Exploring the mechanism of aging is not only an ancient problem, but also a brand-new scientific research field. In the long historical development of medicine, some people think that the general manager has put forward hundreds of aging hypotheses. Traditional Chinese medicine has accumulated rich experience in anti-aging, and put forward the theory of yin-yang imbalance, the theory of viscera deficiency and the theory of essence and qi failure. , which is permeated with a macro understanding of nature. Ancient foreign doctors and philosophers also explained aging from different angles, and put forward warmth theory, entropy theory, wear theory and self-poisoning theory, which played a positive role in our understanding of aging. However, due to the limitation of historical conditions and scientific level, these theories have great limitations.
With the development of the times, a series of new theories have emerged, including error theory, free radical theory, autoimmune theory, network theory, telomerase theory and so on. On the basis of the original theory, great progress and perfection have been made, but at present these theories have not been recognized by academic circles. The lag of aging theory research is an important reason for the slow progress of anti-aging work. The substantial extension of human life requires great progress in the study of aging theory and aging countermeasures. This chapter introduces some popular aging theories.
(A) the loss of the essence of Chinese medicine theory
Traditional Chinese medicine in China believes that deficiency of essence leads to aging. "Su Wen Jin Kui Yan Zhen" has a record: "The husband is fine, and the body is also this." Lingshu itself records that "essence comes from life", and Lingshu Ren Ping is absolutely ancient records that "the essence of Shuigu comes from life". Zhu Danxi listed various signs of aging of the elderly in Gezhi Yulun, and thought that the reason was the exhaustion of essence and blood. Song believes that the old people's qi and blood are gradually declining, their true yang is less, their essence and blood are exhausted and their spirit is weak.
Ancient doctors believed that the vitality of the human body itself was called essence, and essence was the driving force for the human body to maintain the normal operation of its organ functions. Essence is divided into congenital essence and acquired essence. The former is inherited by parents and forms the original motive force of human life, while the latter comes from Shui Gu. Congenital essence is born, inherited from parents, can not be continuously supplemented, is limited; The essence of the day after tomorrow comes from diet and some other activities, which can be continuously supplemented. According to this reasoning, the essential reason of aging is congenital deficiency of essence.
Some macro-operational mechanisms mentioned in the theory of deficiency of essence and qi in traditional Chinese medicine have certain enlightenment and positive help to the research of anti-aging theory in modern medicine, but they are abstract and lack of evidence at the cellular and molecular levels.
(2) Somatic mutation theory
This theory holds that in the life of an organism, physical factors such as ionizing radiation, X-rays, chemical factors and biological factors are induced. Spontaneous mutation destroys the genes and chromosomes of cells, which accumulates to a certain extent and leads to the decline of cell function, and then the cells die. The evidences supporting this theory are as follows: X-ray irradiation can accelerate the aging of mice, and the chromosome aberration rate of short-lived mice is higher than that of long-lived mice, and the chromosome aberration rate of the elderly is higher; Some people have studied the frequency and types of spontaneous mutation in the aging process of transgenic animals, which also provides a certain basis for this theory.
But this theory also has some unexplained facts, 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/gene locus/generation. Such a low mutation rate will not cause the death of the whole group of cells, but according to this theory, cells should have an unusually high mutation rate; Aging is caused by mutation, and transformed cells can continue to grow in vitro. In this respect, transformed cells should not mutate, but this is not the case.
(3) Free radical theory (recognized by international academic circles)
The free radical theory of aging was put forward by Denham Harman in 1956. It is believed that the degradation in the process of aging is caused by the harmful effects of free radicals produced in the normal metabolism of cells. The aging process of organisms is the result of the accumulation of free radicals produced by tissues and cells. Free radicals can cause DNA damage, lead to mutation and induce tumor formation. Free radical is an intermediate product of normal metabolism, which has strong reaction ability and can oxidize many substances in cells and destroy biofilm. It can also cross-link macromolecules such as protein and nucleic acid, affecting its normal function.
The evidence supporting this theory mainly comes from some in vivo and in vitro experiments. Including interspecific comparison, dietary restriction, determination of age-related oxidative stress phenomenon, giving animals antioxidant diet and drug treatment; In vitro experiments mainly include the observation of oxygen pressure and metabolism of diploid fibroblasts in vitro, oxygen pressure and doubling ability and the effect of antioxidants on cell life. This theory can explain some experimental phenomena, such as: free radical inhibitors and antioxidants can prolong the life of cells and animals. The defense ability of free radicals in the body decreases with age. Vertebrates have a long life and low production of oxygen free radicals. However, the free radical theory does not provide the experimental basis that free radical oxidation reaction and its products are the direct cause of aging, nor does it explain what factors lead to the decline of free radical scavenging ability of the elderly, why transformed cells can not age, and why germ cells can be passed down from generation to generation to maintain the reproductive system. In addition, free radicals are secondary products of metabolism and are unlikely to be the main cause of aging.
(D) Cross-linking theory
This theory was put forward by Bjorksten in 1963, and then developed by Verzar. The main argument is that macromolecules such as protein and nucleic acid in organisms can form huge molecules through valence * * *. These huge molecules are difficult to be hydrolyzed and accumulate in cells, which interferes with the normal function of cells. This cross-linking reaction can occur in nuclear DNA or extracellular collagen fibers. At present, there is some evidence to support the crosslinking theory. The extractability and digestibility of skin collagen decreased with age, while its thermal stability and tensile strength increased with age. The number of stripes on rat tail tendon and its thermal contraction force increase with age, but the solubility decreases with age. These results show that the polypeptide chain of collagen is cross-linked in old age and is increasing day by day. This theory is similar to the free radical theory and cannot explain the fundamental mechanism of aging.
(5) The theory that mistakes lead to disasters.
The theory of false disaster was clearly put forward by ogle. It is believed that mistakes in DNA replication, transcription and translation can continue to expand and lead to cell aging and death. If there are slight differences in the DNA transcription process of mRNA, the slightly different mRNA will be translated into further deviated protein, and if protein belongs to DNA polymerase, more different DNA will be synthesized. Such mistakes will be amplified after each information transmission, forming a vicious circle, leading to the accumulation of many wrong molecules in cells, causing disasters, the normal function of cells can not be brought into play, leading to cell aging and death.
There have been many studies and reports on this hypothesis, and there are different opinions. Lewis and Tarrant published data that they thought supported this theory: the enzymes needed to synthesize biological macromolecules have age-dependent changes, such as the correctness of DNA polymerase synthesis in mouse liver and human fibroblasts, which all decrease with age; At the same time, the speed of DNA repair has also decreased.
However, the inconsistent result is that the life span of diploid cells grown in sublethal concentrations of amino acid analogues has not been shortened. If aging is caused by an error in protein synthesis, the factors that can accelerate this process will shorten the life of cultured cells under the above unfavorable circumstances, but this is not the case. Gupta found that continuous treatment with mutagens for several cycles would not shorten the life span of fibroblasts cultured in vitro; In addition, tumor cell lines can be preserved without restriction, which seems to be inconsistent with the wrong hypothesis.
Scholars including hayflick also questioned the difference theory. Holland and hayflick compared the virus yield in young and old cultured cells, and no difference was observed in the pathogenicity and protein composition of the virus. The virus synthesizes protein by using a cellular machine, which means that the accuracy of this machine can still be maintained in old cells. In addition, there was no significant difference in protein amino acid composition between the elderly and animals and young people.
(6) biological clock theory
This theory, also known as genetic programming theory, holds that aging is an arranged procedure in the life cycle, and it is only one aspect of the whole growth and differentiation process. Every species has a genetic "time plan", that is, it occurs according to the gains and losses of survival in the evolution of nature through biological clocks or similar mechanisms. Specific genetic information activates the degradation process on time, gradually unfolds, and eventually leads to aging and death.
Some scholars believe that aging caused by genetic programming is the need of evolution. When individuals live for a certain period of time without evolutionary benefits, they will begin to lose the control of evolutionary forces and move towards aging. There are some evidences of cytology and molecular biology, which have also been preliminarily verified in biological life statistics.
The phenomenon of biological clock is obvious in the early life, such as the degeneration of tail. In early life, the degeneration of some organs and cells is necessary for morphogenesis. Aging should not be regarded as an isolated stage in an organism's life. Differentiation, development and aging are different aspects of the same event. If aging only occurs because of the loss of evolutionary control, then genetic polymorphism will inevitably occur, that is, non-aging variants, which have not been found yet. It can be inferred that aging is not an active event controlled by genes, and it can also be said that there is no programmed aging gene. In addition, the explanation of biological clock theory on the molecular basis is not enough.
(7) Gene regulation theory (the theory that cell division gradually slows down and finally stops) (recognized by international academic circles)
Gene regulation theory explains two important characteristics of aging: the adaptability of organisms to the environment is gradually declining; Life span has a characteristic. According to this theory, aging is due to the orderly activation and inhibition of some genes in the process of biological differentiation and growth: the products of genes responsible for differentiation and growth stimulate the genes responsible for reproductive period, while some gene products in reproductive period inhibit some genes needed for differentiation and growth. Continuous reproduction can exhaust some factors, lead to the closure of some genes, and eventually lead to functional decline; The length of development, reproduction and senescence of a species depends on several groups of special genes that are activated and inhibited in turn. The duration of these periods can be changed within a certain range, and it will be influenced by some external factors such as internal factors and nutrition, so the life span of different individuals in the same species is different.
Differentiation, development, reproduction and aging are inseparable stages of the whole life event, so it may not be appropriate to divide genes into differentiation and growth stages and reproduction stages in isolation. These genes are responsible for their functions in a certain period of time, and their gene products affect each other and life span, which cannot explain that many genes expressed in neonatal period are still expressed in old age. The agelessness of germ cells is also difficult to explain with this theory.
(viii) Residual information theory
Medvedev is the main advocate of this theory. In mature somatic cells, only 0.2-0.4% of the genetic information contained in DNA molecules plays a role, and the rest are suppressed. Some genes, action factors and other regions on DNA molecules are selectively repeated, showing residual information. One copy of the gene is defective or inactivated, and other copies are activated until the last copy is exhausted. At this time, due to the lack of some gene products, the normal function of cells can not be well played, leading to cell aging. Medvedev believes that the longevity of different species may be a function of the degree of gene sequence repetition. Longevity species should have more residual information than short-lived species.
The study of DNA, rRNA and tRNA of different species shows that there is no specific relationship between the lifespan of mammals and the repetitive sequences of genes. However, a few important genes with only a few copies, such as hemoglobin gene and histone gene, should probably play a decisive role in longevity. In order to study this possibility, some people use the correlation analysis rate of DNA RNA to analyze the relationship between the life span of different mammals and mRNA repeat sequences. The results show that there is a positive correlation between them, but the conclusion is not credible because too many assumptions are used in analyzing this set of data. If gene inactivation only occurs in regulatory genes, but not in structural genes, then it should be explained why structural genes are not easy to inactivate. If it occurs in structural genes, the allotypic markers of cells may change with age. But in fact, heteromorphism often lasts for life. In addition, the number of chromosomes and the DNA content of each cell have no clear relationship with the life span of animals. For example, the DNA content of locusts can reach 19uug/ nucleus, while that of humans is only 7.3uug/ nucleus. However, human life expectancy is much longer than that of locusts.
(9) Immune theory of aging
The immune theory of aging can be divided into two views: first, the aging of immune function is the cause of aging; Second, autoimmune theory holds that autoimmune related to autoantibodies plays a decisive role in the aging process. Aging is not a passive process of cell death and shedding, but the most active self-destruction process.
It can be seen from the immune theory of aging that the strength of immune function seems to be closely related to the individual's life span. So far, studies have shown that the aging process of human body is indeed accompanied by important changes in immune function:
1, the change of individual level immune function with aging shows that the immune response to foreign antigens decreases and the immune response to autoantigens increases. According to Whittingham's report, after immunization with antigen, the antibody titer of the elderly is significantly lower than that of the young. In addition, the detection rate of autoantibodies increases with age. Cellular immunity will also decline with age.
2. Organ and tissue level: After birth, the human thymus gradually becomes larger with the increase of age, reaching the peak at the age of 13- 14, and then it begins to shrink and its function deteriorates, and it is obviously reduced after the age of 25. After thymectomy, newborn animals lose their immune function. After thymectomy, young animals lose immune function, antibody formation and graft-versus-host reaction.
3. At the cellular and molecular level, the function and quantity of T cells in the aged animals and people decreased. With the increase of age, the body's ability to respond to mitogen concanavalin A(con A), phytohemagglutinin (PHA) and anti-CD3 antibody decreased. This is one of the immunological characteristics of aging. With the increase of age, the secretion of cytokines has changed obviously. The production of IL-2 and the appearance of IL-2 receptor are very important in the proliferation of T cells. The production of IL-2 in the elderly is reduced, and the appearance of IL-2 receptors, especially high affinity receptors, is also reduced.
From the point of view of autoimmunity, the out-of-control of the immune system at any level will lead to the over-expression of autoimmune reaction, showing many evidences of accelerating aging.
There is also much evidence to the contrary that the immune system controls aging. There is a long-lived inbred line C57BL/6 in mice. The proportion of antinuclear antibodies and the content of thymic cytotoxic antibodies are relatively high, but they do not show high immunopathological damage. Nude mice are a kind of mice with congenital athymia and hairless syndrome, and their T cell immune function is very poor, so they can accept allogeneic or even xenotransplantation. This kind of mice can die early if raised under ordinary conditions, but if raised under aseptic conditions, their life span is not lower than that of normal mice. If the thymus of newborn mice is removed under normal feeding conditions, they will die in about 3 months. If they are kept in a sterile environment, most of them can live longer. It can be seen that although the immune system can affect the survival time, it is not the decisive factor. According to the immune theory, the immune system is the dominant and fundamental cause of aging. However, there is no obvious reason why the immune system deteriorates with age. The aging change of immune system is also the manifestation of various effects caused by aging, which should be regarded as a part of the whole aging, not the initial cause of aging.
(X) Transposable element hypothesis
Macieira-Coelho proposed the transposable element hypothesis to explain aging. It is considered that aging may be the transfer of transposable elements from one part of chromosome to another, and then the required functions are inactivated. This model is consistent with the occurrence and development of cancer and other transposon changes in immunology. The changes observed in cultured cells may indicate that transposons may play an important role in aging. However, whether this change is the cause or result of aging is uncertain, and the hypothesis lacks reliable evidence.
(1 1) telomere theory
Telomere theory was put forward by Olovnikov, which holds that cells can't completely copy their chromosomes at each division because of the dysfunction of DNA polymerase, so the last copied DNA sequence may be lost, which will eventually lead to cell aging and death.
Telomere is a complex structure composed of many simple sequence repeats and related proteins at the end of eukaryotic chromosomes, which can maintain the structural integrity of chromosomes and solve the problem of terminal replication. Telomerase is a reverse transcriptase composed of RNA and protein. It uses its own RNA as a template to synthesize telomere repeats and add them to the end of the newly synthesized DNA chain. In human body, telomerase appears in most embryonic tissues, germ cells, inflammatory cells, proliferative cells of new tissues and tumor cells. For this reason, every time a cell divides, it loses a telomere sequence. When the telomere length is shortened to a certain extent, cells will stop dividing, leading to aging and death.
A large number of experiments show that telomere and telomerase activity are related to cell aging and immortality. The first direct evidence of telomere shortening in aging cells comes from the observation of fibroblasts cultured in vitro. Through the relationship between telomere length and mitotic ability of donor fibroblasts of different ages and ages, it is observed that telomere length is gradually shortened and mitotic ability is obviously weakened with aging. Hastie found that with the increase of donor age, the length of colon telomere restriction fragments gradually shortened, and an average of 33bp repetitive sequences were lost every year. Incomplete chromosomes in plants can be repaired by fertilization, but not in differentiated tissues, which also proves that telomerase activity in somatic cells is inhibited in higher eukaryotes. The telomere of sperm is longer than that of somatic cells, and the telomerase activity of somatic cells will gradually age without it, while the telomere of germ cell line can maintain its length; Transformed cells can completely replicate telomeres through telomerase activity and achieve immortality.
But many problems can't be explained by telomere theory. The telomere length of somatic cells is directly proportional to mitotic ability, which has been confirmed by experiments. However, the mitotic ability of different somatic cells is not the same. Gastrointestinal mucosal cells divide and proliferate faster, while nerve cells divide slowly. Some people have studied the telomere length of corneal endothelial cells of donors of different ages, and found that the telomere length in corneal endothelial cells has remained at a high level for a long time, but telomerase is not expressed. In addition, kipling found that mouse telomeres are nearly 5- 10 times longer than human beings, but their life span is much shorter than human beings. All these indicate that the telomere length of somatic cells is not consistent with the life expectancy of individuals and different tissues and organs. Telomerase activity of germ cells remains at a high level for a long time, but it will not divide and reproduce indefinitely like a tumor. Telomere length is controlled by telomerase, so what factors control telomerase? Germ cells have high telomerase activity, why somatic cells don't have high telomerase activity. It seems that whether telomere shortening is the cause or result of aging needs further study.