feel drowsiness earlier, and subjectively it manifests itself more strongly (dark gray line). Young people are more resistant to sleep deprivation (light gray line). In addition, subjectively, the sleep of the young (light gray shaded areas) is more effective than the sleep of the elderly (dark gray shaded areas). Figure from [4], adapted.

"Genes of circadian rhythms" and aging

The work of any organ is, ultimately, the work of its genes. Our "internal clock" is no exception. The suprachiasmatic nucleus expresses a number of genes that are inactive in other parts of the brain and body in general. Among such genes are BMAL1 (aka MOP3 and ARNT3), CLOCK and NPAS2 [7, 8]. These genes were identified in studies with the help of knockout mice – such that one or more genes were disrupted by genetic engineering methods.

As a rule, the life expectancy of rodents with one or more "periodicity genes" turned off is reduced. In particular, mice with non-functioning BMAL1 live less than their counterparts. At the end of their life, they show all the characteristic signs of aging: their organs decrease in size, muscle mass and subcutaneous fat are lost, senile cataracts develop, the content of reactive oxygen species in tissues increases [9]. With a constant shortage of BMAL1 and CLOCK proteins, memory deteriorates, intelligence decreases: animals learn worse and forget new information faster [10].

BMAL1 and CLOCK act differently: if you "turn off" the CLOCK gene without affecting BMAL1, the life of mice undergoes less global changes. The average life span of rodents without CLOCK is 15% shorter than that of wild-type animals, and premature aging is manifested in them only in changes in the structure of the skin and the development of cataracts [11].

The changes described above occur at the level of individual organs. But after all, organs are made up of cells, and the real action always unfolds there in the first place. Therefore, it makes sense to look at what the "genes of circadian rhythms" do at the cellular level*. Most of their effects can be classified into one of several categories (Fig. 3).

* – Here is one example of the connection of circadian rhythms with metabolism in general: "A connection between metabolism and circadian rhythm has been found" [12]

Figure 3. Examples of aging manifestations at the cellular level. A detailed explanation of these manifestations is given below in the text in the form of a numbered list.

1. Changes in the cell cycle. The cell cycle is an alternation of the stages of cell growth and division. Different types of cells divide at different frequencies, and this frequency is not random. The routine of cell life is subject to circadian rhythms. If the latter for some reason (for example, due to an irregular working day or as a result of aging) get lost, the probability of untimely cell division increases, and with it the probability of tumor formation increases [13]. Biochemical processes that control the change of stages of the cell cycle depend on enzymatic reactions that ensure the manifestation of circadian rhythms. Therefore, if the latter are violated, the former will also suffer. For example, a cell may begin to divide, although it should no longer do so. But uncontrolled division is a sign of a cancer cell.
   

2. Genome instability. The unstable composition of DNA in the cell does not bode well. Genome instability means an increased number of mutations and an increased probability of malignant cell degeneration. Of course, there are a number of mechanisms that resist genomic instability. This is, for example, the action of the SIRT6 protein [9] (by type of activity it is a NAD-dependent deacetylase). He directs, among other things, the work of the BMAL1 and CLOCK proteins [10]. In turn, changes in their activity have a direct effect on SIRT6, and hence on the stability of the genome. Mice with a lack of SIRT6 die very quickly – at the age of four weeks. They look unimportant at the same time: they lose muscle mass, their backs are hunched, the number of lymphocytes in the blood decreases, and along with this, immunity worsens. Once again we see signs characteristic of old animals.

3. Decreased telomerase activity. Telomerases are enzymes that prevent telomeres from shortening – meaningless DNA fragments located at the ends of chromosomes and protecting "meaningful" genes closer to the center of these chromosomes from disappearing. Before it's time for a cell to share, its chromosomes must double. But due to the peculiarities of the mechanism of such doubling, the chromosomes are shortened a little at the ends each time. For the time being, their genes protect telomeres from damage. After about 50 divisions, telomeres shrink so much that they actually disappear. After that, gene damage begins, and with it cell mutations and their aging. The activity of telomerase complexes and their components, in particular a protein called TERT, depends on circadian rhythms. The expression of mRNA of the telomerase complex is directly regulated by the CLOCK and BMAL proteins (they combine into a single molecule called a heterodimer) [14]. Apparently, this is why mice with CLOCK protein deficiency have shorter telomeres and, as a result, a shorter lifespan: their telomerases work worse.

4. Epigenetic modifications of various genes. It is important not only the composition of genes, but also where, when and how intensively the proteins encoded by them are formed. To make a gene more or less accessible for transcription (reading information, that is, translating it into the form of RNA), you need to either methylate it or deacetylate histones around it. As a rule, methylation suppresses gene expression (i.e. fewer proteins encoded by this gene are eventually produced), and deacetylation of histones, on the contrary, enhances (DNA is wound around histones, and when the density of this "winding" weakens, it becomes easier to read the sequence of nucleotides). Histone deacetylase SIRT1 enhances the expression of BMAL1 and CLOCK genes. And they, as we remember, are involved in the regulation of circadian rhythms. Their activity decreases with age. Perhaps this gives feedback to SIRT1, as a result of which its expression also changes. Bottom line: with age, the availability of many genes changes, and this cannot but affect the functions of the body [15].

5. Loss of proteostasis. The constancy of the internal environment of the organism (homeostasis) is one of the signs that this organism is still alive. The internal environment includes proteins too. Each protein must be present in a certain concentration, and its molecules must be "folded" in a certain way. The ideal state of proteins in the body is called proteostasis. With age, the ability of cells to neutralize foreign substances and metabolic products and neutralize the consequences of improper protein stacking decreases. Part of the detoxification processes that take place in liver cells is regulated by circadian transcription factors (RNA synthesis controllers) PAR-bZip [16]. That is, with age, when circadian rhythms are disrupted, the ability to proteostasis also decreases, because it is controlled by circadian transcription factors.

6. Recognition of nutrients. The metabolic pathway TOR (target of rapamycin) helps to understand whether there is something suitable for food in the cell environment. The biochemical reactions in this pathway are too intense in diabetes and other metabolic disorders, as well as ... yes, you guessed it: in mice deprived of the BMAL1 gene. Their life expectancy is reduced, but it can be increased by 50% by introducing a TOR– rapamycin pathway inhibitor [17].

7. The work of mitochondria. Oxidation and reduction reactions are constantly taking place in mitochondria, and they serve as the main source of energy for most cells. One of the main roles in these processes is played by the NAD+ metabolic pathway. His work directly depends on circadian rhythms. In particular, in mice lacking the BMAL1 gene, the energy metabolism in mitochondria is disrupted [18].

8. Depletion of the stem cell pool. Circadian rhythms maintain a balance of self-renewal of many stem cells. They also regulate whether stem cells differentiate into other cell types. This balance is very important. If stem cells give rise to their own kind too rarely, the body slowly recovers from damage. If stem cells divide very often, their abilities may be prematurely exhausted. The tissues of various organs will cease to be effectively renewed, and then aging will manifest itself. Interestingly, the work of different genes affects the division of stem cells differently. In mice lacking the BMAL1 gene, the number of resting stem cells is increased (plus the aging of the epidermis begins early), and in mice lacking the Period1/Period2 genes, on the contrary: the number of non-dividing stem cells is reduced [19].

9. Intercellular communication. Admittedly, little else is known in this area. However, it is already clear from experiments with very old mice that the synchronization of the neurons of the suprachiasmatic nucleus is disrupted with age. The violation occurs at the level of nerve contacts [20]. Cells cannot work in concert because they lose the ability to transmit or receive signals from their neighbors (or maybe both). Since we are talking about the "sleep center", it is clear why sleep worsens in old age: SCN neurons simply can no longer agree with each other.

10. Salt metabolism and blood pressure. Mice lacking the Cry2 gene (cryptochrome-2) have abnormally high blood pressure. It is especially strongly dependent on the salt content in the body, because such rodents produce huge amounts of aldosterone, a hormone that causes water retention and sodium ions in body fluids [21]. This would not matter for the narrative of sleep if it were not for the fact that Cry2 is a gene that affects circadian rhythms [22].

Studies are usually conducted on large groups of animals, and data on these animals are averaged. But we remember that every organism has its own unique genome, and a lot depends on how the genes in its composition interact with each other. In two mice, the operation of the same CLOCK may be disrupted, but at the level of individual organs and the organism as a whole, this violation will manifest itself in completely different ways. Yes, even if the gene variants are all right, two organisms will not age the same way. The fact is that the genotype of a particular organism also plays a role in the strength and nature of changes in sleep with age. This was confirmed by studies on mice [23, 24], in which the sleep quality of rodents was assessed by electroencephalograms, and also looked at how eyesight worsens with age in these rodents.

Laboratory mice come in several lines (this concept is quite close in meaning to the term "breed"), moreover, each line has its own designation of numbers and letters *. Rodents of the same line were born as a result of crosses of close relatives. They are similar to each other both externally and internally – both in genotype and phenotype. Mice of the C57BL/6, DBA/2J, AKR/J and some others lines are most often used.

* – For rats, this is also true: "A rodent of special purpose" [25].

Rodents of the C57BL/6 line develop cataracts more often than others with age, which means that vision almost disappears. Apparently, therefore, in old age (at the age of about a year) these crepuscular animals are more and more active in the daytime and less and less active in the dark. In addition, the elderly C57BL/6 stay awake the longest, and AKR/J sleep the longest. DBA/2J mice spend the most time in the REM sleep stage, and AKR/J mice spend the least. If one-year-old mice of these three lines are prevented from sleeping for a while, and then given the opportunity to sleep, then the C57BL/6 rodents return to their normal routine the fastest.

Sleep and metabolism

We have found out how the disruption of the "genes of circadian rhythms" affects the state of individual cells. And how does sleep disorders, so frequent in old age, affect them?

Although sleep is considered a time of rest, during sleep, the purification of neurons from "waste" metabolic products occurs faster than when awake [26]. By the way, not only the nervous system is cleansed at night. During sleep, the expression of a number of genes also increases or decreases. In lung tissues, the expression of 3% of genes differs during sleep and during wakefulness. There are 6% of such "sleep-dependent" genes in the heart tissues. During sleep, the content of markers of cellular stress in the tissues of the lungs, heart and brain is reduced [27].

Perhaps one of the functions of sleep is to rid the body of waste metabolites and the overall recovery of cells after stress. If this assumption turns out to be correct, it will be able to explain some facts. For example, it is known that regardless of nationality, 46-57-year-old women who have frequent complaints about sleep quality have a particularly high risk of metabolic syndrome [28]. However, the latter may be due to the fact that these women eat during the extra waking hours [29]. This means that they consume more calories per day than women without sleep problems. This hypothesis is supported by the fact that experimental sleep disturbance did not cause metabolic syndrome in rats [30].

According to epidemiological studies, deprivation (time limitation) sleep increases the likelihood of dyslipidemia, type 2 diabetes and glucose intolerance (Table 1).

Table 1. The effect of sleep problems (too short, too long and intermittently) on metabolism. Summary table for a variety of studies in which hundreds and thousands of subjects of different ages, gender and hormonal status participated at different times. Almost all of these studies have revealed that both lack of sleep and too long sleep increase the risk of developing metabolic syndrome or even diabetes. Table from [31].

In addition to metabolic disorders, replication errors and an increased percentage of dying cells compared to the norm [30], sleep deprivation can lead to negative consequences for the immune system. In patients with constant lack of sleep during the day, the content of markers of inflammation – tumor necrosis factor (TNF), interleukins 1 and 6, as well as cortisol increases in the blood [31, 47]. But inflammation goes hand in hand with an increased risk of many diseases, ranging from stroke to Alzheimer's disease. For example, with the latter, microglial cells (these are macrophages in the brain) secrete noticeable amounts of interleukins 12 and 23 – one of the most important signals of inflammation. Normally, of course, this does not happen, because there is no Alzheimer's disease or inflammation. Apparently, the command of microglia to produce inflammatory factors is given by beta-amyloid itself. Further, in Alzheimer's disease, astrocytes (a type of glial cells that nourish and support neurons, direct their growth in embryos) they become susceptible to IL-12 and IL-23 (again, this is not normally observed.) Beta-amyloid deposits are increasing in size, astroglial cells are becoming more and more, and neurons next to them are getting smaller [48]. If you reduce the production of IL-12 and IL-23 in glial cells, the pathology will slow down its development.

The interrelationships of inflammation, the release of interleukins and the work of astrocytes in Alzheimer's disease have yet to be understood, but it is already clear that such relationships exist. In fact, many such correlations have already been identified. And there will be a separate article about the connection between sleep disorders and various diseases (nervous, and not only) (What is the difference between the sleep of the elderly and sick from the sleep of the young and healthy).

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