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