Mitochondria in aging, part 1
Mechanisms and prerequisites
Josh Mitteldorf, Mitochondria in Aging, I: Mechanisms and Background
For links, see the original article
Translated by Evgenia Ryabtseva
A popular theory proposed a generation ago states that the cause of aging is oxidative damage originating in the mitochondria. Each cell of the body has hundreds and thousands of mitochondria, inside which a high-energy chemical process takes place, the toxic by-product of which are reactive oxygen species (ROS). Presumably, the neutralization of ROS can stop the aging process.
Mitochondrial free radical theory has a fragile theoretical basis, and antioxidants do not increase life expectancy. However, mitochondria are involved in the aging process. Historically, mitochondria acted as mediators of the first complex organisms with programmed death more than a billion years ago, and they retain a role in signal processing regulating life expectancy. It is curious that, despite the fact that a quadrillion (million to the fourth degree) mitochondria are dispersed throughout the body, they function to a certain extent as a single organ that sends coordinated signals that regulate metabolism affecting the aging process.
Mitochondria are present in the cells of all plants and animals – hundreds or thousands of miniature power plants in each cell. They burn carbohydrates and produce electrochemical energy suitable for use by the cell. Now they are devoted and vital servants. But that wasn't always the case. More than a billion years ago, mitochondria entered the cells as invading bacteria. Despite the fact that their "domestication" happened a long time ago, mitochondria retain part of their autonomy in memory of the past. They have their own DNA. Like bacterial DNA, mitochondrial DNA has the shape of a loop, more like a plasmid than a chromosome. Each mitochondria contains several copies of the plasmid.
Since their pathological past, mitochondria retain the ability to destroy a cell. This orderly process is known as apoptosis – programmed cell death. Mitochondria do not play the role of judges sentencing cells to death, they only carry out the sentence under the influence of external signals.
The aging of the organism as a whole is coordinated centrally, but the nature and localization of the "clock" controlling the corresponding processes remains the main unsolved problem. Communication about the age status of the body is carried out with the help of signaling molecules released into the blood, to which the tissues react accordingly. Mitochondria not only pick up these signals, but also participate in the process, also releasing their own signals into the bloodstream. The level of apoptosis increases with aging. Along with inflammation, it is the primary local mode of the self-destruction process, which is aging. Through apoptosis, the body loses too many healthy and functional cells and mitochondria are the direct cause of their death.
Signals – up, down and sideways
The overall picture can be described as follows: mitochondria receive orders from the cell nucleus, where almost all of its DNA is stored. Transcription factors that determine which of the mitochondrial genes are expressed are located in the nucleus. In addition, there is feedback – signaling mechanisms by which mitochondria transmit to the nucleus information about the state of their own health and about the level of energy metabolism of the cell as a whole. The nucleus reacts to this by transcription changes based on information received from mitochondria.
It is believed that the various positive effects of a low-calorie diet and, possibly, exercise are due to mitochondrial signals.
In addition to sending and receiving signals from the cell nucleus, mitochondria communicate with each other. They coherently function inside the cell, and also generate hormones carried by the bloodstream to communicate with distant cells and their mitochondria.
Mitochondria and cancer
Cancer cells have defective mitochondrial metabolism. They burn carbohydrates not by using the usual highly efficient mechanism that consumes the maximum amount of oxygen, but by fermentation – the anaerobic breakdown of carbohydrates. Malignant cells use this mechanism even in conditions of excess oxygen, despite the fact that it produces significantly less energy per carbohydrate molecule. These cells lack energy and absorb carbohydrates in large quantities. (Positron emission tomography allows you to visualize tumors based on data on the amount of carbohydrates consumed.) Following a diet with a very low carbohydrate content is a kind of antitumor therapy.
90 years ago, Nobel Prize winner and outstanding thinker in the field of biomedicine Otto Warburg put forward the hypothesis that mitochondria with impaired glucose metabolism are the root cause of cancer. Traditionally, it is considered that cancer begins with mutations leading to uncontrolled cell growth and proliferation, but according to the metabolic theory of cancer, mutations and proliferation are secondary to this shift in mitochondrial chemistry.
To date, the supporters of Warburg's theory make up a small but enthusiastic minority, operating with facts and arguments that have not yet been analyzed by the author of the article. However, it is very impressive that when transplanting the nucleus of a cancer cell into a healthy cell, the latter remains healthy, whereas a malignant cell remains malignant after transplantation of the nucleus of a healthy cell. This is very convincing evidence that the primary source of cancer is not in the chromosomes of the nucleus.
Decrease in the pool and efficiency of mitochondria and increase in the amount of toxic waste with age
As we age, the number of mitochondria in human cells decreases, which, in all likelihood, is correlated with a decrease in muscle strength and endurance, as well as the energy of the organ that consumes energy most intensively, the brain. This relationship is so subtle that, despite decades of work by researchers who adhere to it, it has not yet been fully understood. Given that mitochondria mediate apoptosis, it is logical to assume that the death of muscle and nerve cells in old age (occurring at least partially due to apoptosis) is also mediated by mitochondria.
The existing problem can be described as follows: our mitochondria lose efficiency as they age. They give our cells less energy and generate more reactive oxygen species. At the same time, cells synthesize fewer natural antioxidants that protect them from reactive oxygen species. Concentrations of glutathione, ubiquinone and superoxide dismutase decrease with age. This is one of the mechanisms of self-destruction of the organism. Oxidative damage accumulates in the old, but not in the young body. Oxidative damage can also contribute to telomere shortening.
Somehow, the reactive oxygen species produced by defective mitochondria produce accumulating damage, while the same compounds generated by cells during exercise act as a signal stimulating the recovery processes in the body, which has a positive effect on health. At the present stage, the line between these two mechanisms is unclear. Perhaps the reason for the uselessness of antioxidants to increase life expectancy lies in the fact that they disrupt the signaling function of reactive oxygen species.
The most detailed mechanism of mitochondrial wear is the appearance of mutations in their DNA. The incomprehensibility of the situation lies not in the fact that mitochondria accumulate mutations throughout the life of the organism, but in the fact that they do not accumulate them from generation to generation (through germ cells). Mitochondria proliferate clonally without sexual reproduction, in which genes are shuffled into many combinations in such a way that good genes can be separated from mutated ones and the latter can be eliminated before they are embedded in the genome. How did non-sexually reproducing mitochondria manage to avoid the accumulation of mutations over millions of years? And if, on the whole, they really managed to avoid the accumulation of mutations over millions of years, then why can't they avoid it over the several decades allotted to the human body.
Are mitochondrial DNA mutations the cause of aging?
Mitochondrial mutations accumulate with age. Genetically modified mice with a defect in the gene responsible for the replication of mitochondrial (but not nuclear) DNA age faster and die earlier than normal animals. This fact was considered proof that mitochondrial mutations are a factor in aging, but this is not necessarily the case. In fact, mitochondria function well and have a high tolerance to genetic errors. To date, it is unclear whether high levels of mitochondrial mutations in aging people can cause serious problems or even whether mutations are associated with a general decline in mitochondrial function as we age. An alternative explanation for mitomutant mice is the fact that they have developmental disorders already in the period of intrauterine development, which can lead to premature aging even without the accumulation of mutations in the DNA of mitochondria.
Mice with mutations in mitochondrial DNA.
Stem cells continue to divide and give rise to new differentiated cells throughout the life of the animal. Apparently, they have mechanisms to minimize the harm caused by mitochondrial mutations. According to the observations, stem cells retain the best mitochondria for themselves and transfer damaged organelles to cells with a limited lifespan. This helps to avoid an increase in the number of errors and benefits the body as a whole. An interesting fact is that in budding yeast, the mother cells act in the opposite way – they retain their damaged mitochondria and transfer the most intact organelles to their daughter cells. There is evidence that mammalian females also select the best mitochondria in order to pass them on to their daughters through eggs. In other words, despite the fact that this behavior is opposite to the behavior of stem cells, both models are adaptive and meet the long-term interests of the organism and its descendants.
In total, the age-related increase in the levels of oxidative damage and the production of reactive oxygen species is relatively small and is insufficient to explain the severe physiological disorders that develop during aging. According to this hypothesis, the absence of a clear correlation between oxidative stress and longevity for different species also indicates that oxidative damage does not play an important role in the development of age-related diseases (including diseases of the cardiovascular system, neurodegenerative diseases, diabetes mellitus) and aging. The data obtained in experiments on mice with mutations in mitochondrial DNA indicate that mutations in the DNA of the mitochondria of somatic cells can lead to the development of progeroid (associated with premature aging) phenotypes in the absence of an increase in the level of oxidative stress. This indicates the ability of mitochondrial DNA mutations causing bioenergetic insufficiency to trigger the aging process, but this has not been proven, since serious disorders develop in such mice already in the period of intrauterine development. To date, there is no convincing evidence that, in general, low levels of mitochondrial DNA mutations in mammalian cells trigger the process of normal aging. One of the methods of experimental solution of this problem is the creation of anti-mutant animal models to find out the possibility of increasing life expectancy by reducing the frequency of mitochondrial DNA mutations.
The mystery of mitochondrial evolution
Mitochondria multiply clonally, like bacteria. In fact, all mitochondria in the body are inherited from one maternal egg, which receives them from its mother, and further inheritance of mitochondria occurs exclusively through the female line. How then do defects not accumulate in the mitochondrial genome?
As far as the author knows, the mechanism of maintaining the integrity of the mitochondrial genome is currently unclear. It is known that the number of mutations in mitochondrial DNA increases with age in some tissues, but not in others. For example, age-related hearing impairment may be associated with defects in the DNA of mitochondria of neurons.
For millions of years, mitochondria have not lost their genetic integrity, despite the fact that the mitochondrial genome evolves faster than the nuclear one, and representatives of different species have different mitochondrial genomes. It is unclear how destructive mutations in the DNA of mitochondria accumulate over decades, but do not accumulate over epochs.
According to the author, this fact is a convincing proof in favor of the existence of a mechanism regulating the evolution of the mitochondrial genome. Perhaps it implies the selection of efficiently functioning mitochondria for reproduction taking place inside the cell. The cell acts as a laboratory that selects mitochondria according to certain characteristics that it finds most useful. Probably, there is also an exchange of genes between different plasmids within the same mitochondria and between different mitochondria, since they sometimes merge throughout the life of the cell (the author's assumption).
What's going on?
The author is of the opinion that aging is not a process of local occurrence of damage dispersed throughout the body, but a centrally regulated process. However, mitochondria are as "off-center" as possible. The quadrillion mitochondria in the human body are scattered throughout all cells of the body, with the exception of red blood cells.
Mitochondria interact with each other inside the cell. They merge and multiply, coordinating their actions with each other and with the cell nucleus. According to the latest data, they transmit signals through the bloodstream (more details in the next publication). Can they function as one organ dispersed throughout the body? Maybe. By determining the level of energy consumption of the body and effectively supplying it with energy, they send signals involved in the formation of life expectancy.
It may very well be that the aging process is coordinated by several biological clocks (centralized, such as the suprachiasmatic nucleus and thymus, or dispersed, like telomeres and methylation profiles), and mitochondria do not belong to these clocks. However, they are important intermediates. According to old ideas, mitochondria generate energy and tissue-damaging reactive oxygen species. And according to the new ones, they are centers of signal transmission, which, quite possibly, are regulated in accordance with first–hand information about the energy status of the organism, which the mitochondria have.
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