Old and new theories of aging
Before proceeding directly to the presentation of various theories of aging, it is necessary to define the term "aging". There are many definitions of this concept. The most successful of them is the following: "Aging is a process of continuous destruction inherent in all objects of living and inanimate nature." The existence and maintenance of the vital activity of living organisms is possible due to the continuous flow of energy, as well as the constant reproduction of genetic information and structures in the process of cell division.
At the moment, there are several dozen theories of aging. Many of them are already only of historical interest, while the rest, reflecting a number of essential aspects of the process, can be put into a logical scheme of a more universal general mechanism of aging. One thing is common to all hypotheses – the aging of the body begins immediately after the division of the fertilized egg begins. Let's look at some of them.
Energy theory of agingThis theory belongs to one of the very first theories of aging.
It was proposed by N. Rubner in 1908, who was the first to draw attention to the fact that large mammals live longer than small ones. For example, a mouse lives 3.5 years, a dog – 20 years, a horse – 46 years, an elephant – 70 years. Being the most primitive, the energy theory considers aging as a simple deterioration of cells and tissues. This conclusion is made from the fact that there is allegedly an inverse relationship between the intensity of metabolism, energy and life expectancy.
According to N. Rubner, for 1 g of body weight of all animals there is a constant amount of energy (200 kcal / g), which can be consumed in a lifetime. Having exhausted this amount of energy, the animal dies. N. Rubner mistakenly believed that the intensity of metabolism and total oxygen consumption are determined by the conditions of thermal balance and depend on the size and surface of the body. The mass increases in proportion to the linear dimensions taken in a cube and the area taken in a square. For example, a dog needs less energy to maintain a stable body temperature than a similar number of mice taken by weight. Mice will have a much larger total surface area than a dog. Consequently, a dog has a lower metabolic rate than a mouse, and a small body weight and a high metabolism cause an extremely short life.
An interesting fact is that the life span of birds, as well as in mammals, increases with increasing size. But compared to mammals, birds of the same size live 2 times longer. This happens because birds have a much more intense basic metabolism.
A person has a much larger energy fund (approximately 4 times). Hence, it was concluded that in order to prolong his life, a person should show as little activity as possible. This was a gross mistake from the point of view of modern gerontology. On the contrary, an active lifestyle not only does not shorten, but prolongs life expectancy.
Neuroendocrine and immune hypothesesThe main regulator of human vital activity is the neuroendocrine system.
Because of this, gerontologists have tried to put forward a theory that could link the main mechanisms of aging with primary disorders in the neuroendocrine system, leading to the development of secondary changes in tissues.
The earliest theories include hypotheses that consider the aging process as a result of dysfunction of a particular gland - the pituitary, thyroid or other, especially sexual, glands. Then there were theories explaining aging as a violation of the function of the entire neuroendocrine system of the body.
Theories that link aging with primary changes in hypothalamic structures are very popular. This is explained by the fact that the hypothalamus is a generator of biological rhythms of the body, which are the main link in the regulation of the function of the endocrine glands. This regulation is implemented through the central endocrine gland – the pituitary gland.
in1968, K. Dilman put forward the theory of the existence of a "hypothalamic clock". He believed that the aging process develops due to a violation of the body's homeostasis, which is the result of an increase in the activity of the hypothalamus. In the body of an elderly person, the production of hypothalamic hormones (liberins) and a number of pituitary hormones (gonadotropins, somatotropin), as well as insulin, increases significantly. It should be noted that along with this dysfunction of the endocrine system, some structures of the hypothalamus decrease their activity, there are pronounced violations of the vital activity of the body.
Molecular genetic theory of agingMolecular genetic theory is one of the most recognized in modern gerontology.
This hypothesis sees the cause of aging in the primary changes in the genetic apparatus of the cell.
Molecular genetic theories are divided into two large groups. Some scientists consider age-related changes in the genetic apparatus of cells as inherently programmed. Other scientists believe that such changes occur by chance. It follows from this that the aging process can be either a hereditary, natural result of growth and maturation, or a consequence of the accumulation of random errors in the system of storage and transmission of genetic information.
The ancestor of the first group of molecular genetic theories is A. Weisman, who hypothesized the separation of functions between somatic and sexual carriers of genetic material. By A. According to Weisman, natural aging is absent in unicellular organisms.
The evolutionary contradiction between the need to differentiate cells and ensuring their immortality by unlimited division led to the need to divide cells into somatic, which were allowed to differentiate and age, and immortal germ, or sexual. In essence, somatic cells are created to ensure the vital activity of germ cells, ensuring the preservation and transfer of genetic material in the population. When performing the function of reproduction, the individual becomes useless to the population.
Also, according to Weisman, as a result of natural selection, species with the best ratio between fertility and life expectancy enjoyed an advantage. Hence, it was concluded that the greatest life expectancy is genetically determined in the form of the number of generations of somatic cells of a multicellular organism.
A number of scientific studies have been conducted to confirm the molecular genetic theory. For example, experiments were performed to detect the relationship between the restriction of nutrition at a young age and the growth rate of animals. With the restriction of nutrition in animals, growth slows down and puberty is delayed, and therefore aging occurs. This happens because the body takes longer to reach its final size, i.e. aging, like other stages of ontogenesis, is controlled by genes.
A follower of A. Weisman's theory was L. Heiflick, who established that normal human somatic cells have a limited mitotic potential and a certain life expectancy. For the experiment, connective tissue cells – fibroblasts - were taken from the body, which were then placed in a nutrient medium. The result of this was the identification of the Hayflick number – a strictly limited number of divisions, after which the culture died. Some authors claim that in fibroblast cultures obtained from young animals, the number of divisions exceeds the number of divisions in the cell culture of old animals.
Later, a molecular mechanism was discovered that limits the number of fibroblast divisions in culture. It turned out that in aging cultures, the activity of the telomerase enzyme decreases, which ensures the preservation of DNA properties in successive generations of cells. When embedding the gene of this enzyme, the number of divisions of cultured fibroblasts increased.
In the course of research, genes have been found that affect the lifespan of yeast, nematode worm, drosophila. All these studies laid the foundation for the development of rejuvenation methods by modeling the "worn out" sections of genes.
It seemed that the molecular genetic theory had been confirmed. But there are certain features here. For example, in the fibroblasts used in the experiment, some properties were absent altogether, but others, on the contrary, worsened. If any other cells were added to the fibroblast culture, the number of their divisions either increased or decreased.
Fibroblasts also acquired the ability to transform into other types of cells, the lifespan of which does not depend on the number of divisions.
Therefore, many leading gerontologists are very skeptical about the prospect of solving it by replacing "bad" genes with "good" ones. According to some data, the influence of hereditary factors on the average life expectancy does not exceed 25%.
The molecular-genetic hypotheses also include the gene-regulatory theory. This theory of aging was put forward by V. Wright together with his collaborators. Its essence is the idea of aging as changes occurring in regulatory genes. These genes are the most active and least protected DNA structures capable of determining the rate and sequence of switching on and off of structural genes. Due to the violation of the rate and sequence of inclusion of structural genes, age-related changes occur in the structure and function of cells.
No direct evidence of the genoregulatory theory has been revealed. But modern research has shown that as the body ages, some areas in the DNA shrink in size.
Also, this type of theory includes the hypothesis of "aging by mistake", which was put forward in1954 by physicist M. Szilard. The scientist conducted scientific research on the effects of radiation on living organisms and proved that the effect of ionizing radiation significantly reduces the life span of humans and animals. Under the influence of radiation, numerous mutations occur in the DNA molecule and some symptoms of aging, such as gray hair or cancerous tumors, are initiated. As a result of his observations, M. Szilard concluded that mutations are the direct cause of aging of living organisms. However, he did not explain the fact of aging in humans and animals that were not exposed to radiation.
His follower L. Orgel believed that the main cause of aging of the body is the accumulation of genetic damage as a result of mutations with age. Mutations in the genetic apparatus of a cell can occur for two reasons. They can be either spontaneous or arise in response to the effects of aggressive factors, such as ionizing radiation, ultraviolet rays, viruses, accumulation of toxic products in the body, etc. As a result of such mutations, genes lose the ability to adequately regulate their activity due to the accumulation of DNA and RNA damage.
Along with this, a special repair system functions in each cell to ensure the stability of the DNA structure and constants in the system of transmission of genetic information. In laboratory experiments on some animal species, the relationship between the activity of DNA repair systems and the life span has been proven.
Over time, the DNA repair system wears out, resulting in aging of the body. The proof of this is the cases of premature aging and pronounced shortening of life expectancy.
Such cases include hereditary diseases in which the repair process is disrupted, such as progeria, Turner syndrome, some forms of Down's disease, etc.
Supporters of this theory include Hayflick, who said that "the loss of accurate or reliable (controlling) information is due to the accumulation of accidental influences that damage vital DNA, RNA and protein molecules. When the threshold value of such "lesions", "damages", "errors" or "errors" is reached, normal biological processes stop, age-related changes become obvious. The true nature of the damage inflicted on vital molecules is still unknown, but the very fact of its manifestation is known."
Free radical theory of agingAmong all the theories of aging, the theory of free radicals, proposed by the American scientist D. Harman in the mid-1950s, is the most generally accepted.
Constantly expanding the scope of its application, the free radical theory of aging includes many of the previously put forward hypotheses and theories of aging. The free radical theory belongs to the group of theories of aging as a result of body wear.
In order to consider this hypothesis, it should be remembered that DNA and RNA are unstable, long chains that consist of thousands of molecules. These chains can break up into links very easily. They are constantly attacked by other molecules, which are either banal products of cellular metabolism, or substances that pollute the environment (lead). As a result, new molecules are synthesized all the time inside the cell in the process of metabolism, which replace the damaged ones.
A large group of attacking molecules are free radicals, which have a pronounced ability to combine with other molecules. Cells from time to time, especially when ionizing radiation acts on the body, independently synthesize free radicals.
Free radicals are atoms or molecules that have an unpaired electron in an outer orbit. These include a variety of "reactive oxygen species" – ROS (superoxide-anion radical, decomposition products of hydrogen peroxide and reactions involving it, nitrogen oxides, etc.). The processes associated with the action of ROS are called oxidative stress, since highly active free radicals can attack and damage any cells.
The formation of free radicals occurs during reactions that consume oxygen to "burn" carbohydrates and proceed with the release of a large amount of energy. Also, free radicals occur randomly, at a time when oxygen, always present in the cell, combines with the cell molecules. It should be noted that in the course of vital activity, toxic metabolic products tend to accumulate in oxygen. Also, oxygen is very often exposed to harmful exogenous factors.
In addition, free radicals are able to activate special molecules inside cells – copying factors.
The copy factor is an absolutely harmless molecule until it is aggressively exposed to free radicals, which contribute to its migration to the center of the cell – the nucleus. Once in the nucleus, the copying factors are embedded in the DNA, after which it begins to synthesize toxic substances. There is a copy factor NFk-B, which has inflammatory properties.
In young organisms, there is a special neutralizing mechanism that eliminates damage – an enzymatic system of antioxidant protection, which wears out over time. The accumulation of damage in cells and the rate of aging depend on the ratio of the formation of reactive oxygen species and the function of this system.
In 1969, E. Cord and M. Fridovich discovered a special enzyme – superoxide dismutase, after which Harman's hypothesis received a new impetus for its development. The activity of this enzyme in human granulocytes, platelets, erythrocytes and lymphocytes is associated with the ability of these cells to form free radicals. This made it possible to trace the relationship of the presence of these aggressive factors with the lifetime of cells in the blood, which varies from 12 hours to several years. Thanks to this discovery, convincing evidence was formulated for the formation of free oxygen forms in living cells, and the function of a complex, multilevel system of antioxidant protection was explained.
In laboratory conditions, it was found that the highest activity of superoxide dismutase is observed in platelets, which often synthesize free radicals. This dramatically reduces their life expectancy. Erythrocytes are also characterized by high levels of superoxide dismutase. But these cells rarely synthesize superoxide radicals. Their life span is longer than that of platelets, but not very high. Lymphocytes never generate free radicals and have a fairly low level of superoxide dismutase. Therefore, their life span is the longest.
One of the variations of the free radical theory is the hypothesis of aging as a result of glycosylation. The complex of glycosylation reactions – the Mayard reaction – is triggered after the appearance of glucose compounds with amino groups of amino acids, peptides, proteins, and nucleic acids. The products formed as a result of the reaction are capable of damaging proteins or nucleic acids. As a result, defective molecules settle on the walls of blood vessels, the bodies of nerve cells. Confirmation of this theory is that with the development of complications of diabetes mellitus, signs similar to changes in the body appear in elderly people. Similar symptoms occur due to the faster synthesis of toxic products of the glycosylation reaction.
Scientists have also revealed that the content of specific products of the Mayard reaction in the human body is closely interrelated with its biological age, which often varies greatly in people of the same calendar age.
It should be noted that studies have been conducted that have been able to prove the ability of some products of the glycosylation reaction to synthesize reactive oxygen species. Hence, it should be concluded that the formation of free radicals and glycosylation are links of a single more complex biochemical reaction, as well as the fact that many diseases associated with the aging process, such as atherosclerosis, renal failure, neurodegenerative diseases, are associated with the reaction of glycosylation and the formation of free radicals.
One of the ways to combat aging, in which free radicals are to blame, is the use of so–called antioxidants.
American Comfort scientists conducted a number of scientific experiments, as a result of which it turned out that the antioxidant ethoxychine contributes to an increase in the lifespan of mice by about 25%.
In 1973, researcher Richard Hochschild injected mice with the drug centrophenoxin. Centrophenoxin is used in some European countries and all over the world (except the USA) to eliminate signs of disorders of the central nervous system. In addition, it has been used for a long time to treat patients with neurodegenerative diseases. It follows from this that it is non-toxic to humans. During the experiment, it was found that the life expectancy of rats increases by 10%. Also, R. Hochschild administered the drug to old mice and showed that it increases the duration of the remaining life of experimental animals by 11%.
Researcher D. Harman conducted experiments proving the dependence of life expectancy on the characteristics of the diet. The scientist believed that unsaturated lipids, in excess contained in oils and vegetable products, take an active part in free radical reactions, thereby contributing to accelerated aging. During the experiment, Harman increased the percentage of unsaturated lipids in the food of mice. The result of this is a reduction in the life span of rodents.
D. Harman believed that due to some dietary supplements, namely by reducing unsaturated fats in the total amount of calories from 20 to 1%, as well as the use of a proper diet, there is the possibility of "prospects for extending the life span over 85 years, as well as the possibility for a significant number of people to live much longer than 100 years."
On the contrary, the enrichment of the diet with vitamin E, which is a protection against free radicals, prevents the aging of the body. The study of the effect of vitamin E on life expectancy was conducted by A. Tappel, who said: "Aging is caused by the process of oxidation, and since vitamin E belongs to the number of natural antioxidants, it can be used to counteract this process in the body." A. Tappel's research has shown that the insufficient content of this vitamin in the feed of rats and mice reduces the life span of these animals by an order of magnitude. But life expectancy, according to Tappel, is also affected by the content of vitamin C in food.
This vitamin is a synergist of vitamin E and promotes more effective removal of free radicals.
Portal "Eternal youth" www.vechnayamolodost.ru29.08.2007