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,
