Unified theory of human and animals aging. Bioenergy concept aging as a disease

The sharp increase in the average life expectancy in the twentieth century was provided by the work of infectious disease specialists, hygienists, parasitologists and epidemiologists, who defeated most of the infections. In the second half of the twentieth century, ecologists, clinical epidemiologists, toxicologists and technologists did it, overcoming the negative consequences of the first technical revolutions associated with chemical and physical pollution of the environment.

Hypoxia, reducing the activity of the main source of free energy – the mitochondrial system of oxidative phosphorylation, leads to a decrease in both phosphate and redox potential of cells. The unique property of hypoxia as the main pathogenic factor causing aging is the presence of numerous enhancers of its action. First, a decrease in oxygen concentration leads to a decrease in the rate of free energy production in the cell, the main mass carriers of which are ATP, NADH, NADPH and gradients of hydrogen, sodium, potassium and chlorine ions on cell membranes.

Cells contain more than 500 NADH- and NADPH-dependent enzymes (dehydrogenases), which, due to the free energy of oxidation of pyridine nucleotides, direct cell metabolism. Also in cells there are more than 200 ATP hydrolases that catalyze reactions that require the supply of free energy for their course. In the plasma membranes of various cells, there are energy-dependent translocases, which, due to the energy of the sodium cation gradient, provide the transport of a large list of metabolites into the cell against their concentration gradients.

Secondly, a decrease in the partial pressure of oxygen in organs and tissues leads to a decrease in the enzymatic activity of a number of oxidases. With a decrease in the activity of even one of the oxidases, important metabolic consequences arise in almost all organs and tissues.

A decrease in the activity of such a huge amount of enzymes under conditions of hypoxia leads to the most catastrophic consequences for cells, causing their death and death of the body.

At the physiological level, with aging, there is also a decrease in the production capacity of carriers of free energy due to a decrease in the supply of oxygen to organs and tissues, due to a decrease in the functions of the respiratory and cardiovascular systems.

The situation is aggravated by the fact that the carriers of free energy and their derivatives (cyclic AMP, cyclic GMP, GTP, CoA, FAD, NAD+) are key regulators of metabolism and cells and the body as a whole.

A decrease in the concentration of ATP and NAD(P)H leads to a decrease in the concentration, including nucleotides – substrates for the synthesis of nucleic acids (RNA and DNA): GTP, CTP, UTP, deoxy-ATP, deoxy-GTP, deoxy-CTP and deoxy-TTP.

There is no more toxic and operatively acting pathogenic factor than oxygen deficiency in the body due to the presence of such a large number of enhancers and distributors of its pathogenic effect on cell metabolism.

The whole history of oxygen life takes place under the sign of the economical consumption of always scarce oxygen, at all levels of the organization.

An important mechanism for this saving is the creation of oxygen reserves, especially in intensively functioning tissues and organs. The central nervous system, which is the most powerful and most intensive consumer of oxygen (per gram of mass per unit of time) as the main energy carrier, uses glucose, a semi-oxidized product containing its own oxygen. Glial cells that perform auxiliary functions contain glycogen, which also allows them to conserve oxygen, which is necessary for the functioning of neurons. I will dwell on other mechanisms for saving oxygen later.

I will list some of the main primary consequences of hypoxia for cells and the body as a whole.

1. Activation of an energy-dependent, regulated process of programmed cell death – apoptosis, which is safe for the surrounding tissues and for the organism as a whole, as a result of external influences. Apoptosis is not self-destruction of a cell, but it killing by external factors, in the extreme case, apoptosis can be considered as forcing cells to commit suicide by external factors: – the main physiological – cortisol (circadian rhythm), which with age increasingly becomes pathological (age-dependent growth basal level of cortisol and distress), and the main pathological one – hypoxia.

There is not enough oxygen for the simultaneous work of all cells of the body, it is necessary to save the “most valuable” ones, getting rid of ineffective cells for the survival of the body under hypoxic conditions, and also get rid of cells that may be restored from stem cells. Cascade mechanisms of the sequential elimination of cell components in a certain order require the expenditure of free energy in the form of ATP hydrolysis (for example, ubiquitin).

1.1. Activation of the production of free oxygen radicals by the respiratory chain of dying mitochondria. Free radicals of oxygen (* OH) and nitrogen (* NO), possessing high values of the oxidative potential, as well as ATP and NAD(P)H are mass carriers of free energy and are involved in the normal energy metabolism of cells. Free oxygen radicals generated by dying mitochondria are products of cell apoptosis, but not vice versa, as is often found in the literature.

It is the oxygen deficiency that leads to a network of events ending in apoptosis: – slowing down of the transport of electrons along the respiratory chain; – a decrease in the electrochemical potential difference of hydrogen ions on the inner mitochondrial membrane; – swelling of mitochondria with disruption of the integrity of the outer mitochondrial membrane; – exit from the intermembrane space into the cytoplasm of cytochrome C, which leads to disconnection from the respiratory chain of cytochrome oxidase and to the termination of direct transfer of electrons to oxygen (disconnection of cytochrome oxidase from the respiratory chain is an elegant evolutionary device that excludes the possibility of senseless and therefore harmful “eating” oxygen that is already deficient under conditions of hypoxia); – activation of the reverse transfer of electrons (against the redox potential of the electron carriers of the respiratory chain) entering the respiratory chain from dehydrogenases of the second conjugation point; – increasing the concentration of the reaction product of one-electron reduction of Coenzyme Q; – chemical reaction of oxygen with the Coenzyme Q radical, leading to an increase in the concentration of free oxygen radicals.

1.2. The main results of the impact of free oxygen radicals generated by dying mitochondria. The most important result of the action of free oxygen radicals is the chemical modification of mitochondrial DNA, which is surrounded on all sides by outgrowths of the inner membrane (cristae), in which the enzymes of the respiratory chain are localized. The number of DNA copies in mitochondria reaches 10, and the number of mitochondrial DNA copies per cell is several tens of thousands due to the large number of mitochondria in it.

The main function of free oxygen radicals generated by the respiratory chain of mitochondria of cells that have entered apoptosis, which is positive for the body, is the covalent modification of mitochondrial DNA and mitochondrial enzymes of its duplication. The meaning of these processes is the inactivation or neutralization of mitochondrial DNA, which is in origin and structure (without introns and without histones) bacterial DNA, capable of integrating into cellular DNA and thereby facilitating cell transformation [20].

This does not mean that the appearance of free oxygen radicals (like many other, especially chemically active metabolites) in the wrong place and/or in unusually high concentrations exceeding the capabilities of antioxidant protection does not harm the cell and the body as a whole. This situation, apparently, is realized under conditions of intense radiation exposure.

The function of free oxygen radicals generated by NADPH oxidase of the plasma membrane of immunocompetent cells is also similar, the activity of which increases when they interact with bacteria and viruses. The meaning of the generation of free oxygen radicals, and in this case, lies in the covalent modification of foreign DNA. To destroy a bacterium or cell means, first of all, to damage its DNA.

The pathogenic function of an excess of antioxidants consumed by humans is to reduce the rate of mitochondrial DNA detoxification by free oxygen radicals, which, apparently, leads to an increase in the likelihood of oncological diseases [10].

1.3. Safety of free oxygen radicals generated by the mitochondria of a dying cell for neighboring cells. Due to the high chemical reactivity of free oxygen radicals and due to the small distances of their free path, neighboring cells with intact mitochondria are probably not susceptible to the pathogenic effects of these radicals.

First, in order to leave the mitochondria of a dying cell and get into a neighboring healthy cell, free radicals need to overcome many membranes with built-in densely packed proteins that contain a large number of potential targets for free radicals (unsaturated bonds in lipids and proteins; strong and numerous reducing agents in the form of natural antioxidants – vitamins, glutathione and thiol groups of proteins; as well as enzymes – catalase, peroxidase and superoxide dismutase, which neutralize radicals.

Secondly, even single free radicals that have reached the mitochondria of a neighboring healthy cell are able to engage in the normal functioning of their respiratory chains due to a chemical reaction with Coenzyme Q, a 50-fold excess of which in relation to other electron carriers (cytochromes, ferredoxins and dehydrogenases) is present in the inner membrane of mitochondria and diffuses freely in the membrane.

2. Activation of the disordered process of cell death – necrosis under conditions of deep or prolonged hypoxia, harmful to the surrounding tissues and to the organism as a whole. Disruption of apoptosis into necrosis is caused by a deficiency of oxygen and, consequently, a deficiency of free energy in the form of ATP and NAD(P)H, which are necessary to bring the energy-dependent process – apoptosis to the logical end.

3. Inflammation and autoimmune diseases. One of the last substrates inaccessible to proteases involved in apoptosis are transmembrane proteins of the plasma membrane. These proteins are present in apoptotic bodies, the end products of apoptosis, which are successfully captured by cells and digested by lysosomal enzymes of cells of the immune system. Interruption of this sequence of events under hypoxic conditions leads to the appearance of transmembrane proteins in the blood and to inflammation. The production of antibodies simultaneously against the external and intracellular epitopes of such proteins is likely to lead to autoimmune diseases accompanied by inflammation.

Some of these proteins may play the role of anchoring, that is, devices for mechanically fixing the contacts of a neuron and its extended processes with neighboring cells that have similar proteins in their membranes, the external water-soluble fragments of which form strong isological dimers with similar fragments of proteins of neighboring cells. After the death of a neuron and the triggering of a specific protease that cleaves off the outer fragments of these proteins, the latter form a densely packed and poorly metabolized conglomerate – beta-amyloid, which accumulates in the tissues of an aging organism.

The transmembrane precursor protein of beta amyloid could play the role of anchor fasteners only if its intracellular part was associated with the polymeric proteins of the cytoskeleton. A candidate for such a polymeric microtubule-forming protein is tubulin. Simultaneously with the appearance of extracellular deposits of amyloid beta during degeneration of neurons and their processes, intracellular deposition of aggregates of tau protein associated with microtubules is recorded. The simultaneous appearance of intracellular and extracellular protein aggregates during neuronal degeneration may be the result of the degradation of a single system that fixes extended nerve processes as they pass through tissues.

4. Selective and reversible inhibition of the metabolism of a number of body cells under hypoxic conditions – mechanisms of oxygen saving (AMP-dependent protein kinase; ATP-dependent potassium channels; reversible inhibition of mitochondrial respiration by * NO radical, with the formation of nitrosylated hemes of cytochromes of the respiratory chain, not conducted by apoptosis). More on this in the second part of the review.

5. Cell poisoning due to a decrease in the activity of energy-dependent reactions for their detoxification and detoxification of the body as a whole: – a decrease in the activity of cytochrome P450 (NADPH-dependent), which carries out oxidative hydroxylation of xenobiotics – a reaction that stands at the beginning of numerous pathways of cell detoxification; – a decrease in the activity of the cell membrane glycoprotein Gp170 – ATP hydrolase, which energy-dependently removes organic pathogens of small molecular weight from the cell; – a decrease in the detoxification function of mitochondria, due to their death, due to the concentration in the mitochondria of a number of organs (liver), toxic metabolites and xenobiotics due to the energy of the difference in the electrochemical potential of the hydrogen ion on the inner mitochondrial membrane, followed by the fusion of mitochondria with lysosomes in the process of autophagy. Mitochondria, which occupy up to 30 % of the cell volume, are the most powerful detoxification systems that cleanse the cytoplasm from a large list of pathogenic factors of chemical and biological nature, thereby preventing chemical modification of various cytoplasmic enzymes by xenobiotics, thereby reducing the likelihood of metabolic chaos.

6. A decrease in the phosphate potential of cells under hypoxic conditions leads to qualitative and quantitative changes in the activity of hormonal systems of cascade regulation of metabolism, built on nucleotides and their derivatives (ATP, GTP, AMP, cyclo AMP, cyclo-GMP), as well as on regulatory enzymes: adenylate cyclases, guanylate cyclases and ATP-dependent protein kinases.

7. Qualitative changes in the systems of nervous regulation of metabolism: – decrease in the value of the potential of the cell membrane, leads to the problem of generation and propagation of the action potential; – a decrease in the ratio of guanine nucleotides (GTP / GDP) leads to significant problems in the synaptic transmission of a nerve impulse with the participation of G-proteins, which energetically remove a strongly bound neurotransmitter from the receptor due to the energy of GTP hydrolysis, thereby turning off the signal (solving the problem of the ratio selectivity and efficiency in the mechanism of synaptic signal transmission).

All of the above indicates hypoxia as a leading pathogenic factor in the disease of aging.

1.2. The Pathogenesis of Aging

This section discusses the sequence of events connected by a network of cause-and-effect relationships and representing the pathogenesis of the disease of aging: – hypoxia; – decrease in the rate of formation of free energy carriers (ATP and NAD(P)H); – degeneration of sensitive nerve endings of the ANS; – irreversible activation of the efferent part of the arc of the unconditioned reflex; – depletion and degeneration of the efferent part of the arc of the unconditioned reflex; – switching the regulation of cellular metabolism and adaptation from the ANS to a less efficient and slow-acting endocrine system; – loss of differentiated properties by the cells of the denervated periphery and the acquisition of the properties of undifferentiated cells – the ability to proliferate and migrate.

In local areas of organs, tissues or blood vessels, the listed stages of pathogenesis are at different stages of development, and therefore, in each organ or tissue, all stages of the pathogenesis of aging are simultaneously implemented. The main pathological consequences of each of the listed stages of pathogenesis and their manifestations in proliferative-degenerative diseases of senile age are considered.

Hypoxia initiates two independent primary structural events.

1) Death of free living cells by apoptosis or necrosis (see above). 2) Degeneration and slowing down of regeneration of afferent nerve fibers of the autonomic nervous system (ANS).

The sympathetic division of the ANS is responsible for stimulating the metabolism of activity (catabolism) associated with the fight-or-flight response. The parasympathetic division of the ANS is responsible for stimulating resting metabolism (anabolism): “rest and digestion” and “feeding and reproduction”.

Afferent fibers are not divided into sympathetic and parasympathetic.

Metabolism at rest is less intense than in a state of physical activity, since the main consumer of free energy is skeletal muscles that are inactive at rest.

The state of activity is characterized by sharp ups and downs of metabolic activity, in contrast to the slow monotonic changes in metabolism in a state of rest. It is in connection with these differences that the degeneration of afferent fibers in the first place negatively affects the efficiency of the functioning of the sympathetic rather than the parasympathetic division of the ANS.

The weak link in autonomic regulation is the afferent, sensitive nerve fibers, each of which departs from a small group of cells or from single specialized receptors (bodies). A decrease, for one reason or another, in the number of cells in such a group or in a specialized receptor innervated by a separate axon leads to an increasingly rare use of the nerve fiber and, as a result, to its degeneration.

The most common cause of degeneration of afferent nerve fibers, apparently, is the death of nerve endings under conditions of deep and/or prolonged hypoxia. Nerve endings are the most distant from the neuron body and oxygen deficiency, leading to a deficiency of free energy, should primarily affect the delivery of nutrients and “building materials” necessary to maintain the integrity of nerve endings and for their regeneration, namely in the nerve endings.

Such degeneration of nerve endings belongs to the physiological category, in contrast to pathological degeneration caused by a violation of the integrity of nerve fibers as a result of injury or inflammation.

Afferent nerve fibers carry out negative feedback in the arc of an unconditioned reflex, turning off the activating effect of efferent fibers on innervated cells.

Due to the presence of a second, nonspecific afferent system of the ANS, the afferent innervation performs not only the passive function of switching off (inhibition) of the efferent part of the unconditioned reflex arc, but also an active function – inhibition of the central structures of the ANS. This function is provided by pacemakers in each small group of cells from which a single nerve fiber originates. Apparently, most of the time, it is the afferent fibers of the ANS that function, supporting with their signaling through the second, nonspecific afferent system, the inhibited state of the cells of the nuclei of the brain stem (including the hypothalamus).

In addition to the specific afferent system, there is a second or nonspecific afferent system. Information from peripheral sensory nerve endings, represented by many types of receptors (baroreceptors, mechanoreceptors, chemoreceptors, thermoreceptors) in this system is depersonalized, coming through collateral connections to the same neurons.

All nerve signals sent to the central nervous system along the sensory pathways of the nonspecific afferent system enter the reticular formation, which takes part in the activation of the cerebral cortex and in the control of the spinal cord. Signals from the periphery keep the reticular formation in a retarded state.

Signals entering the reticular formation from the cerebral cortex, for example, during stress or upon awakening, activate the reticular formation, thereby providing an integral response of the body to stress or to the initiation of wakefulness.

The nonspecific afferent nervous system of the ANS is an important part of the system of regulation of adaptation metabolism, which makes it possible to increase its rate tenfold.

The property of the most vulnerable link of autonomic innervation, afferent nerve fibers “owe” to several features.

1) The peripheral part of the afferent system of innervation is a “servant of two states” – the sympathetic and parasympathetic divisions of the ANS, working alternately, and the “master” of the central division of the ANS, participating in the regulation of its work through the second nonspecific afferent system. Afferent connections of the ANS function around the clock, which leads to their primary depletion and degeneration.

One of the most probable mechanisms for the depletion and death of afferent axons is the competition of two energy-consuming processes for a secondary energy source – a gradient of sodium cations on the plasma membrane. One of these processes is represented by the transmission of nerve impulses along an extended axon, and the other is the work of Na+-dependent glucose transport into a large volume of the cytoplasm. This is a system with mutual exhaustion, in which each of the processes slows down the other.

2) The presence of unique pseudo-unipolar neurons, when the same neuron provides energy-consuming transport of nutrients and mitochondria over long distances in two different directions, connecting the innervated periphery with neurons of the brain stem or with neurons of the spinal cord.

3) A large network of collaterals that communicate with the neurons of the second afferent system (additional energy costs).

4) A dense network of extended afferent nerve fibers of the ANS, each of which departs from a small group of cells of internal organs or blood vessels (high energy consumption for the operation of the network).

5) A decrease, for one reason or another, in the number of cells in such a small group, connected by electrotonic contacts and innervated by a separate axon, leads to an increasingly rare use of the nerve fiber and, as a result, to its degeneration.

As for the efferent part of the arc of the unconditioned reflex, it is devoid of this “disadvantage”, since its functioning is based on a huge number of neurons and neural networks of the central division of the ANS.

The efferent part of the arc of the unconditioned reflex of the sympathetic division of the ANS also has vulnerable links that contribute to its age-related degeneration.

1) The ganglia of the sympathetic part of the ANS, in which the neurons of the efferent part of the arc of the unconditioned reflex are localized, are supplied with blood (oxygen and nutrients) on a common basis with other cells of the body. while the neurons of the afferent part of the arc, located in the nerve nodes of the spinal cord and the brain stem, are supplied with oxygen and nutrients in priority, like the neurons of the central nervous system.

2) Degeneration of the afferent part of the arc of the unconditioned reflex, which provides negative feedback between the periphery and the central structures of the ANS located in the parts of the brain stem, leads to irreversible activation of the work of the efferent part of the arc. Long-term non-stop work of neurons of the efferent part of the arc leads to their depletion and death.

However, even before the onset of depletion and subsequent death of neurons in the efferent part of the arc, such irreversible activation of neurons in the sympathetic part of the ANS leads to a number of pathological manifestations. Apparently, it is the long-term functioning of only the efferent part of the autonomic reflex arc, without feedback from the periphery that leads to hyperactivity of the sympathetic nervous system and to the initiation of the development of metabolic syndrome with an increased risk of developing type 2 diabetes, cardiovascular diseases and premature mortality [11].

An obvious additional mechanism for accelerating the pathogenesis of aging at this stage is the wasted oxygen consumption for the excessive and generally not required by the periphery of the activity of the sympathetic nervous system in the absence of a reverse inhibitory afferent connection with the periphery (autocatalytic process). This is one example of the aggravation of hypoxia at one of the stages of the pathogenesis of aging. The second mechanism for the aggravation of hypoxia, initiated by impaired afferent connections, is due to the cessation of the supply of inhibitory signals to the brain stem structures through the neural networks of the second afferent system.