US, WASHINGTON (ORDO NEWS) — Biologist Vadim Gladyshev on chronic diseases, metabolic errors and theories of aging
Chronic human diseases have a characteristic age structure: in their youth they are practically absent, but the older the person, the more they appear. Age is the main risk factor for chronic diseases. If you find a mechanism for influencing this process, then chronic diseases can be “pushed aside.” In this formulation, aging becomes the most important issue in biology, but how to determine it? Oddly enough, this still remains incomprehensible.
A couple of months ago I was at a conference on aging in Canada, where they conducted a survey. Experts from the conference were asked: “What is aging?” 35 people answered, 35 different definitions turned out.
At an intuitive level, we understand that aging is associated with the passage of time of the body’s life, with the loss of functions, with the accumulation of damage, such as problems with hearing and sight, the latter of which could be down to a huge variety of conditions, some of which may even require medical intervention, like Fuchs Dystrophy treatment. And, of course, with aging comes the likelihood of mortality. But all these features of aging vary greatly in different situations. For example, time may flow, but mortality will not increase, or damage may accumulate, but this will not lead to loss of functions.
In the XIX century. German scientist August Weisman suggested that aging is a programmed process: there is a special program that leads to aging and death of organisms in order to free up space and resources for future generations. Such a program will definitely be genetic, which means that there are genes on which selection is so strong that they are found in all complex organisms on Earth.
For example, this idea can be compared with the development process – this is a specific program that has many genes, and each gene can be cut down, mutated. If you remove specific genes, the program will be disrupted, and the body will cease to develop. But in the case of the program theory of aging, not a single case is known where the process of cutting down genes worked according to the same scheme.
Evolutionary Theory of Aging
There are other ideas about aging, such as evolutionary theories of aging. One of these theories has been proposed by Nobel laureate Peter Medawar. He suggested that aging is associated with the accumulation of mutations that have a harmful effect on the old organism. When the body has already left offspring, it becomes unimportant for procreation, the strength of selection decreases, and it is easier for mutations to seep out. At a young age, these mutations have no effect, so the body does not remove them, and when the effect begins to manifest, it will be too late.
A concept similar to the evolutionary idea was proposed by George Williams. He came up with the theory of antagonistic pleiotropy. Williams suggested that in old age mutations are harmful, but at a young age they give an advantage. For example, a new gene appears that allows us to be stronger or see better, think better. This gene will be fixed during evolution, even if it has a strongly pronounced harmful effect at the end of life, therefore it is impossible to get rid of such genes. The theories of Medawar and Williams were proposed almost sixty years ago, but so far nothing is specifically known about mutations, their number, the number of genes that are antagonistically pleiotropic, so there are many questions.
Harmful oxygen function
The next idea that was proposed to define aging is the free-radical theory of aging. It is associated with the harmful function of oxygen. Oxygen is a necessary molecule that we breathe. But oxygen is still reactive and leads to damage to other molecules. For example, DNA, carbohydrates, and proteins can be damaged by oxygen. American physician Denham Harman suggested that these lesions accumulate and that the body dies from them in old age. But in this theory, it remains unclear why oxidative damage is the most harmful. There are other injuries in the body, so this theory has been criticized, and now it is unpopular.
Another theory was proposed by British chemist Leslie Orgel. He began to consider damage that is associated with the most important processes, for example, the process of creating proteins. But, despite the importance of these processes, they do not cover the entire biology, so the choice of processes remains unclear.
The next idea is the expenditure theory proposed by British scientist Tom Kirkwood. He said that organisms live in conditions of limited resources, so they should always fight for them. If resources are limited, and they need to be partially spent on reproductive function, then maintaining the body cannot be completely effective, so damage accumulates, and the body dies.
There are questions to this theory related to the fact that all organisms always exist in conditions of limited resources. It is possible to imagine a situation where the body for several generations lives in conditions of complete abundance of resources, but even such an organism will show aging.
Theory of Hyperfunction of Aging
The last and one of the main theories was proposed by Russian oncologist Mikhail Blagosklonny. He introduced the theory of hyperfunction, which is associated with ongoing development. A person reaches maturity, finishes development, but this trajectory continues further, it cannot be stopped, because not one hundred percent selection is in effect. As a result, the damage still accumulates, and the body dies. Regarding the damage aspect, the Favored Theory is partly related to evolutionary theory.
Useful and harmful functions of protein
There are many different directions of thought, but all these theories only partially describe aging, so there is still no common understanding in terms of the definition and essence of aging.
To understand the main idea of aging yourself, you need to study protein. Take a protein that supports some kind of biological function of the body. It is encoded by the gene, so this function has a genetic program. But this protein is imperfect, because in biology there is nothing ideal. Protein is built from only 20 types of amino acids. This is a polymer that sometimes interacts with the wrong thing, or produces the wrong product. In other words, there is a non-zero probability that a protein that supports a particular function will do some damage, it will have a harmful function. This means that the protein has a positive function encoded in the genome, and there is a harmful function that is a consequence of the positive function, and it is also indirectly programmed in the genome.
If we expand this idea to other biological molecules, then we can say that all the damage and other harmful effects of life come from biological functions. Imagine tens of thousands of functions that are associated with different genes and with the integration of these processes. If you add up the harmful functions of molecules and external damage, then there will always be more damage than functions.
Detecting all these injuries is very difficult, so you can’t say exactly how the body copes with all the injuries. On the one hand, we have many protective systems: enzymes that remove damage, transporters, kidneys, the lymphatic system, and stem cells. But even so many protective systems cannot cover the full range of damage.
It is important to understand that there is no major damage. Aging is not only associated with mitochondria, or telomeres, or DNA damage. It is associated with all the consequences of all the functions in the body that are. Aging happens because we live. The main cause of aging is life. Aging is a more complex process than life than metabolism. But this complexity is important for us, because we understand who our enemy is, and having understood this, we can come up with experiments that will allow us to fight this process, push it aside.
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