(1) Somatic mutation theory

This theory holds that during the life of an organism, induced (physical factors such as ionizing radiation, X-rays, chemical factors, biological factors, etc.) and spontaneous mutations destroy the genes and chromosomes of the cell, and this mutation accumulates to a certain extent, resulting in a decline in cell function, and after reaching a critical value, the cell dies. Pen @ fun @ pavilion wWw. ｂｉｑUｇE。 The evidence supporting this theory is that X-ray irradiation can accelerate the aging of mice, and the chromosomal aberration rate of short-lived mice is higher than that of long-lived mice, and the chromosomal aberration rate of older people is higher; Some people have studied the frequency and types of spontaneous mutations that occur in transgenic animals during aging, which also provides a certain basis for this theory. However, there are also facts that cannot be explained by this theory, such as whether aging is an increase in damage or a decrease in chromosome repair ability; In addition, modern biology has proved that the mutation rate of genes is 10-6-10-9/cell/locus/generation, and such a low mutation rate will not cause the death of the whole group of cells, and according to this theory, cells should have an abnormally high mutation rate; Senescence is caused by mutations, and transformed cells can continue to grow outside the body, so in this regard, transformed cells should not undergo mutations, which is not the case.

(2) Free radical theory (recognized by the international academic community)

The free radical theory of aging was proposed by Denhamharman in 1956 and argues that the degenerative changes in the aging process are due to the harmful effects of free radicals produced during the normal metabolism of cells. The aging process of an organism is the result of the accumulation of free radicals produced by the body's tissue cells, which can cause DNA damage that can lead to mutations and induce tumor formation. Free radicals are intermediate products of normal metabolism, and their reactivity is very strong, which can oxidize many substances in cells and damage biological membranes. It can also cross-link proteins, nucleic acids and other macromolecules, affecting their normal function. The doctrine of free radicals

The evidence supporting this theory comes mainly from a number of in vivo and in vitro experiments. These include interspecies comparisons, dietary restrictions, measurement of age-related oxidative stress phenomena, antioxidant diets and drug treatments; In vitro experiments mainly include the observation of oxygen stress and metabolism in diploid fibroblasts, oxygen stress and multiplication capacity, and the effect of antioxidants on cell lifespan. The idea of this theory can explain some experimental phenomena such as free radical inhibitors and antioxidants can prolong the lifespan of cells and animals. The body's defenses against free radicals weaken with age. Vertebrates have a long life span and a low yield of oxygen radicals in the body. However, the free radical theory has not yet proposed that the free radical oxidation reaction and its products are the direct cause of aging, nor has it explained what factors lead to the decline of free radical scavenging ability in the elderly, why transformed cells can not age, and why germ cells can maintain germline from generation to generation. Moreover, free radicals are secondary products of metabolism and are unlikely to be the primary cause of aging.

(3) The theory of natural cross-linking of biomolecules

The main argument is that macromolecules such as proteins and nucleic acids in the body can be covalently cross-combined to form huge molecules. These huge molecules are difficult to digest and accumulate inside the cell, interfering with the normal function of the cell. This cross-linking reaction can occur on the nuclear DNA or in the extracellular collagen fibers. There is currently some evidence to support the cross-linking theory. The extractability of skin collagen and the digestion of collagenase decreased with age, while its thermal stability and tensile strength increased with age. The number of stripes and the thermal contractility on the tail tendon of rats increased with age, but the solubility decreased with age. These results suggest that the polypeptide chains of collagen are cross-linked and increasing in old age. This theory has similarities with the free radical theory, but it does not explain the fundamental mechanism of aging. The theory of natural cross-linking of biomolecules: This theory points out that organisms are unstable chemical systems and belong to dissipative structures when demonstrating the molecular mechanism of aging in organisms. The various biomolecules in the system have a large number of active groups, and they must interact with each other and undergo chemical reactions, so that the biomolecules are slowly cross-linked to the stability of chemical activity. With the passage of time, the degree of cross-linking increases, the active groups of biomolecules continue to decrease, and the original molecular structure gradually changes, and the accumulation of these changes will cause the gradual aging of biological tissues. On the one hand, these changes in biomolecules or genes will show different activities or even completely altered gene products, and on the other hand, they will also interfere with the recognition and binding of RNA polymerase, thereby affecting the transcriptional activity, showing that the transcriptional activity of genes is gradually lost in an orderly manner, promoting progressive and regular phenotypic changes and even aging and death in cells and tissues. The basic arguments of the theory of natural cross-linking of biomolecules to demonstrate the molecular mechanism of biological aging can be summarized as follows: First, various biomolecules are not static, but occur naturally and progressively over time according to a certain natural pattern. Second, progressive natural cross-linking causes the biomolecules to slowly connect, the intermolecular bond energy continues to increase, and the solubility and swelling ability are gradually reduced and lost, and its phenotypic characteristics are the aging of cells and tissues. Third, progressive natural cross-linking leads to the orderly inactivation of genes, causing cells to grow and differentiate according to specific patterns, so that organisms exhibit a dynamic process of programmed and patterned growth, development, aging, and death. With the increase of age, macromolecules that are important for life have a tendency to increase cross-linking, or cross-linking bonds may be produced between the same molecules or between different molecules, which changes the physical and chemical properties of the molecule and makes it unable to function normally. The cross-linking of extracellular collagen has been described above, and it is assumed that intracellular macromolecules such as nucleic acids and proteins will also be cross-linked, but it has not been confirmed in vivo so far. It is only speculation that cross-linking is a primary factor in aging, but it is a worthy approach to the study of aging.

(4) The immunological theory of aging

The immunological theory of aging can be divided into two views: first, the aging of immune function is the cause of the aging of the body; Second, the theory of autoimmunity, which holds that autoimmunity related to autoantibodies plays a decisive role in the process that leads to aging. Senescence is not a passive process of cell death and shedding, but the most active process of self-destruction. From the immunological theory of aging, it can be seen that the strength of immune function seems to be closely related to the life span of individuals, and so far studies have shown that the body is indeed accompanied by important changes in immune function in the process of aging: 1. The changes in immune function accompanying aging at the individual level are characterized by a decrease in the immune response to exogenous antigens and an increase in the immune response to autoantigens. According to Whittingham, antibody titers decreased significantly in older adults compared to younger adults after immunization with antigens. In addition, the detection rate of autoantibodies increases with aging. Cellular immunity also decreases with age. 2. Organ and tissue level: The thymus gland gradually becomes larger with age after birth, reaching its peak at the age of 13-14, and then begins to atrophy, degenerate, and shrinks significantly after the age of 25. Newborn animals lose their immune function after thymus resection, and young animals gradually decline their immune function after thymus resection, and antibody formation and graft-versus-host response decrease. 3. At the cellular and molecular levels, the function of T cells in elderly animals and humans decreased, and the number also decreased. With age, the body's ability to proliferate mitogenulin A (Cona), phytohemagglutinin (PHA) and anti-CD3 antibodies decreases. This is one of the immunological features of aging. With aging, the secretion of cytokines changes significantly. IL-2 production and the emergence of IL-2 receptors are important in the proliferation of T cells, and the presence of IL-2 receptors, especially high-affinity receptors, is also reduced in the elderly. The autoimmune view suggests that the loss of control of the immune system at any level can lead to overexpression of the autoimmune response, which has led to much evidence of accelerated aging. There is also many contrary evidence that the immune system controls aging. There is a long-lived inbred line, C57BL/6, which has a relatively high proportion of antinuclear antibodies and the content of thymic cytotoxic antibodies, but does not show a high degree of immunopathological damage. Nude mice are a kind of mice with congenital athymic hairless syndrome, whose T-cell immune function is extremely lacking, so that they can accept allografts or even xenografts, and this kind of mouse can cause early death if kept under normal conditions, but its lifespan is not less than that of normal mice under sterile conditions. If the thymus of newborn mice is removed under normal feeding conditions and dies at about 3 months of age, most can live longer if they are placed in a sterile environment. It can be seen that although the immune system can have an impact on survival, it is not the determining factor. Immunology theory says that the immune system is the leader and root cause of aging, but there is no obvious reason for the deterioration of the immune system with age, and the aging changes of the immune system are also manifestations of multiple effects caused by aging, and should be regarded as a part of the overall aging, rather than the initiation of aging.

(5) Telomere theory

The telomere theory, proposed by Olovnikov, holds that cells are unable to completely replicate their chromosomes due to DNA polymerase dysfunction during each division, so the final replicated DNA sequence may be lost, eventually causing cell senescence and death. Telomeres are a complex structure composed of many simple repeats and related proteins at the end of eukaryotic chromosomes, which has the role of maintaining chromosome structural integrity and solving the problem of terminal replication. Telomerase is a reverse transcriptase enzyme composed of RNA and protein, which uses its own RNA as a template to synthesize telomere repeats and add them to the end of the newly synthesized DNA strand. In humans, telomerase is found in most embryonic tissues, germ cells, inflammatory cells, hyperplastic cells of renewed tissues, and tumor cells. Because of this, every time a cell has mitosis, a piece of telomere sequence is lost, and when the telomere length is shortened to a certain extent, the cell will stop dividing, leading to aging and death. A large number of experiments have shown that telomere and telomerase activities are related to cell senescence and immortality. The first direct evidence of telomere shortening in senescent cells comes from the observation of in vitro cultured fibroblasts, through the relationship between telomere length and age and mitotic ability of donor fibroblasts of different ages, it was observed that the length of telomeres gradually shortened with age, and the ability of mitosis gradually weakened. Hastie found that the length of telomere restriction fragments in the colon gradually decreased with the age of the donor, and the average annual loss of repeats was 33 bp. Incomplete chromosomes in plants are repaired in fertilization but not in differentiated tissues, which also confirms the inhibition of telomerase activity in somatic cells in higher eukaryotes. The telomeres of spermatozoa are longer than somatic cells, and somatic cells will gradually age if they lack telomerase activity, while the telomeres of germ cell lines can maintain their length; Transformed cells are able to completely replicate telomeres through telomerase activity in order to gain immortality. Telomere Theory

But many problems cannot be explained by the telomere theory. The length of telomeres of somatic cells is directly proportional to the mitotic ability, which has been confirmed by experiments, and the mitotic ability of different somatic cells is different, the division and proliferation rate of gastrointestinal mucosal cells is relatively fast, and the speed of nerve cell division is relatively slow. A study on the telomere length of corneal endothelial cells from donors of different ages has found that the telomere length of corneal endothelial cells is maintained at a high level for a long time, while telomerase is not expressed. In addition, Kippling found that rats have telomeres that are nearly 5-10 times longer than humans, but their lifespans are much shorter than those of humans. These suggest that somatic telomere length is not consistent with the lifespan of individuals and the life expectancy of different tissues and organs. The telomerase activity of germ cells is maintained at a high level for a long time, but it does not divide and multiply indefinitely like tumors. Telomere length is controlled by telomerase, so what factors control telomerase? Telomerase activity is higher within germ cells, why is there no higher telomerase activity in somatic cells. It appears that whether the shortening of telomere length is a cause or a consequence of aging needs further research.

(6) Mitochondrial theory

Wallace (1999) proposed that mutations in mitochondrial DNA (mtDNA) accumulate with age, which is also an important factor in cellular senescence. Since then, there has been a lot of literature that reflects this. It has been found that the increase in cell age is positively correlated with cytochrome C oxidase (COX), a protein directly related to cellular respiration, which is caused by MTDNA mutations, which have been reported in human muscle cells, brain cells, intestinal cells, etc. If the MTDNA mutation in the cell reaches a high level, it can hinder the production of ATP and the supply of bioenergy to the cell.

(7) AlteredProteins Theory and Waste Accumulation Theory

The metabolism of proteins is essential during life. In order to protect the normal function of the cell, it is obvious that the new protein will remove damaged or excess protein at the same time. Many medical studies have found that the ability to metabolize proteins declines with age, including a range of geriatric diseases such as cataracts, Alzheimer's disease, and Parkinson's disease. In 2002, Carrard et al. published evidence that "the activity of proteases and proteins decreases with age". Later, in 2003, SOTI and Csermely also discovered the relationship between chaperone protein and aging, that is, chaperone protein activity decreases because the body enters aging, or conversely, because chaperone protein activity decreases, so the human body enters aging. Terman and Brunk then went on to argue that they are only part of the waste of cells, and that a broader perspective should be on the "garbage disposal" process of cells.

(8) WorktheoriesOfAging

Through the above theories, we can already see that there are multiple complex mechanisms of cellular senescence. In practice, most research still focuses on a single mechanism. This obviously limits the observation of the aging process. Therefore, Kirkwood et al. proposed the aging network theory, which believes that a variety of life mechanisms and cytopathies jointly cause aging, and there is a synergistic effect between them, and the network theory focuses on the role between them. For example, mtDNA mutations accumulate with age, resulting in a gradual decrease in ATP content and an increase in reactive oxygen species (ROS). This also leads to the depletion of intracellular protein stress and the accumulation of waste materials. These depletions can be diluted by mitotic in proliferating histiocytes, but active DNA replication also increases the frequency of somatic mutations and telomere erosion.

The advantage of this network observation approach is that it can cover a variety of mechanisms of cellular senescence, and it can also be applied to differences between different species, or specific types of molecular damage.

Aging is to avoid cancer?

While all of these theories explain that senescence is the result of damage inside and outside the cell, they do not get around another problem, which is self-apoptosis, or autophagy. Unlike cell necrosis, cells in tissues are generally able to be induced by biological signals to actively enter the apoptosis program. In fact, the level of apoptosis also increases in the cells of old organs, why is that?

Many studies suggest that they are also due to the accumulation of longer-term cell damage. But the more likely explanation is that apoptosis reflects a protective mechanism. This important question relates to the cellular response to injury. In some cases, particularly stem cells from proliferative tissues, such as bone marrow and intestinal epithelial cells, damaged cells pose a significant tumor threat. This is probably why such cells tend to respond to DNA damage by initiating apoptosis. If interpreted in this way, aging can be seen as a protective mechanism against cancer, rather than aging causing cancer. The causal arrows in it will be reversed.

Life makes a trade-off between aging and cancer, which manifests itself as a balance between deleting and maintaining damaged cells. In this regard, Tyner et al. published a study in 2002 using p53 mutant mice. Mice with this genetic mutation were greatly reduced in cancer incidence. But at the same time, they also show faster aging, including the acceleration of aging of various tissue cells such as liver, kidney, spleen, ****, etc., as well as the decline of phenotypes such as skin thickness, hair growth rate, and wound healing speed.

(To be continued.) )