Unified theory of human and animals aging. Bioenergy concept aging as a disease. Алексей Фёдорович Фитин
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For example, hypoxia of cell culture of cytotoxic T lymphocytes leads to an increase in the number of more than 7600 proteins [8]. Considering the huge variety of cells involved in the response to hypoxia, a large amount of the body's energy expenditures for adaptation to hypoxia should be assumed.
In my opinion, it is hypoxia that is the most common cause of changes in cell enzymatic patterns. A feature of hypoxia as a leading pathogenic factor is the high frequency of its manifestation in certain local volumes of organs and tissues. With age, the frequency of episodes of local hypoxia, their duration and depth increase, and, therefore, the expenditure of free energy both for adaptation and for exiting the adapted state and return to normoxia, also accompanied by a change in enzymatic patterns, increases.
The constant implementation of such cycles, initiated by episodes of local or general hypoxia, makes the adaptation process the most energy-consuming process that accelerates aging.
Such operational adaptation of the organism to changes in its internal environment occurs not only at the intracellular level, but also at the level of changes in the ratio of cells, one or another specialization. When it is necessary to survive, the body “puts under the knife” even the cells and tissues that are important for it, using them as a full-fledged, operative endogenous nutrition, completely restoring them in conditions of rest, sleep or anabiosis. Thus, deficient oxygen and free energy are also spent on changes in the cellular composition of the body in the process of adaptation.
In this brief review, I will not consider the expenditure of energy for the work of adaptive mechanisms for the consumption of deficient oxygen at the physiological level, which consists in the redistribution of blood between organs and tissues.
In general terms, adaptation is a positive phenomenon, without which life is impossible. But, adaptation is an energy-consuming process. The pathogenic nature of the operational adaptation constantly going on in the body in the cycle: is due to the large additional costs of energy and, accordingly, oxygen, thereby aggravating hypoxia.
Unlike the operational adaptation to hypoxia that is constantly going on in the body, long-term adaptation to oxygen deficiency, especially from the very beginning of ontogenesis, has an absolutely positive character, which manifests itself in longevity. In the second part of the review, two examples of longevity due to constant hypoxia are considered – the example of the naked mole rat and the example of mountain dwellers.
One of the first results of the constantly occurring adaptive reactions of the body are structural changes accumulating with age in cells, tissues and organs. Signs of aging begin to appear on the connective tissue formations.The system for maintaining homeostasis prevents the accumulation of changes in actively functioning components of cells, and therefore such pathological changes occur and accumulate over time in changes in structural components that are less susceptible to the influence of homeostatic mechanisms. We are talking about changing the content of each of these components or about changing their localization both inside and outside the cells.
I will list a number of examples of structural age-related changes: – replacement of noble cellular elements with connective tissue (according to I. I. Mechnikov); – additional age-dependent collagen deposits around most cells in compactly organized tissues and in the basement membranes of organs; – connective tissue cords in tissues, which are the remnants of remnants of small blood vessels, without endothelial cells and without SMC media of vessels; – deposition of lipofuscin and tau protein inside neurons; – deposition of beta-amyloid in the intercellular space; – pathological slowly metabolized fatty deposits on the organs of the chest and abdominal cavities; – «sliding» of fatty deposits in the lower part of the facial part of the skull under the influence of gravity; deposits of kidney stones and gallbladder; deposition of arteriosclerotic plaques on the walls of blood vessels.
Cells of actively functioning tissues can maintain homeostasis, including due to the surrounding connective tissues, dumping metabolic waste and excess metabolites into them (for example, lactate from cells living on glycolysis). The formation of blood clots in the capillaries of the circulatory system is also a possible result of such local discharge. Structural changes can be accompanied by the loss of components, a striking example of which is osteoporosis, accompanied by the loss of the mineral component of bone tissue, mainly due to its rare use.
Thus, senile changes, which we judge about aging, are manifested primarily at the level of structural (morphological and anatomical) changes: – changes in the skeleton; changes in the connective tissue basis of organs; – an increase in the number of elements of extracellular connective tissue and its subsequent ossification. Ultimately, all slowly metabolized waste of cell life first enters the extracellular fluid and then into the blood before being excreted in the urine.
Structural pathological changes in cells, tissues and organs act as secondary pathogenic factors, entailing malfunctions of functional elements.
The second category of free energy expenditures includes the costs of operating security systems and overcoming metabolic chaos in the form of diseases, which I wrote about above. The more energy is spent on the operation of security systems and on overcoming metabolic chaos, the less it remains for vital functions and the lower the average life expectancy. One of the results of metabolic chaos, manifested in the form of inflammation that accompanies many diseases, is an increase in body temperature, indicating a decrease in the efficiency of bioenergetic mechanisms.
Spending funds (energy) on conditioning the environment, that is, removing from habitat pathogenic microorganisms, toxic substances and reducing the levels of negative physical (radiation) and mental influences, humanity thereby provides the economy of free energy by organisms, which they spend on combating various pathogenic factors and metabolic chaos, thereby reducing the rate of pathological aging and increasing life expectancy.
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