Planetary Metronome as a Regulator of Lifespan and Aging Rate: The Metronomic Hypothesis

A metronomic mechanism for the duration control of ontogenetic cycle periods of an animal is proposed. The components of the proposed metronomic system include the ventricular system of the brain, planet Earth as a generator of metronomic signals, and temporal DNA (tDNA) as a substrate that is epigenetically marked to measure elapsed time of ontogenesis. The metronomic system generates repetitive signals in the form of hydrodynamic disturbances in the cerebrospinal fluid (CSF). The metronomic effect arises due to the superposition of two processes – the near-wall unidirectional flow of CSF and oscillations in the movement of the planet. Hydrodynamic impacts of the metronome are transformed into nerve impulses that initiate epigenetic modification of tDNA in neurons, changing the content of factors expressed by this DNA for innervated targets of the body. The duration of ontogenetic cycle periods, including duration of the adult life, depends on the rate of addition of epigenetic marks to tDNA. This rate depends mainly on the frequency of the metronomic signals used by each particular species. But epigenetic modifications can also be influenced by factors that modulate metabolism and the rate of chromatin modifications, such as a calorie-restricted diet.


INTRODUCTION
Theories of aging are divided into two main classes: stochastic or programmed [1][2][3][4]. Evidence supporting a programmed process of aging is accumulating. Weismann proposed aging as a part of ontogenetic program more than a century ago [5,6]. New variants of this view continue to appear along with alternative approaches to the problems of evolutionary gerontology [7][8][9].
While the field of biogerontology has made significant progress, some researchers assess its current state as a crisis. In particular, Gems and de Magalhães suggest that the field needs a paradigm shift [10]. Gladyshev emphasized the need for a universal concept of aging, the potential future significance of which might be comparable to "the role of proton gradient in ATP synthesis, periodic table of chemical elements, and evolution by natural selection" [11].
The hyperfunction theory of aging has been suggested as a potential unifying paradigm [12,13]. According to an alternative view, neither the idea of hyperfunction, nor other theories have yet proposed an integrative concept that can help raise the right questions for further progress in the study of aging [11]. Other authors come to a similar conclusion, emphasizing the lack of a holistic understanding of the interactions between genetics and the environment in explaining aging and lifespan expectancy [14].
In any case, advances in identification and studies of biomarkers of aging (genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, impaired nutrient sensitivity, mitochondrial dysfunction, cellular aging, stem cell depletion, and altered intercellular communication) already provide a glimpse beyond the horizon [15]. The ordered appearance of signs of aging seem to point to an underlying program. But what is the aging program?
The list of hierarchically ordered hallmarks of aging, that illustrate the hyperfunctional activity of an aging organism, include hypertension, hyperlipidemia, hyperinsulinemia, hyperglycemia, pro-inflammation, hyperplasia, and altered proteolysis [13]. The long list of age-associated pathologies as manifestations of hyperfunction may create the illusion that the main mechanism of aging is understood or the false impression that a paradigm exists. In the mentioned work by Gems and de Magalhães, who criticize such an illusion, it is aptly stated that just as a hoverfly, having no sting, mimics a wasp, some classifications "give the impression of a paradigm where one does not exist" [10]. The fact that "postgrowth" disruption of intracellular signaling pathways leads to age-related diseases at the organismal level is not a full explanation. We need to understand the primary cause of these age-dependent intracellular abnormalities that initiate aging. The crisis of modern biogerontology is explained by the lack of understanding of what exactly is the driving force behind aging. Although there are more arguments in favor of programmed aging versus stochastic mechanisms, the driver behind the ontogenetic program that unfolds in time and leads to aging remains a mystery.

ONTOGENESIS AND THE COURSE OF BIOLOGICAL TIME
Marking of ontogenetic events in time does not seem to be organized only on the basis of events like stimulus-response, induction-differentiation, and proliferation. A multicellular animal is not capable of independently (without the use of an external independent trigger) ensuring the necessary duration of different periods of its ontogenetic cycle. To do this, an external source is required. I suggest that this external source is the planet Earth itself with its uneven movements in space.
If the planet's temporal cues play a role in marking ontogenetic events in time, animals must have evolved a special physiological system for detection of these external signals. This physiological system is designated here as metronomic and proposed to be located in the ventricles of the brain. It is possible that the development of central nervous system from the neural tube and the appearance of the brain ventricles in evolution were largely secondary to this central task -the development of an apparatus serving as a timer during the ontogenetic cycle.

ROLE OF THE EARTH IN THE OPERATION OF THE ANIMAL METRONOME
The processes known in molecular biology, such as transcription, translation, etc., seem to be fundamentally insufficient for measuring the course of time. DNA on its own, without an external stimulus, cannot perform time control, neither can cells organize this process. If biochemical and biophysical factors are not sufficient on their own, there is nothing to prevent nature from making use of geophysical factors such as uneven movement of the Earth in space. This property of our planet could be sensed by animals and used as a basis for creating a metronomic system for the temporal marking of ontogenesis.
Movements of the Earth in space include a number of periodically repeating processes, including changes in the speed of the Earth's axial rotation, as well as the polar movement of the Earth, that is, movement of the Earth's axis relative to its crust, and also nutation (wiggle of the Earth's axis). Multiscale variations in the parameters of the Earth's rotation consist of highfrequency variations in polar motions and longer-period f luctuations [16,17]. The polar motions of the Earth, or oscillations of the earth's pole, are displacements of the axis of rotation in the body of the Earth. Oscillations of the Earth's axis, called nutations, depend on the gravitational pull of the equatorial bulges by the Moon and the Sun, on the tilt of the Earth's axis to the plane of orbit, as well as on continuous changes in the position of celestial bodies interacting gravitationally with the Earth and with each other. The oscillations of the Earth also depend on dynamic changes in the structures of the Earth, both in the depths and on the surface [18][19][20][21][22].
Gravitational pull, mainly from the Sun and Moon, but also from other celestial bodies (tidal forces) causes small periodic changes in the orientation of the Earth's axis, which can be measured using observations of very distant quasars. Tidal action in the diurnal frequency range causes resonant excitation of nutation of the free liquid core and free nutation of the inner core [23,24].
The main types of motion of the Earth's axis, which affect the periodic changes in its orientation in space, and thus cause the planet's oscillations are: polar motion (oscillation of the Earth's axis of rotation relative to its geographic axis), nutation (nodding movement of the planet's axis), and variations in the length of the day. Nutation consists of many micronutations with small amplitude and high frequency. Nutation amplitudes also depend on the internal structure of the planet, including the liquid core inside the constantly rotating mantle, which itself is affected by the external tidal action. An additional contribution to the pattern of oscillations of the Earth's axis is made by the surface processes related to the oceans and atmosphere [25][26][27][28].
Oscillatory-rotational processes in the motion of the Earth, including changes in the orientation of the axis, can be observed as movements of the poles in space. In the perturbed oscillatory-rotational motions of the Earth caused by gravitational forces from the Sun and the Moon, a tidal-like mechanism of pole oscillations was revealed, due to the rotational-translational motion of the barycenter of the "double planet" Earth-Moon around the Sun [29]. The main characteristics of these f luctuations remain stable. Analysis of the observational data of the movements of the Earth's pole over a longtime interval showed that the oscillations of the Earth's pole are in phase with the precessional movements of the Moon's orbit, which ref lect changes in the orientation of the Moon's axis in space [30]. Existence of the intradiurnal oscillations of the Earth's pole caused by the gravitational-tidal moments of the Sun and Moon was also demonstrated [31].
While moving along its orbit, Earth constantly experiences small oscillations of the axis, which are characterized by different frequencies. The series of short periods of oscillations are caused mostly by the tidal moments of the Sun and the Moon. Many Earth oscillations have subdiurnal frequencies, although variations in planetary oscillations vary on time scales from subdiurnal to multidecadal [19,27,32]. A contribution to these gravitation-mediated oscillations is also made by the geophysical processes in the form of redistribution of masses inside the Earth and on its surface, i.e., by the oceans and atmosphere. Together, the gravitational forces of the Sun, the Moon, and the geophysical processes associated with their impacts are involved in short-term and longterm periodic changes in the orientation of the Earth's axis in space [17,[33][34][35][36][37].
Thus, the Earth is constantly experiencing physical movements including vibrations and various forms of rotation. Orientation of the Earth's axis is constantly changing over time. As for the Earth's trajectory in space, various small oscillations are a manifestation of constant deviations from the uniform and unidirectional motion of the planet. Due to this, the Earth as a planet has the ability to play the role of a "converter" and translate its gravitationally determined movements into a type of hydrodynamic signal relayed by the cerebrospinal fluid and recognized by the specialized structures of living beings. In higher animals, including humans, this may be the responsibility of the metronomic system, which evolved on the basis of the brain ventricles and CSF flow. An analogue of the metronomic system should also exist and operate in invertebrates. The dependence of the metronome on periodic geophysical oscillations is shown in figure below.

VENTRICULAR SYSTEM OF THE BRAIN AS A STRUCTURE FOR THE GENERATION OF METRONOMIC BEATS WITH THE PARTICIPATION OF THE PLANET AND PARIETAL FLOW OF CEREBROSPINAL FLUID
It is possible that constant deviations in the trajectory of the Earth are cues utilized by a metronomic system in animals, proposed here as a key mechanism of adjusting Key principles of the metronomic theory (a model) the duration of ontogenetic cycles. The structure of the brain (or its equivalent) used for this purpose is the ventricular system. It is made up of connected cavities along which CSF flows.
The ventricles and the central canal of the spinal cord are lined with ependymocytes (neuroglial cells). Ependymal cells expose their motile cilia, miniature whip-like organelles, to the inside of cerebral ventricles and promote CSF f low. The motile cilia of the ependymal cells tightly coordinate their contractions to promote a powerful and directed f low of CSF. This f lux is required for nutrition, protection, and waste removal from the brain [38]. In addition, young neuroblasts in the subventricular zone of the adult brain use this f low for their migration from the walls of the lateral ventricles to the olfactory bulb [39].
The complex and even bizarre architectonics of the ventricular system of the brain, however, cannot be explained only by the above [40]. Various populations of motile ciliated cells (and the beating of their cilia) are spatially organized so that the directed CSF f low is limited to individual ventricular cavities with little f luid exchange between the ventricles, despite the pulsatile movements of CSF caused by the heartbeat [41].
A striking feature of this system is the neurons of the brain, which are directly washed by the f low of CSF. Vigh et al. described in detail the morphology of the system of CSF-contacting neurons, emphasizing their apparent role in the perception of various signals associated with the CSF [42,43]. These neurons contact the CSF through their perikaryons or axons, and most of them have dendrites within the ventricular cavity, where they form cilia-like extensions.
A significant proportion of these sensory cells are present in different areas of the hypothalamus, such as paraventricular organ and vascular sac. It has been suggested that the CSF-contacting nerve cells from the specialized nuclei of the hypothalamus are involved in the hypothalamic-adenohypophyseal regulation. Other CSF-contacting neurons, according to the same group of researchers, could be sensitive to CSF pressure or f low, as well as to illumination of brain tissue [42].
The CSF-contacting nerve cells present in the brain ventricular walls and central canal of the spinal cord have been found in all studied vertebrates. In the lamprey spinal cord, the ciliated somatostatin/GAGA-expressing CSF-contacting neurons have been shown to function as both pH sensors and mechanoreceptors. It has been proven that the hypothalamic CSF-contacting neurons respond to mechanical stimulation of f luid movements along the wall of the third ventricle [44]. In the lamprey hypothalamus, this response is mediated through the channels like Acid-Sensing Ion Channel 3 (ASIC3). These mechanoreceptor CSF-contacting hypothalamic neurons have extensive axonal branching. Rodents also have similar neurons.
The CSF itself is a liquid as transparent as water that washes the central nervous system and f lows with pulsating movements. Cardiac and arterial pulsation is the main source of pulsatile CSF movement, with the exception of deep abdominal breathing, which can also help directing CSF f low [45,46].
The parietal and luminal flows in the channels of the ventricular system are organized by motile cilia that act as nanomachines that move the fluid in one direction along the inner surface of the channels [41,47,48]. The nearwall CSF flow is constantly forced, due to inertia, to maintain its instantaneous direction in space, despite the also instantaneous displacements of the planet. The walls of the ventricular channel, along which the CSF flows, change their position in space simultaneously with the planet. Under such conditions the CSF flow, while retaining its previous direction for a short time, must hit the wall of the channel or deviate from it, depending on the direction of the instantaneous displacement of the planet. These changing mechanical interactions cause inevitable hydrodynamic disturbances in the near-wall CSF flow.
Thus, hydrodynamic perturbations of the CSF f low must inevitably arise in the immediate vicinity of the surface of the ventricular system. On the inner surface of cerebral ventricles, as noted above, mechanosensory endings of the nerves of the periventricular network of the nervous system are exposed to and can potentially respond to mechanical disturbances that arise in the nearwall f luid f low due to uneven movements of the planet. The strict unidirectionality of the parietal CSF f low maintained by cilia would allow the sensory neurons of the ventricular system to recognize deviations in the movements of the Earth and translate the hydrodynamic signals of the CSF f low into specific nerve impulses.
Through the course of evolution, each species of multicellular animal with a ventricular system (or its analogue in more primitive taxa) may have selected hydrodynamic perturbations generated by the movements of the planet in the near-wall CSF f low that are repeated with optimal frequency for that species. These periodic perturbations are translated into nerve impulses in specialized neurons, which can be referred to as "chrononeurons", that reside in the periventricular region. Nerve impulses periodically arising in chrononeurons, could serve as metronomic signals necessary to adjust the duration of each ontogenetic cycle. Under this proposed system the frequency of repeated beats of the metronome chosen in evolution is optimal for each species.
Metronome signals are responsible for the rate of epigenetic modifications of temporal DNA (tDNA) in chrononeurons. All things being equal, the rare metronome beats are favorable for the slow tDNA modification, leading in particular to a long reproductive life. The high-frequency metronomic rhythm, on the contrary, corresponds to a faster "depletion" of tDNA, which controls the duration of a certain ontogenetic period. This does not exclude however the possibility that the same species can be guided by metronome beats of different frequencies during different periods of its ontogenetic cycle. The motions of the Earth generate a wide range of perturbations in the CSF f low, so there is no lack of options for the evolutionary choice.
Given the complex structure of the ventricular system, researchers have repeatedly suggested that CSF, an evolutionarily conserved brain transport system, must have some other, perhaps key, physiological function that is still unknown [38,49].
It is possible that each ventricle performs its part of a common task in fulfilling the purpose of the ventricular system. Its complex shape can be explained by the fact that certain compartments of the system have neural connections with different regions of the brain and, accordingly, the body, in order to send different region-specific metronomic signals. It is possible that the metronomic system of different ventricles is evolutionarily tuned to hydrodynamic signals with different characteristics. All other things being equal, the longer the interval between the metronomic beats, the slower the change in the biological age of the target (which is controlled by the metronomic signals of a particular ventricular compartment). Ultimately, this could lead to heterochrony in the implementation of ontogenetic processes so that different organs and tissues of a single organism have non-identical rates of development, maturation, and aging.
It should be emphasized that the movements of the organism itself are incomparably slower than the instantaneous displacements of an oscillating planet. Therefore, its individual movements cannot affect the characteristics of the metronomic signals.
Mechanosensory genes contribute to polarization of epithelial cells of the ventricles of the brain, and such architecture, in its turn, promotes the directed CSF f low, which is important for the successful operation of the proposed metronomic system [50].
Uniform ciliary action determines the direction of the parietal f luid f low in each ventricle, regardless of its volume. Therefore, the mechanism is able to perform the role of a metronome regardless of the size of the brain. The complexity of the nervous system is not important for its work, it can operate in both vertebrates and invertebrates, the only requirement being stable near-wall f luid f low in the nervous system and presence of mechanosensory neurons.
Neurons contacting the CSF are present in all studied vertebrates. They are reinforced with cilia to help perceive hydrodynamic impacts of the CSF. The ventricular system, similar to the auditory system, converts the energy of vibrations into neuron firing [44]. Mechanosensory neurons immersed in CSF seem to be an ideal candidate for capturing signals generated by the movements of the planet.
In the proposed metronomic system, each speciesspecific metronomic signal processed by chrononeurons initiates a new act of epigenetic recording and successive modification of regulatory sites would occur in these neurons. The complete modification of the tDNA region, allotted for the particular period of the ontogenetic cycle, would be a necessary and sufficient condition for the transition to the next period of ontogenesis. The beat frequencies of the metronome, and thus the periods of the metronomic rhythm, obviously differ greatly between short-and long-lived species such as the fly and the elephant.
It should be emphasized that the rhythm used by a species for the functioning of its metronome is fundamentally different from biological rhythms, sometimes used to explain the features of development or aging, because the metronomic rhythm is of exogenous rather than endogenous origin. And therefore, it is more stable, which is essential for measuring large time intervals. It is possible that the main purpose of the nervous system going through the stage of the neural tube, which then gives rise to the ventricular system, is the formation of the metronome.

HYDROMECHANICAL IMPACTS OF CSF FLOW ON MECHANOSENSORY NEURONS
The main purpose of maintaining a strictly directed parietal f low of CSF in the ventricles is perhaps to generate signals of the metronomic system. An organism's mechanosensory neurons do not receive signals as long as the planet Earth rushes with great speed in outer space in a constant direction. However, when the Earth makes a small change in the orientation of its motion, the following events occur: the organism and the wall of its ventricular canal, together with the planet, change their position, while the trajectory of the near-wall CSF f low, due to the inertia, retains the same direction and collides with the channel wall. As a result, the mechanosensory neurons of the ventricle, are exposed to the hydromechanical impact. Consequently, periodic perturbations in the f luid f low, perceived by mechanosensory neurons, can be used as a planetary clock that functions due to the gravitational interactions of the Earth with other celestial bodies, mainly with the Moon and the Sun. Each signal, specific for a given species, is converted to an epigenetic marker on tDNA in chrononeurons.
It is important to note that the body does not need to perceive all the movements of the Earth. Moreover, this would disorganize the operation of the entire metronomic system which must evolve to ignore all irrelevant signals. The necessary filtering could be achieved either at the level of mechanosensors or chrononeurons.
It is also important to take into account that the speed of movements of the body is incomparably lower than the speed of the Earth's oscillating displacements in space. Therefore, arbitrary changes in the position of the body cannot affect the necessary characteristics of the generated metronomic signals.
In general, the proposed metronomic system, comprised of different factors such as mechanosensory neurons, CSF f low, and planetary movements, performs the key function of ordering the ontogenetic periods in time. This includes the course of aging.

TEMPORAL DNA (tDNA) AS A SUBSTRATE FOR THE ANIMAL METRONOME THAT CONTROLS ONTOGENESIS, LIFESPAN, AND AGING
The main periods of the ontogenetic cycle of a multicellular animal include development, growth, puberty, reproductive life, and post-reproductive period. All these processes are examples of time-dependent changes; however, their current study is focused mainly on interorgan interactions and regulation of the body size [51,52]. More and more data in this area point to the key role of epigenome in the regulation of genes in hypothalamus and pituitary gland [53].
Here, we propose a temporal mechanism that explains both the control of the lifespan and the origin of aging. Animals (at least, vertebrates) use two important entities, metronomic system and tDNA, to regulate their ontogenetic cycle in time. Together they perform the function of a chronograph, marking the elapsed period of ontogenetic cycle, that is organism's age.
What causes the body that has completed development and growth to generate conditions that lead to aging? Why can't it stop there? How exactly are the duration of reproductive life span, as well as other periods of the ontogenetic cycle regulated?
All periods of ontogenesis are carried out with the participation of many genes and signaling pathways, but we postulate that they operate under the integratory control of a metronomic system, which unites several heterogeneous components to perform a single function.
Each period of ontogenesis has its own tDNA sequence. The "expenditure" of tDNA (in the form of its epigenetic marking) occurs in chrononeurons specialized in controlling the ontogenetic time. Epigenetic marking of tDNA sites responsible for controlling the duration of the adult reproductive life reduces the efficiency of functioning of genes modulated by regulatory RNAs transcribed from tDNA templates. Decrease in the productivity of epigenetically edited tDNA (reduction of both composition and expression levels of transcripts) could be associated not only with the modification of its promoters, but also with modification of other tDNA regions. In sum, these processes lead to the formation of age-dependent dysfunctions in the body, that is, to aging.
Aging is characterized by the loss of optimal interactions between cells in different tissues and organs and weakening of their coordination. For example, the two most common age-related neurodegenerative diseases, Alzheimer's disease and Parkinson's disease, are characterized by synaptic dysfunction, which leads to the loss of control over targets [54].
It should be emphasized that the coordinating functions of the tDNA-encoded transcripts have little chance of manifesting their coordinating properties in cell culture and, conversely, the strongest chance within an organism.
Gerontologists have repeatedly suggested that aging should be considered as a consequence of the developmental process [13,[55][56][57][58][59], in particular, developing Dilman's ideas about the role of hypothalamus in aging.
Why cannot selection eliminate aging as a non-adaptive phenomenon? Probably not for the protection of the ecological niche from overpopulation. The reason for the existence of aging in the vast majority of animal species including humans may be because the same substrate (tDNA) is responsible both for the duration of reproductive ability and longevity. As for the significant increase of the post-reproductive lifespan, for example, in humans and killer whales, this is probably a later evolutionary acquisition as a response to the benefits of long-term parental care for offspring [60].
Reproductive lifespan program as part of the animal ontogenetic cycle program is carried out at the level chrononeurons that process metronome signals coming from the ventricular system. In chrononeurons, with each beat of the metronome, one act of epigenetic modification at the next site of their tDNA takes place. This occurs at the level of a promoter or other specific tDNA sequences. During the reproductive period, this process could lead to gradual weakening of some inhibitory regulatory pathways, causing hyperfunctioning of the corresponding processes, which is unfavorable for the organism. Other epigenetic modifications could lead to the loss of effective proteostasis and other events unfavorable for survival.
It is important to emphasize that in this case, a program regulating the duration of the fertile period, supported by natural selection, is continuously working. And harm to the body is a direct side effect of this benefit. Thus, as mentioned above, the process of sequential epigenetic marking of tDNA, while fulfilling the program of reproductive lifespan, is forced to simultaneously cause aging. A striking example of deviation from this scenario is acute phenoptosis, such as programmed death of Pacific salmon immediately after spawning, for the sake of survival of their offspring [8].
Some segments of chromosomes, which in animals are associated with their lifespan, could perform the function of tDNA. For example, during the interspecies comparison of genetically heterogeneous mice with genomes of other mammals, several quite large loci associated with longevity were identified in the mouse genome. One part of the chromosome 12 affected lifespan in all mice. The life expectancy of females was also affected by a region of mouse chromosome 3. Some of these genetic traits differed between male and female mice, and some affected lifespan only after a certain age [14].
Usually, genetic mapping of longevity is focused on the search for genes, combinations of genes, and genetic pathways responsible for longevity [61][62][63][64]. Analysis of the Drosophila lifespan showed that the majority of lifespan loci are sex-specific [65]. On the one hand, the search for the corresponding genes is quite justified, since both aging and longevity are very complex traits, the implementation of which involves many processes controlled by genes. However, a different evolutionary path may have been taken to control lifespan. A special segment of DNA which, in addition to the regulatory function, started to perform a fundamentally new mission and play a role of "consumable" material. The role of this tDNA is somewhat similar to that of a voice recorder tape. By epigenetically marking tDNA, the organism records the time interval that has already elapsed in the course of ontogenetic cycle.
Since aging is a time-dependent functional change in many processes [15], it is reasonable to assume that it is the ability to evaluate the passage of time that is central to understanding the problem of aging and determination of lifespan.
What is encoded in tDNA? Perhaps, neuropeptides, neurotransmitters, regulatory RNAs, etc., with the help of which chrononeurons regulate their targets, including cells of the autonomic nervous system, which, in turn, are important for the coordinated work of all tissues and organs.

DISCUSSION
The purpose of life is self-maintenance and proliferation. Ontogenetic cycle of each species also serves this purpose. Duration of distinct periods of this cycle is coordinated with each other and ultimately ensures the reproduction of the species. Natural selection pursues the main goal of life, its eternal continuation, and for this reason it ignores the side-effects of age-related pathologies.
Natural selection may use tDNA as a tool to modify certain features of species with long and short lifespans, such as drastic differences in fertility. Most species with a short lifespan are highly fertile, while the opposite is true for the species with a long lifespan. These animals are classified according to their types of ontogenetic cycle as r-and K-strategists, respectively [66,67]. Selection for postponed reproduction usually creates populations with increased longevity, and these populations often exhibit increased fertility late in life [68]. It has been reported that both reproductive longevity and lifespan increased as a result of a coordinated response to selection of mice with increased reproductive longevity [69]. A historical research of Saami women found that natural selection favored earlier onset and later cessation of reproduction. Although fertility in general did not correlate with lifespan, women who gave birth to their last child later in life also lived longer. Therefore, reproductive longevity and adult lifespan correlated in these populations [70].
Signs of aging and mechanisms aggravating it [15,71] are likely a consequence of some primary process that was not previously taken into account. In this work, we postulate two mutually complementary and indispensable factors of ontogenesis that are important for understanding the species-specific limits of lifespan and the origin of aging. It is proposed that the program regulates the duration of the adult reproductive life and that natural selection leads to correlation of the reproductive longevity and lifespan.
Regarding infradian biorhythms that are sometimes considered as a mechanism controlling the ontogenesis, their stability evidently depends on exogenous synchronizers too. This fact strongly limits the possibilities that endogenous biorhythms serve as checkpoints of ontogenesis. The relevance of circadian rhythms for this purpose is even less likely (especially for the long-lived species) due to the extremely short periodicity of these rhythms. The metronome system proposed here is assumed to be free from all these restrictions.
In this context, there is one more important question: Why can adult life be longer than reproductive life? The answer may be as follows. For the effective reproductive life, the organism must have high viability; therefore, by the end of reproductive life, some portion of tDNA should still be able to be expressed. If the lifespan is significantly longer than the reproductive period, this effect is likely caused by additional selection pressure.
Losing a sufficient coordinating support of neuronal factors with age (this support from the epigenetically modified tDNA gradually decreases over time), some genes could possibly begin to behave as harmful, showing signs of antagonistic pleiotropy. Actually, there is no harmfulness in the genes themselves, but the loss of their control caused by the tDNA-produced factors is harmful.
Ceteris paribus, the more chrononeurons are established during development, the longer the lifespan may be. The reason for an expected slight increase in lifespan in this case is that the total levels of neuronal products (neuropeptides, microRNAs, etc.) delivered to their targets will be higher in the case of a larger number of chrononeurons.
A calorie-restricted diet slows down the epigenetic realization of signals of the metronomic system and therefore increases lifespan. Factors such as altered mitochondrial and hormonal activity associated with calory restriction also contribute to extended lifespan, but these factors are secondary to the role of metronomic system beat frequency and tDNA pool. Although it is known, for example, that mice with a genetic defect or resistance to growth hormone live longer than their normal siblings [72], the main reason for the lifespan increase in this case is probably the delayed epigenetic marking of tDNA.
In the course of evolution, natural selection must have contributed to the reduction of sensitivity of those sensory systems that allow the brain to recognize the impact of abrupt changes in orientation of the Earth in space. Too high sensitivity to the movements of the Earth, affecting the hydrodynamic behavior of the cerebrospinal fluid, would interfere with normal consciousness, and therefore act as an anti-adaptive mechanism that systematically causes anxiety or disturbance of life functions.
It is noteworthy, that the movements of the organism itself are incomparably slower than the abrupt movements of an oscillating planet. Therefore, movements of the body are not able to systematically inf luence the generation of metronomic signals.

CONCLUSION
This theory proposes a universal mechanism that explains both the origin of aging and the regulation of the lifespan of animals and humans. It is assumed that organisms use two important entities for the regulation of their development in time (i.e., temporal regulation of the ontogenetic cycle): metronomic system and tDNA required for chronometry. In the genome of each species, a certain length of tDNA is assigned for each period of ontogenesis, with some individual deviations. The species-specific tDNA and the metronome, tuned to the species-specific frequency, together perform the function of a chronograph. It records the part of the ontogenetic cycle completed to the moment, fixing the period of the organism's life already accomplished.
In the structures and functions of an animal organism that has already completed development and growth, physiological abnormalities leading to aging are observed. This is because the aging process is driven by epigenetic modifications of the same tDNA that is used for the adaptively beneficial control of reproductive lifespan. This concept is offered here both as an explanation of the origin of organismal aging and as a way of regulating species lifespan. Evidently, aging in the overwhelming majority of cases is a non-adaptive process, but being the result of the work of an adaptive reproductive program encoded in tDNA, it becomes an inevitable side effect. By supporting the metronome-mediated beneficial reproductive lifespan program, natural selection is unable to overcome aging precisely because both processes depend on a common substrate -tDNA sequence. So, it should be emphasized that there is no specific aging program for most animal species, and the succession of aging processes in time is a consequence of the fulfillment of the reproductive lifespan program. The ventricular brain system is an organ that was created by evolution, most likely, primarily for the functioning of metronomic system and temporal setting of ontogenesis. It is probably the reason why the nervous system architecture is developed in embryogenesis from the neural tube, which is not only a precursor of brain regions, but also of the cerebrospinal fluid circulation system, that is indispensable for the metronome function.
To perform its functions, the metronome system uses small vibrations of our planet. Previously, I discussed the role of uneven Earth motions, which plants can use in the complex process of orientation relative to the vector of gravity [73]. Here, planetary movements are proposed to have a role in the temporal organization of the ontogenetic cycle of animals. If the proposed mechanism is correct, then the control over the aging process is possible through the control of the new physiological system proposed here -the metronomic system. and I.A. Olovnikov for their help in editing, advice, and discussion of the manuscript.
Ethics declarations. The author declares no conf licts of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by the author.
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