What is aging?(2/2)

3. Theory that the cause lies in mitochondria (mitochondrial abnormality theory) Bioenergy (ATP) Due to incomplete energy metabolism (electron transport) in mitochondria, which produce most ofROS (superoxide) is unavoidable. Highly reactive from superoxideROS (Hydroxy radical) is created. mitochondriaDNAis the nucleusDNAUnlike other proteins, it is not covered with histone proteins, so it is produced by itself.ROSIn addition to being susceptible to injury, the repair activity of injured molecules is weak. It has its own protease that breaks down and removes oxidatively damaged proteins, but its activity is weaker than in the cytoplasm and abnormal molecules tend to increase. As explained below, there is a mechanism by which damaged mitochondria are removed by autophagy, but as we age, this becomes insufficient, leading to an increase in abnormalities in mitochondria, which are central to life support, and may contribute to the progression of aging.

of cellsROSis thought to originate mainly from mitochondria, but there are many types of oxidizing enzymes such as xanthine oxidase in cells, and unlike mitochondrial electron transport, normal enzymatic reactions occur.ROSis being produced. For example, the bactericidal action of white blood cells (neutrophils)ROSmay play an important role, as mentioned in the previous section.ROSConsidering the diverse functions ofROSIt is thought that various problems will arise if the data are uniformly erased.

4.Theory that the cause is an error in genetic information transmission (error catastrophe theory/lower translation fidelity theory)

This theory isDNAWe believe that the accuracy of information transmission during the process by which genetic information is expressed into proteins decreases with age, resulting in protein molecules containing amino acid sequence errors, which in turn generate further errors, resulting in a gradual decline in cell function. May be directly related to cellular function.

1960Although there are few experimental results that support this theory, which first appeared with the development of molecular biology in the 1990s and attracted attention, it has recently been reported that there is a positive correlation between the longest lifespan of an individual and the accuracy of protein synthesis in cells of various rodents into which a reporter gene has been introduced, and this research is attracting attention as a result that does not contradict this theory.

5. Theory that this is due to the accumulation of abnormal proteins and abnormal organelles (abnormal protein homeostasis function theory)

A theory that suggests that protein abnormalities are the cause of aging.

The research began with the observation that abnormal cross-linked structures increased in extracellular proteins (collagen fibers in the tail) of aged rats.”). Later, it became clear that the molecular activity of various enzymes in intracellular proteins decreases with age, and as mentioned above.4This theory has been largely disproved, and protein abnormalities due to post-translational modifications have attracted attention as a mechanism. In addition to the above-mentioned oxidative stress, the mechanism of abnormality is the modification (glycation,Advanced glycation end products ： AGEsproduction)

There is.

Neurodegenerative diseases that increase with age (Alzheimer's

amyloid, which is thought to be the cause of diseases such as Parkinson's diseaseband abnormal tau protein, abnormalaQuantitative and qualitative protein abnormalities such as synuclein that cause noticeable symptoms are well known, but it is also necessary to consider the possibility that abnormalities that occur in proteins in general cells affect overall biological functions that progress with age and become the cause of gradual aging.”。

The increase in abnormal proteins is determined by the balance between production and degradation. As protein synthesis (biosynthesis) is emphasized in biological homeostasis maintenance mechanisms, we conducted research on the degradation of biomolecules using amino acids and lipids labeled with recently discovered stable isotopes. He was the first to point out the significance of biosynthesis and decomposition (turnover).Rudolf SchonheimerIt is. Research on degradation, which was initially unappreciated, gained attention with the discovery of the lysosome, an intracellular organelle that contains proteolytic enzymes such as cathepsins.3. However, while the substrate specificity of protein degradation by lysosomes was thought to be low, other protein degradation systems were explored because the degradation half-lives of intracellular proteins were diverse. As a result, the ubiquitin proteasome system was discovered and research progressed. The relationship between aging and protein degradation has been clarified, including the prolongation of the degradation half-life of normal and abnormal proteins and decreased proteasome activity in aged animals.

Regarding the degradation of abnormal proteins during the aging process, the ubiquitin-proteasome system, which mainly contributes to the degradation of soluble proteins, and protein aggregates and abnormalities are involved.

The autophagy system, including lysosomes, which is involved in the degradation of organelles, is involved, and a decline in its activity is said to greatly contribute to the decline in cell function associated with aging, regardless of animal species. The rate of protein abnormalities associated with aging isDNACoupled with the fact that it is higher than membrane lipids, this theory is very important as a mechanism of aging.

6. Theory that the cause is due to changes in gene expression (epigenetic theory/cell differentiation theory)

epigenetics isDNAThis is a field of study that studies the phenomenon in which gene expression changes over a long period of time without causing changes in the nucleotide sequence (base sequence).

30About a year ago, we discovered that globin, which is naturally present in red blood cell progenitor cells, was found in the brain and liver of aged mice.mRNAIt was discovered that this phenomenon occurs and was proposed as a cell differentiation theory of aging.

This theory, which did not receive much attention at first, was later developed based on the lymphocytes of identical twins.DNAIt has been reported that differences in methylation and histone acetylation patterns become larger as people get older, leading to an increase in research on aging and epigenetics. In this paper, we will discuss the topics that have been reported and have received attention in recent years.DNAWe will discuss the methylation of

Steve Horvathet al., the nuclei of various animal and human tissues.DNAadjacent cytosine-guanine dinucleotides (CpG) Cytosine base methylation (DNAm), and proposed the concept of an epigenetic clock, claiming that it is possible to predict biological age by examining age-related changes in”. Since then, many reports have been published claiming that it is possible to predict healthy life expectancy and life expectancy based on measurements of healthy people and patients with age-related diseases. However, a report that conducted a meta-analysis of related papers found that frailty (decline in physical strength due to aging), which is considered an indicator of aging,DNAmIt is said that the correlation with the whole genome is not high.DNAThe methylation level ischronological age: Even if it becomes an indicator ofbiological ageIt would be premature to conclude that it is a watch that measures*。

in generalDNAIt is thought that when methylation increases in the promoter region involved in the initiation of gene expression, expression is suppressed;DNA

There are few studies focusing on age-related changes in methylation. It has been reported that there is a predicted correlation between the methylation level and gene expression of the promoter regions of genes for energy metabolic enzymes and contractile proteins in the skeletal muscles of elderly subjects who exercised (decreased methylation increases expression).4), but similar verification will be necessary for the relationship between aging and changes in biological functions.

Can aging be treated?

Many of the claims that aging can be treated have in mind the symptomatic treatment of aging changes that occur in old age. It is not intended as a general intervention in the biological aging mechanisms discussed in this paper.

The mechanism of the biological phenomenon of aging is thought to have remained largely unchanged over hundreds of millions of years of biological evolution. Controlling biological aging will require intervention in fundamental aging mechanisms common to living organisms.

Even if the aging phenomenon can be partially controlled based on the individual aging mechanisms examined in this paper, it is unlikely that the understanding has progressed enough to make it possible as a whole.

Currently, cancer (malignant neoplasms), heart disease, and cerebrovascular disease are common in Japanese people.3It is said to be a major cause of death. One might imagine that if these could be eradicated, average life expectancy would be greatly extended.

Ministry of Health, Labour and WelfareHPBased on the data of3What if each or all of the major causes of death could be completely cured?65This example illustrates the increased life expectancy of older Japanese women. Life expectancy even if individual diseases are eliminated1,2It only increases the number of years, and even if everything can be eliminated, at most4It is the year.

To extend lifespan, at least3It is necessary to eliminate major causes of death, but even so, the current average life expectancy (for women)87.88age is91.92I'm just getting older.

At the bottom of the figure, mortality rate data for the elderly in modern Japan is shown.100The predicted maximum lifespan for women calculated based on the age at death of people over 20 years of age (122year) is shown.42. This figure is the result of a French woman who is considered to be the oldest human being in gerontology.Jeanne-Louise Calmantage at death (122age6months)

is almost the same.122If the predicted value of age is correct,65The biological maximum life expectancy for a Japanese woman of57It's been a year. Even if this estimate is excessive, a survey of Japanese centenarians shows that110～115Since there are many reliable examples of people who survived to the age of3Expected life expectancy to increase with eradication of major causes of death (approx.4It seems clear that there is a possibility of living considerably longer than 2000.

To achieve this goal, it may be more realistic to attempt to extend lifespan by intervening in the aging mechanism discussed in this article to delay biological aging, rather than treating aging as a disease and treating it symptomatically.。