(I) Somatic mutation theory

The theory believes that in the life of an organism, induce (physical factors such as ionizing radiation, x-rays, chemical factors and biological factors) and spontaneous mutations destroy the genes and chromosomes of cells. This mutation accumulates to a certain extent and causes the cell to decline. After reaching the critical value, the cell will die. The evidence supporting this theory is that x-ray irradiation can accelerate the aging of mice, short-lived mice have higher chromosomal aberration rates in long-lived mice, and the chromosomal aberration rates in elderly people are higher; some people have studied the frequency and type of spontaneous mutations that appear in the aging process of genetically modified animals.

, which also provides a certain basis for this theory. However, this theory also has unexplainable facts, such as whether aging is increased damage or reduced chromosome repair ability, this theory cannot explain it; in addition, modern biology has proved that the mutation rate of genes is 10-6-10-9/cells/gene loci/generation. Such a low mutation rate will not cause the death of cells in the entire population. According to this theory, cells should have an abnormally high mutation rate; aging is caused by mutations, and transformed cells can continue to grow in vitro. In this regard, transformed cells should not undergo mutations, but this is not the case.

(II) Free radical theory (recognized by international academic circles)

The theory of free radicals of aging was proposed by Denhamharman in 1956, believing that the degenerative changes in the aging process are caused by the harmful effects of free radicals produced by the normal metabolism of cells. The aging process of organisms is the result of the accumulation of free radicals continuously produced by the tissue cells of the body. Free radicals can cause DNA damage, resulting in mutations, and induce tumor formation. Free radicals are intermediate products of normal metabolism, and have strong reaction ability, which can oxidize various substances in the cell and damage biofilms. They can also cross-link large molecules such as proteins and nucleic acids, affecting their normal functions. Free radical theory

The evidence supporting this theory mainly comes from some in vivo and in vitro experiments, including interspecies comparison, dietary restrictions, age-related oxidative pressure measurement, and administration of antioxidant diet and drug treatment to animals; in vitro experiments mainly include observation of the oxygen pressure and metabolism effects of diploid fibroblasts in vitro, oxygen pressure and doubling ability, and the impact of antioxidants on cell lifespan. The view of this theory can explain some experimental phenomena, such as: free radical inhibitors and antioxidants can prolong the lifespan of cells and animals.

Free radical defense ability weakens with age. For vertebrates with long lifespans, the yield of oxygen free radicals in the body is low. However, the free radical theory has not yet proposed that free radical oxidation reaction and its products are the experimental basis for the direct cause of aging, nor does it explain what factors cause the reduction of free radical scavenging ability in the elderly, why transformed cells can not aging, and how germ cells can pass on generations to maintain the germline. Moreover, free radicals are secondary products of metabolism and are unlikely to be the primary cause of aging.

(III) Theory of natural crosslinking of biomolecules

The main argument is that proteins, nucleic acids and other macromolecules in the body can be covalently cross-binded to form huge molecules. These huge molecules are difficult to enzymatically dissolve, accumulate in cells, and interfere with the normal function of the cells. This cross-linking reaction can occur on the nucleus DNA of the cell or in the extracellular protein collagen fibers. At present, there is some evidence to support the theory of cross-linking. The extractability of skin collagen and the digestion effect of collagen enzymes on it decrease with age, while its thermal stability and tensile strength increase with age; the number of stripes on the tail tendon of rats and the heat contraction force it possesses increases with age, but the solubility decreases with age. These results show that the polypeptide chain of collagen is cross-linked when old, and

The theory is similar to the theory of free radicals, and it cannot explain the fundamental mechanism of aging. The theory of natural crosslinking of biomolecules: When proofreading the molecular mechanism of aging of organisms, this theory points out that organisms are an unstable chemical system and belong to a dissipative structure. Various biological molecules in the system have a large number of active groups, and they inevitably interact and undergo chemical reactions to slowly crosslink the biological molecules to tend to stabilize chemical activity. Over time, the degree of crosslinking continues to increase, the active groups of biological molecules continue to consume, and the original molecular structure gradually changes. The accumulation of these changes will cause biological tissues to gradually age. On the one hand, these changes in biological molecules or genes will show different activities.

Even gene products whose effects have been completely changed will interfere with the recognition and binding of RNA polymerase, thereby affecting transcriptional activity, showing that the transcriptional activity of the gene is gradually lost in an orderly manner, prompting progressive and regular phenotypic changes in cells and tissues and even aging and death. The theory of natural crosslinking of biomolecules The basic argument that argues for the molecular mechanism of biological aging can be summarized as follows: First, various biological molecules are not static, but undergo progressive natural crosslinking in a certain natural pattern over time. Second, progressive natural crosslinking causes biomolecules to slowly connect, increase in intermolecular bond energy, gradually increase in molecular bond energy, gradually decrease and lose solubility and swelling ability. The phenotypic characteristic is that cells and tissues have aging.

Third, progressive natural crosslinking leads to the orderly inactivation of genes, causing cells to grow and differentiate according to specific patterns, and causing organisms to show a dynamic change process of programmatic and patterned growth, development, aging and even death. As we grow older, macromolecules that are important to life tend to increase crosslinking, or crosslinking bonds may be generated between the same molecules or between different molecules, thus changing the physical and chemical characteristics of the molecules and preventing them from functioning normally. The crosslinking of extracellular collagen is as mentioned above. This theory envisages that intracellular macromolecules such as nucleic acids and proteins will also be crosslinked, but it has not been proven in the body so far. It is only a speculation to regard crosslinking as a primary factor of aging, but this is a way worth exploring in the study of aging.

(IV) Immunology theory of aging

The immune theory of aging can be divided into two views: First, aging of immune function is the cause of the aging of the body; Second, the autoimmune theory believes that autoimmunity related to autoantibodies plays a decisive role in the process of aging. Aging is not a passive process of cell death and shedding, but the most active self-destruction process. From the immunity theory of aging, it can be seen that the strength of immune function seems to be closely related to the lifespan of an individual. Research so far has shown that the body does indeed have important changes in immune function during aging: 1. The characteristic of changes in immune function at the individual level with aging is that the immune response to exogenous antigens is reduced, and the immune response to autoantigens is enhanced. According to the report of Whit Tingham, after immunization with antigens, the antibody titer ratio of elderly people

Young people show a meaningful decline. In addition, the detection rate of autoantibodies increases with age. Cell immunity also decreases with age. 2. Organ and tissue levels. Human thymus gradually grows with age. It reaches its peak at 13-14 years old, and then begins to atrophy and deteriorate its function, and it shrinks significantly after 25 years old. Neonatal animals lose their immune function after thymus is removed. After young animals remove thymus, their immune function gradually declines, and their antibody formation and graft-versus-host response decreases. 3. Cell and molecular levels. T-cell functions of elderly animals and humans decrease and the number also decreases. With age, the body's ability to respond to mitogen a (ona), phytohemagglutinin (pha) and anti-cd3 antibodies decreases. This is the immunological feature of aging.

One. With aging, the secretion of cytokines has obvious changes. The production of il-2 and the emergence of il-2 receptors in the proliferation of T cells are very important. The production of il-2 in the elderly is reduced, and the emergence of il-2 receptors, especially high-affinity receptors, is also reduced. The autoimmune view believes that any level of the immune system can lead to excessive expression of the autoimmune response, and thus show many evidences of accelerated aging. There is also many opposite evidence for the control of aging in the immune system. There is a long-lived inbred strain-c57bl/6 in mice. Its anti-nuclear antibody ratio and thymic cytotoxic antibody content are relatively high, but it does not show a higher degree of immunopathological damage. Nude mice are a mouse with congenital athymic hairless syndrome, and its T cells are immune.

The epidemic function is extremely lacking, so it can accept allogeneic or even xenografts. If these mice are raised under ordinary conditions, they can cause early death, but their lifespan is not lower than that of normal mice under sterile conditions. If the thymus of newborn mice are removed under normal conditions and die at about 3 months of age, if they are placed in a sterile environment, most of them can live longer. It can be seen that although the immune system can have an impact on survival, it is not a determinant. The immune theory says that the immune system is the leader and the root cause of aging. However, there is no obvious reason to explain the cause of the deterioration of the immune system with age. The age-growing changes of the immune system are also manifestations of various effects caused by aging. It should be regarded as part of the overall aging, rather than the cause of the initiation of aging.

(V) Theory of telomeres

The telomeres theory was proposed by olovnikov, which believed that cells cannot completely replicate their chromosomes during each division due to DNA polymerase dysfunction. Therefore, the final replicate DNA sequence may be lost, eventually causing cell aging and death. Telomeres are a complex structure composed of many simple repeat sequences and related proteins at the end of eukaryotic chromosomes, which have the function of maintaining chromosome structural integrity and solving the problem of terminal replication. Telomerase is a reverse transcriptase

, composed of RNA and protein, is composed of RNA and protein, and uses its own RNA as a template to synthesize telomeres repeat sequences and add them to the end of the newly synthesized DNA chain. In the human body, telomerase appears in most embryonic tissues, germ cells, inflammatory cells, renewed tissue proliferation cells and tumor cells. Because of this, every time a cell mitosis occurs, a telomeres sequence is lost. When the telomeres length is shortened to a certain extent, the cells will stop dividing, leading to aging and death. A large number of experiments show that telomeres,

Telomerase activity has a certain connection with cell aging and immortality. The first direct evidence for telomeres shortening in senescent cells is from the observation of in vitro cultured fibroblasts. Through the relationship between the telomeres length and age and mitotic ability of donor fibroblasts of different ages, it is observed that with age, the length of telomeres gradually shortens, and the ability of mitotic gradually weakens; Hastie found that the length of telomeres restricted fragments in the colon gradually shortens with the increase of donor age, on average, each

33bp repeat sequences lost annually; incomplete chromosomes in plants can be repaired in fertilization, but cannot be repaired in differentiated tissues. This also confirms that the activity of telomerase in somatic cells is inhibited in higher eukaryotes; the telomeres of sperm are longer than that of somatic cells, and the activity of telomerase in somatic cells will gradually age, while the telomeres of germ cell lines can maintain their length; transformed cells can completely replicate telomeres through the activity of telomerase to obtain immortality. telomerism theory

However, many problems cannot be explained by the theory of telomere. The telomeres length of somatic cells is proportional to the mitotic ability. This experiment has confirmed that different somatic cells have different mitotic abilities. The division and proliferation rate of gastrointestinal mucosal cells is relatively fast, and the division speed of nerve cells is relatively slow. Someone once conducted research on the telomere length of corneal endothelial cells of donors of different ages found that the telomere length in corneal endothelial cells has been maintained at a higher level for a long time, but telomerase is not expressed. In addition, kippling found that mice

The telomeres are nearly 5-10 times longer than humans, but their lifespan is much shorter than that of humans. These all suggest that the telomeres length of somatic cells is not consistent with the individual's lifespan and the life expectancy of different tissues and organs. The telomeres activity of germ cells is maintained at a high level for a long time but will not be as restricted as tumors. The telomeres length is controlled by telomerase, so what factors control telomerase? The telomerase activity in germ cells is high, so why does not have higher telomerase activity in somatic cells? It seems that the shortening of telomeres is the cause of aging or the result needs further research.

(VI) Mitochondrial theory (tohond daily altheory)

Wallae proposed in 1999 that mitochondrial DNA (MtDNA) mutations will accumulate with age, which is also an important factor in cell aging. Afterwards, many literatures have reflected this point. The study found that the age of cells is positively correlated with the defect of cytochrome C oxidase (ytohreoida color, cox, a protein directly related to cell respiration) in cells, which is caused by mtDNA mutations, and their existence in human muscle cells, brain cells, intestinal cells, etc. If mtDNA mutations in cells reach a higher level, they can hinder the production of cells atp and the supply of biological energy.

(VII) Protein change theory and waste accumulation theory (altered protein instheory and waste accumulation theory)

In life, protein metabolism is essential. In order to protect the normal function of cells, new proteins will remove damaged or excess proteins, which is obvious. Research in many medical fields has found that the metabolic capacity of proteins will decrease with age, including a series of elderly diseases, such as cataracts, Alzheimer's disease, and Parkinson's disease. Carrard and others released evidence that "protein activity decreases with age" in 2002. Later, in 2003, Soti and C-color Rmely also discovered the relationship between molecular chaperone protein and aging, that is, molecular chaperone protein will decrease activity due to the human body's entry into aging, or conversely, because the activity of molecular chaperone protein is reduced, the human body enters aging. Subsequently, Terman and B-Muls NK further believed that they are only part of cell waste materials, and a broader perspective should lie in the "garbage disposal" process of cells.

(8) Aging Network Theory (orktheoday esoaging)

Through the above theory, we can already see that there are many complex mechanisms for cell aging. In practice, most studies are still mainly focused on a single mechanism. This obviously limits the observation of the aging process. Therefore, Kirkood et al. proposed the aging network theory, believing that multiple life mechanisms and cell lesions together cause aging, and they have a synergistic effect. The network theory focuses on studying their roles. For example, mtdna mutations gradually accumulate with age, resulting in a gradual decrease in the Atp content and increasing reactive oxygen species (Ros). This also causes protein stress loss in cells and accumulates waste materials. These losses can be diluted by proliferating tissue cells through mitosis, but at the same time, active DNA replication also increases the frequency of somatic mutations and telomeres erosion.

The advantage of this network observation method is that it can cover various mechanisms of cellular aging and is also applicable to differences between different species, or specific types of molecular damage.

Is aging a goal to avoid cancer?

Although the above theories can explain that aging is the result of internal and external damage, they cannot bypass another problem, namely cell self-apoptotic or autophagy. Unlike cell necrosis, under normal circumstances, cells in tissues can be induced by biological signals to actively enter the apoptosis program. In fact, the apoptosis level in older organ cells also increases, why?

Many studies believe that they are also caused by longer-term cell damage accumulation. But the more likely explanation is that apoptosis reflects a protection mechanism. This important question involves the cell's response to damage. In some cases, especially stem cells in proliferating tissues, such as bone marrow and intestinal epithelial cells, the damaged cells will pose a significant tumor threat. This is probably why such cells often respond to DNA damage by initiating apoptosis. If explained in this way, aging can be regarded as a protective mechanism for cancer, rather than aging causing cancer. The causal arrows in it will be reversed.
Chapter completed!