08 September 2017

Circadian rhythms and aging of stem cells

Skin and muscle stem cells change biorhythms differently during aging

Polina Loseva, "Elements"


Fig. 1. Age-related changes in mouse skin and muscle stem cells. The rhythm of the processes remains, but the processes themselves undergo changes: with aging, it is necessary to respond to the accumulated stress. However, restrictions in the caloric content of food allow reprogramming cycles towards a younger state. Image from the discussed article in the journal Cell

Daily cycles affect not only the general activity of the mammalian body, but also the processes inside cells, including stem cells. It is also known that with age, the number and efficiency of these cells decreases. Scientists from Spain and the USA studied what happens to cyclic processes in stem cells of different mouse tissues during aging. It turned out that the life of stem cells continues to obey biorhythms, but the set of cyclic processes varies depending on the type of tissue and its needs. At the same time, scientists were able to minimize the effects of age-related biorhythm adjustment by putting mice on a low-calorie diet.

The activity of most living organisms directly depends on the time of day. The signal about the level of illumination enters the nervous system (or its analogues), which, in turn, secretes hormones acting on different body systems. The result is diurnal (or circadian) biorhythms – fluctuations in the work of organs, tissues and even individual cells. For example, in humans, the suprachiasmal nucleus of the hypothalamus is responsible for biorhythms, the neurons of which send a signal to the pineal gland and trigger the release of the hormone melatonin in the dark. And melatonin already regulates the work of individual organs. As a result, people's temperature and pressure decrease at night, as well as the activity of the intestine and cardiovascular system. Cyclic processes are also observed at the cell level – for example, in accordance with biorhythms, liver cells absorb substances, and hair follicle cells divide. The study under discussion – we note right away – was conducted on mice, which are characterized by a nocturnal lifestyle, so most cycles work exactly the opposite, and peak activity occurs at night.

Cyclic activity is important, apparently, only for an adult organism – mice mutated by biorhythm control genes are born healthy, and defects in the work of organs begin to manifest later. But with age, even in healthy organisms, some biorhythms are disrupted. For example, the production of melatonin by the epiphysis gradually decreases in humans, so sleep and wakefulness cycles are disrupted, and older people suffer from insomnia more often than young people. And then the question arises: does aging affect cyclic processes at the level of individual cells and can we somehow influence or even stop it?

Stem cells, capable of dividing throughout a person's life, represent resources for the renewal of body tissues. As in other cells, certain daily cycles are observed in them, that is, the expression of one set of genes is increased at night and some processes occur, and others occur during the day. The authors of the study examined two types of mouse stem cells – epidermal (EpSC) and muscle (MSCs) as examples of frequently and rarely dividing cell populations, respectively.

The physiology of stem cells in the body varies according to the needs of tissues. EPSCs are located in the skin, which means they must often divide and differentiate into skin cells. In mice, the division of EpSC is controlled by the daily biorhythm and occurs at night. This is due to the fact that the most valuable thing in a stem cell, that is, DNA, must be protected from errors and breakdowns, and their main cause is usually light. Under the influence of solar ultraviolet light, nitrogenous bases in DNA can form crosslinking with each other, disrupting the overall structure of the molecule. At the moment of doubling, the DNA of stem cells is most vulnerable: it unwinds, so it is easier to damage it, and the error is more likely to get into the daughter cells. But even if the error is noticed in time by DNA repair systems, then with a large number of errors, cell division will be stopped. At the same time, the process of programmed cell death – apoptosis - will start, and the cell will die. Therefore, DNA doubling in dividing stem cells should, if possible, occur at night. At the same time, cells need energy to divide, that is, a high level of glucose in the blood. This means that the division should occur during the period of activity of the organism (see M. P. Antoch, R. V. Kondratov, 2010. Circadian Proteins and Genotoxic Stress Response). This turned out to be convenient for mice with their nocturnal lifestyle, but completely inconvenient for a person who is active during the daytime. This is probably another reason for the prevalence of skin cancer in humans – the inevitable accumulation of errors in dividing cells under the influence of daylight.

The functioning of the MSC is arranged differently. Their function is to keep themselves at rest and be ready to start dividing if necessary. To do this, you need to regularly scan the DNA for errors and update the protein composition of the cell. In dividing cells, obsolete proteins are evenly distributed among the offspring and cause little harm. But in resting MSCs, their accumulation can lead to stress, in which many cell functions are disrupted at once. Therefore, autophagy – partial self–eating - plays an important role in adult cells, during which the cell digests its own proteins. In mice, this usually occurs during the day, during the dormant period (see L. Garcia-Prat et al., 2016. Autophagy maintains stemness by preventing senescence).

It is known that with age, the number and activity of stem cells decreases, that is, the body's resources are depleted to repair damage. However, the reasons for this are not fully known. By analogy with the disorder of sleep cycles with aging, it can be assumed that the daily cycles of stem cells should somehow change, impairing their work. However, until recently, no one has checked this. The authors of the study measured the expression of multiple genes in EPSCs and MSCs of adult and old mice during the day. Then, using statistical criteria, those genes whose expression showed stable peaks at a certain time of day were selected. Such genes will continue to be called "cyclic", unlike the rest, which were expressed uniformly or with one-time bursts. The presence of cyclic genes allows us to conclude that the cellular processes for which they are responsible are subordinated to diurnal biorhythms. That is, comparing a set of cyclically expressed genes in the stem cells of adult and aging mice, the authors draw conclusions about how these cells express certain functions.

The first thing the researchers noticed was that the daily cycles are preserved even in old stem cells, that is, they show cyclic gene expression. At the same time, the amplitude of the gene oscillations remained unchanged. As for the set of cyclic genes, a certain percentage of them (approximately the same in both types of cells) remained, but a significant part (more than 70%) changed: other genes became cyclic. This means that with aging, new cyclic processes are triggered in stem cells that require the work of other genes.


Fig. 2. The number of cyclic genes in EPSCs and MSCs. Image from the discussed article in Cell

A more thorough analysis of the composition of cyclic genes has shown that the key functions of stem cells are preserved during aging. In the case of EPSCs, for which the main thing is rapid regular division, the genes regulating the biorhythms themselves, as well as DNA synthesis and mitosis (cell division) remain cyclic. At the same time, the genes responsible for cell differentiation disappear from the cyclic list, but genes associated with the reaction to stress, the release of pro-inflammatory substances and DNA repair are added. The cause of stress is presumably the following: with age, DNA doubling takes longer in stem cells (possibly due to the number of accumulated errors), so it starts at night and continues throughout the day, and division occurs at the same time as in adult cells - at the end of the night. Due to the fact that DNA synthesis occurs during daylight hours, light damage appears, and this causes stress in the cell. Therefore, it is important to trigger the expression of repair and stress response genes and synchronize it with the cycles of genes that stimulate DNA doubling.


Fig. 3. Cycles of expression of genes controlling the circadian rhythm in EpSC. Black lines represent expression in the cells of adult mice, gray lines represent aging mice. The time is postponed along the horizontal axis: ZT0 – the beginning of daylight, ZT12 – the end of daylight. Image from the discussed article in Cell

The situation with the Moscow Time is somewhat different. Since regular division is not required from them, cyclic expression of mitosis genes was not detected in them. But both adult cells and old ones have cyclic genes associated with the cellular skeleton and contacts with intercellular matter. This is necessary in order for the cells to stay in their niche and respond to environmental changes. At the same time, adult MSCs are ready for division at any moment, so they were expected to have cyclic DNA repair genes (for checking for errors and repairs) and autophagy (for eliminating unusable proteins). All these processes – readiness for division, repair, autophagy – in old cells no longer obey biorhythms, since the corresponding genes lose the cyclicity of expression. But cyclic genes responsible for the release of inflammatory proteins appear – probably as a reaction to stress (both intracellular and external, associated with the general aging processes in the body).

Thus, the authors of the work under discussion have shown that with age, stem cells lose part of their cyclic processes, switching to an anti-stress response. However, it is still unclear what factors are causing this switch. The authors attempted to influence the functioning of stem cells through dietary restrictions. It has long been known that a low-calorie diet (containing 30% fewer calories than necessary to fully saturate the animal) improves the condition of mice, increases their cognitive abilities and prolongs their life. In addition, it was found that it stimulates the activity of muscle stem cells (see M. Cerletti et al., 2012. Short-term calorie restriction enhances skeletal muscle stem cell function).

Therefore, a group of mice was kept on a low-calorie diet for six months, and then the cyclicity of gene expression in stem cells was compared with the control group (which ate fully) and with adult animals. It turned out that dietary restriction prevents changes in daily cycles associated with aging of stem cells. After six months on a diet in the EpSC, the cyclicity of differentiation genes remained, and DNA synthesis did not shift to daytime, although during this time the cells should have aged a lot (by the standards of mouse life, six months is quite a long time). However, a small number of cyclic repair genes were found, which is typical for old cells. In MSCs, after six months, autophagy remained cyclical, as in adult cells. Then the authors conducted a reverse study: a group of adult mice were kept on a diet with a high fat content. As expected, the set of cyclic genes has become more similar to that characteristic of old cells. However, the cells did not fully reach the state of old age, preserving the integrity of DNA (EpSC) and the ability to cyclic autophagy (MSC). However, cyclic genes characteristic of inflammation and stress response have appeared. In addition, the number of MSCs has become less, that is, their division has been further slowed down.

Finally, the authors of the study set out to test whether it is possible to cause aging by destroying the daily expression cycles. It turned out that there were no signs of aging in cells mutated by genes controlling biorhythms.

The work under discussion brings us closer to understanding what changes occur in the body during aging. Apparently, at the cellular level, the cyclicity of gene expression does not disappear, but sets of cyclic genes change. Aging stem cells retain their basic properties: the ability to divide (in skin cells) and contacts with the environment (in muscle cells). However, instead of preparing for differentiation (cyclically expressing differentiation genes) and maintaining the constancy of the internal environment (that is, regularly performing autophagy), cells switch to stress protection and correction of accumulated errors. At the same time, the type of protective reaction depends on belonging to a particular tissue.

The reasons for such changes in the work of stem cells remain unknown. However, it is possible that this is due to the general level of stress in the body, which increases with aging. Perhaps that is why in an experiment with a fatty diet, which increases the load on the body, signs of aging of stem cells were noted. A more detailed study of cyclic processes at the intracellular level can tell us new ways to slow down aging. However, we should not forget that in humans, the circadian rhythms are not arranged in the same way as in a mouse, which means that the aging of human stem cells requires a separate thorough study.

Source: Solanas et al., Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress // Cell. 2017.

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