Four-level regulation of lifespan through the biopsychological clock

Berezina Tatiana Nikolaevna Doctor of Psychology Professor of the Department of Extreme Psychology at Moscow State University of Psychology and Education. 123290, Russia, Moscow, nab. Shelepikhinskaya, 2a, room 508 tanberez@mail.ru Other publications by this author

Introduction.

Regulation of the vital activity of the body is carried out by a complex system of biological clocks. The biological clock is an internal system of the body that determines all the rhythms of its vital activity: from the heart rate to the organization of all life (biological rhythms or biorhythms).   We proposed the existence of a single meta–resource - a common reserve of vital forces associated with biopsychological aging. This meta-resource determines the general state of human performance and affects the rate of biological aging ^[1].

Thus, it seems relevant to us to develop a holistic model of regulation of human life expectancy, taking into account its extremity, based on modern data on the work of psychological and biological clocks.  This is exactly the purpose of this work.

Biopsychological concept of regulation of life expectancy.

We have assumed the existence of 4 levels of biopsychological clocks associated with life expectancy.

The first level. The topmost level is the biological clock that regulates the overall life expectancy. We called it the regulation of the lifetime, and the time that is regulated at this level is the lifetime.

The regulation of life expectancy is usually not included in the hierarchy of biological rhythms. This is largely due to the fact that biological rhythms, by definition, are periodically recurring changes in the nature and intensity of biological processes and phenomena, and individual life is a single unidirectional irreversible process. Nevertheless, the regulation of the lifespan and development of the organism at the subcellular level is regulated by the biological clock.  Researchers identify several different molecular processes capable of acting as a biological clock responsible for the lifespan of an organism. Most often in this regard, researchers consider the average length of telomeres in cells (chromosomal clock)  ^[2] and the level of DNA methylation (epigenetic clock) ^[3]. 

One of the very first models of biological clocks encoding life expectancy is the concept of telomerase (chromosomal) biological clocks. The work of the chromosomal biological clock is organized as follows. Genetic information is programmed by special DNA molecules that are grouped into chromosomes. At the end of each chromosome there are special sections – telomeres.  With each division, telomeric DNA molecules become shorter by 200-300 nucleotides (we can say letters), shortening occurs due to the activity of special enzymes – telomerases. The length of telomeric DNA is about 10-15 thousand letters. If we divide fifteen thousand by three hundred, we get fifty, i.e. fifty cell divisions.  The telomerase-telomeres system, according to the authors, is the biological clock of life of living beings, but they go at different speeds for each person. Telomerase can be compared to an engine, and telomeres can be compared to the hands of a clock. Only these hands are gradually shortened, and do not move along the dial. Thus, it is assumed that the duration of life and its finiteness are encoded ^[2].  Later, the concepts of epigenetic clocks were proposed. There are the epigenetic clock of Horvath ^[3] and the epigenetic clock of Khanum ^[4].

The work of the biological clock is related to the energy of the cell ^[5]. For example, the metabolic theory is that aging is the inevitable result of toxic by-products of normal metabolism, such as by-products of cellular respiration or reactive oxygen species.  A telomerase theory of aging (telomere shortening)  it offers more complex mechanisms of regulation of metabolism, as well as theories of somatic mutations.   In any case, it is the limitation of the possibility of metabolism that redefines life expectancy.  And the management of metabolism is carried out by means of biological clocks of different levels.

Speaking about the energy of life, I would like to cite the opinion of the Russian physiologist K.P. Ivanov, who studied the metabolism of a living cell ^[6]. He justified the concept of "life energy". 

A person spends several times more energy during the day than he needs to meet the needs of the body. In an active person who consumes about 2300 kcal per day, about 60% of energy consumption occurs at full muscular rest, i.e., at the level of the basic metabolism, when a person does nothing, just lies, or even sleeps. It is for this "nothing" that a person spends 1800 kcal per day. When asked where this energy goes, they most often answer that it affects the activity of internal organs. But physiologists have calculated that he spends about 20% of his energy on the activity of internal organs. That leaves 1400 kcal.  They are used to maintain the life of the body. But what is "life support" The author of the article claims that this energy is spent, firstly, on protein recovery, since under normal conditions there is a constant destruction of proteins (aging). Proteins are constantly destroyed, for example, by the action of water; water in its mechanical action on living molecules due to thermal vibrations can destroy the integrity of living cell structures. Secondly, for the restoration of cells: the fact is that most cells in a living organism exist from 1.5 to 10 days, and then they are destroyed. The author of the article claims that the complexity of the structure of living matter is so great that thermodynamically it is very far from the equilibrium state, which is why there is a constant self-destruction of tissues. I.e., energy is spent on cell repair, and this is the energy of life.

However, this energy is finite. Here is the opinion of another physiologist Max Rubner: in his mechanistic theory of wear, which he considered the basis for all other theories, he studied the energy expenditure of the body necessary for vital activity. He studied the metabolic rate of animals of different sizes – from guinea pigs to cows. He calculated that the energy consumption per unit of body weight is fixed: each gram of body tissue consumes the same amount of energy before death for all the species he studied. Thus, he came to the conclusion that the change in life expectancy is due to a change in the metabolic rate ^[7]. 

Thus, it can be concluded that the biological clock of this level has its own energy reserve, which determines the duration of their functioning.

The second level of the biopsychological clock ensures the distribution of energy through the stages of the life path – this is time management, most likely, the biological clock that regulates the annual and monthly cycles is responsible for this.  For a person, personal regulation of activity time is associated with these biological clocks.

The idea of personality as a subject of life was laid down by S.L. Rubinstein, in the concept of personal organization of time, this idea was supplemented and refined to analyze the ways of organizing life. Based on her concept of the personal organization of time, K.A. Abulkhanova proposed to consider the personal regulation of life expectancy through three spatial-temporal value-semantic characteristics of the life path: "life position", "life line", "life perspective" ^[8]. An important indicator is the length of the time perspective.  The duration of such regulation is individual – most people build for up to a month, sometimes up to a year, very rarely a person develops a real plan for several years. For example, studying at a university cannot be considered a real plan, because for most students it is completely external regulation, and not the implementation of plans developed by them.

Violation of the established rhythms of life can reduce performance, have an adverse effect on human health. The nature of biological rhythms is taken into account when organizing a rational work and rest regime of a person, especially in extreme conditions (in polar conditions, in space, with rapid movement to other time zones, etc.) ^[9]. People make their plans based on endogenous (for example, alternating periods of sleep and wakefulness) and exogenous (seasonal cycles winter – summer) biological rhythms. An attempt to build personal plans independently of biorhythms leads to their desynchronization, violation of the timing of human biorhythms to periodic changes in the external environment is called desynchronosis. An example is a flight to another time zone, etc. The consequences of desynchronosis can be exacerbations of chronic diseases, increased fatigue and decreased performance ^[10].

How is life expectancy related to the personal organization of time? There is no definite answer to this question.

Most often, researchers offer data that a certain way of organizing a person's life contributes to an increase or decrease in life expectancy.  Life expectancy can be reduced by bad habits: drug addiction, alcoholism, tobacco smoking, and a healthy lifestyle, respectively, contributes to its increase. The choice of a particular lifestyle depends on the personality of the person himself ^[11].   Moreover, it is shown that lifestyle also affects the regulation of the previous level:  human behavior, lifestyle, daily routine, attitude to the world affect the biological age, even determined at the chromosomal level ^[12]. Telomeres and telomere-related proteins are known to play an important role in cell aging, which is important for global health. As the C study showed . According to Werner, changes in the usual behavior of healthy people, in particular, the inclusion of endurance training in the normal daily routine affect telomerase activity and telomere length ^[13].

We believe that the regulation of life expectancy is carried out from top to bottom. A certain amount of life energy is put into the system of biological clocks of a lower level, in this case controlling the infradian and circadian rhythms, and then distributed with the help of these clocks for months and for a year.

Adaptation and aging of biosystems increase the periods of biorhythms. Due to training and habituation, energy costs are minimized, and the efficiency of life processes is increased. However, at the same time, the homeostatic power of the biosystem decreases, the corridor of permissible deviations of the parameters of the biosystem and the variation of biorhythm periods narrows without loss of stability. Control of the accuracy of the work of the genetic and protein–synthesizing apparatus of the cell is provided by self-regulation - maintaining an acceptable range of changes in the periods of transcription and translation biorhythms. The aging of the ribosome increases the synthesis period of protein molecules, which can lead to errors in the protein structure and disruption of intracellular processes. Correction of such errors is provided by timely enzyme destruction of "bad" ribosomes and restoration of temporary coordination of intracellular processes ^[14].

Nevertheless, it should be noted that lifestyle affects the acceleration of metabolism, but this does not always lead to a change in life expectancy. There have been studies with attempts to accelerate metabolism in laboratory animals through lifestyle ^[15].  The authors investigated the effect of increased energy consumption caused by exposure to cold on the lifespan of mice. Longevity was measured in groups of 60 male mice, which were kept at a temperature of 22°C or 10°C throughout adult life. Exposure to cold increased the average daily energy consumption by about 10%-48%, however, the authors did not observe significant differences in average life expectancy between the control and experimental groups.

We believe that the acceleration of metabolism due to lifestyle changes is associated with the work of the biological clock of the 2nd level, and not the 1st, i.e., it will not directly lead to a decrease in life expectancy (regulated at the 1st level), most likely on the contrary - mechanisms that prevent this will be activated. In humans, overloading with activities beyond the planned can lead to overspending of energy, acceleration of biological aging and activation of mechanisms in the body that prevent this, in other words, to a feeling of chronic fatigue, weakness and diseases ^[16].   These mechanisms are likely to lead to lifestyle changes and, accordingly, a slowdown in metabolism.  Only in rare extreme cases, prolonged disruption of the normal functioning of a living being can lead to death.

The third level is regulation based on daily (circadian, circadian) or circadian biorhythms with a period of 20-28 hours. We called it the regulation of waking time. This is the most studied area of chronobiology and chronopsychology. Each of us practically faces the need for such regulation, this is a well-known human daily routine. Even those who do not make it specifically, live by it (sleep at night, and stay awake during the day). 

We believe that the regulation of this level is related to health and immunity ^[17]. Sleep deprivation can reduce immunity, while good sleep improves it.  Many aspects of human physiology and behavior demonstrate rhythmicity with a period of about 24 hours. Rhythmic changes are controlled by an endogenous timekeeper, the circadian clock, and include sleep-wake cycles, physical and mental performance, blood pressure and body temperature. Researchers note that many diseases, such as metabolic, sleep disorders, autoimmune and mental disorders, and cancer, are associated with circadian rhythm ^[18]. 

The mechanisms of alternation of sleep and wakefulness in physiology are well studied and they are in good agreement with our model of biopsychological regulation. According to our model, each level has its own mechanisms that are associated with the accumulation of energy reserves and its distribution through biological clocks.  Based on this, for this level, energy should be restored at night and consumed during the day.

In 2017, Jeffrey Hall, Michael Rosbash and Michael Young received  Nobel Prize for research on the regulation of circadian rhythms. Studying the genotype of the drosophila fly, they discovered a gene and a period protein, the concentration of which fluctuates with a frequency of 24 hours and determines the work of the insect's "biological clock". Scientists have determined that this gene produces a protein that accumulates in cells during the night and then accumulates during the day ^[19]. 

For humans, the hormone melatonin can perform a similar function.  The secretion of melatonin occurs mainly at night, in the dark, and in the morning and daytime – in the light – the production of the hormone is sharply suppressed. With the help of melatonin, the daily periodism is organized, it acts as an intermediary between the pacemaker mechanism of the nuclei and peripheral organs. In addition, it has antioxidant activity and is necessary to ensure psychological and somatic health ^[20].

There is also data on the relationship of this level of regulation with life expectancy.  At the annual conference at the World Congress of Cardiology in the USA, a study of the relationship between sleep and health was presented, the study used data from 172,321 people with an average age of 50 years who participated in a national health survey from 2013 to 2018 ^[21]. Based on the results obtained, the authors concluded that men who regularly sleep well can live almost five years longer, and women can live two years longer. Good sleep, according to the authors, was based on five different factors: the ideal sleep duration from seven to eight hours a day, difficulty falling asleep no more than twice a week, sleep problems no more than twice a week, the absence of any sleeping pills and a feeling of good rest after waking up for at least five days a week a week.

And prolonged sleep deprivation leads to an increase in mortality of experimental animals (from insects to rats) ^[22]. For example, it was shown that sleep deprivation, similar to rest, led to an increase in metabolic rate in the Pacific cockroach beetle and to a significant increase in mortality in the experimental group, starting from day 17 (on average 0.57 deaths per day after that), while in the control group, mortality remained at the same level all the time (on average 0.17 deaths per day throughout the entire period) ^[22]. There is also evidence that the only cause of the sudden death syndrome of newborns is a violation of the rhythmic production of melatonin, a hormone that regulates the sleep and wakefulness cycle in humans and animals; as it turned out, a certain amount of it is necessary in the body to maintain the normal functioning of the nervous system and the health of all organs ^[23].

Based on our concept, the biological clock of each level is responsible for its own piece of regulation of life expectancy. Despite the connection of the body's energy with life expectancy, at each level there is its own regulation and mechanisms that prevent the unprogrammed transition of energy from top to bottom work.  As a rule, these are mechanisms that prevent an increase in energy costs and try to return the metabolism to its natural level.

For example, violations of biological rhythms in an adult does not lead to sudden death, but leads to states of reduced performance (and, accordingly, reduced energy consumption). Desynchronosis occurs when internal circadian rhythms mismatch due to pathology of systems or organs, as well as due to night work or transmeridian flights. In turn, a violation of the natural structure of biorhythms (desynchronosis) leads to sleep disturbances, headaches, daytime drowsiness, decreased performance, decreased resistance of the body, etc. [24 All this leads to a decrease in the overall activity of a person and a gradual adaptation of his biorhythms to a new situation. A similar effect appears when deprived  sleep of adults [25].  Firstly, sleep deprivation leads to a decrease in the overall activity of a person, physical and mental retardation, and secondly, sleep states spontaneously begin to occur, a person involuntarily falls asleep for a short time and he simply cannot keep awake without some special exercises.

The fourth level is the regulation of circadian rhythms of the cardiac and respiratory systems. We called it the regulation of cardiac activity time (heart time).

It should be noted that it is the disruption of these biorhythms that is the actual cause of the termination of life.  Registration of death is almost always carried out unambiguously: this is cardiac arrest and cessation of breathing. This is the grassroots level of regulation. All other levels and all biological clocks that control them, in this case, can only act through cardiac arrest. It is the heart rhythm of F. Halberg called cycles tipping the scales between death and life.

This level is connected to others. Many factors can affect the heart rhythms, tilting this cup in one direction or another.   Systematic chronobiological outpatient monitoring of blood pressure and heart rate, carried out around the clock during the week, showed the dependence of the heart rate on circadian rhythms of alternating sleep and wakefulness, as well as on light cycles [26. Experimental study of the chronostructure of the rhythms of the cardiovascular system in a ground laboratory and in space flight showed their relationship with the influence of external factors Wednesday [27]. The author cites data showing that the circadian system of the heart flexibly and consistently changes in cycles with long-term, infradian and multi-day periods, for example, such as an eleven-year cycle of solar activity, about 28-day, about 14-day, about-week rhythms. They also showed that heart rhythms can be influenced by external stimuli, for example, social factors and changes in the rhythms of illumination and geomagnetic field.

Thus, the termination of life is always due to cardiac arrest. And what does cardiac arrest depend on? We assume that, as always, the reasons are energetic, i.e. the biological clock that controls cardiac activity also has its own reserve of energy that accumulates (or is released)  at a certain moment of functioning, and then it is consumed. Most likely, this energy reserve is comparable to the interval of clinical death, during which a person can still be brought back to life.

A possible mechanism for this was proposed by the Russian scientist S.L. Zaguskin, who believed that the integrating factor of all types of biochemical regulation of cell energy is the aggregation of mitochondria with inhibition of energy with an increase in gel and the disaggregation of mitochondria with increased energy with an increase in sol ^[14].

However, it is precisely for this level of regulation that excessive energy expenditure turns out to be fatal, because it can lead to sudden death. In recent years, the study of the phenomenon of sudden death in adults who do not have previous health problems has begun. Most often, sudden death is registered in athletes after prolonged exercise.  This phenomenon has been known since ancient times – the death of a messenger, the first to run a marathon distance. Currently, research is ongoing.  For example, the sudden cardiac death of 387 young American athletes (under the age of 35) was analyzed in a 2003 medical review, the authors show that the cause of sudden death is most often previously unnoticed heart problems, but in many cases the causes of death cannot be determined ^[28].

As we believe, there are mechanisms in the human body that prevent excessive waste of energy.   They also exist at the level of regulation of cardiac activity. In this case, most likely, they are provided by mechanisms that prevent a person from developing exorbitant efforts. These are the mechanisms of fatigue, weakness, pain, heaviness in the muscles, the emergence of a subjective feeling of "I can't move my arm or leg." Therefore, it is understandable why sudden death of adults is most often registered in athletes: all their training is aimed at being able to withstand extreme loads and achieve the application of super-strength. Perhaps this leads to a depletion of energy potential. In any case, this may occur in situations where other causes of death could not be established.

Conclusion.

We propose the concept of biopsychological regulation of life expectancy through biological clocks of four levels. We assume the relative independence of each level. If we continue the metaphor of the clock, then the biological clock at each level is wound independently through its own mechanisms and performs its regulatory function. We associate the work of the biological clock with the cell's own energy and rely on domestic and foreign studies of intracellular metabolism. According to these concepts, the change in life expectancy is due to a change in the metabolic rate. A person produces more energy than he needs to meet the needs of the body, this energy goes to restore the structure of protein and restore the integrity of cells, in other words, it goes to support life, and this energy is finite. Each level of the biological clock has its own mechanisms of accumulation and consumption of this energy. We believe that it may be a certain structure of molecules, enzymes, hormones or some other mechanisms.

The first level is the molecular genetic clock located inside the cell; they are associated with the regulation of maximum lifespan (lifetime). Life expectancy is determined either by the size of telomeres, the length of which decreases with each cell division (the number of such divisions is finite) or by the peculiarities of DNA methylation, which naturally change with age.

The second level is the biopsychological clock that regulates the time of activity. They are based on personal time regulation (time management) based on exogenous and endogenous biological rhythms (annual, monthly planning).   When drawing up such plans, a person unconsciously focuses on infradian rhythms with a periodicity of 23-28 days and circadian rhythms, which are repetitive changes in the intensity and nature of biological processes and phenomena with a period of about a year. The mechanisms of energy accumulation and consumption at this level have not been studied. We believe that this level determines a person's professional longevity and, ultimately, the success of pension reform.

The third level is regulation based on circadian (daily) biorhythms with a period of 20-28 hours (regulation of sleep and wakefulness).  Sleep is a condition necessary for survival, this is confirmed by its prevalence, obvious health problems with mismatch of circadian rhythms and a possible fatal outcome with prolonged sleep deprivation. We believe that regulation at this level is related to health support and immunity.

The fourth level is the regulation of circadian rhythms by the cardiac and respiratory systems, – regulation of the time of cardiac activity (heart time). It is this level that is associated with the cessation of life. Most likely, the biological clock of this level also has its own energy reserve, comparable to the interval of clinical death, during which a person can be brought back to life. The proof of this is the phenomenon of sudden death of adults without previous health problems. Most often, it is registered in athletes after excessive exercise. The biological clock that regulates life expectancy at other levels can cause its completion only through cardiac arrest, i.e., through exposure to this level.    

Each level is responsible for its own aspect of life expectancy. The first is for the maximum life expectancy, the second is for professional longevity, the third is for the state of health and immunity, the fourth is for the probability of premature death and generally for the termination of life. There is an interaction between the levels, but its mechanisms have not been studied much. In addition, there are also mechanisms that ensure the autonomous functioning of the metabolism of each level. They prevent the uncontrolled movement of energy between levels.  To achieve practical goals, such as restoring health or preventing sudden death, it is necessary to work at the level of the biological clock that provides regulation of these processes.  Accordingly, an increase in the maximum life expectancy is possible only at the molecular genetic level. The existing data that certain methods and lifestyle affect its duration are most likely associated with a slowdown or acceleration of the rate of biological aging, but not an increase in its maximum duration.

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