2023 Author: Bryan Walter | [email protected]. Last modified: 2023-05-21 22:24
Why are we getting old? And is it possible, if not to stop, then at least slow down this process? In the book Counterclockwise: What is Aging and How to Fight It (Alpina Non-Fiction Publishing House), biologist, science journalist and editor of N + 1 Polina Loseva tells how the human body ages, why age-related changes are not always bad and what prevents science from finally discovering a pill for old age. The Organizing Committee of the Enlightener Prize included this book in a “long list” of 25 books, among which the finalists and laureates of the Prize will be selected. N + 1 invites its readers to read an excerpt on the free radical theory of aging and retribution for a temporary victory over old age.
The most important poison
Adherents of the theories of aging as wear and tear love categorical statements. For example, Suresh Rattan, a gerontologist at Aarhus University, describes his vision of the problem as follows: “Every time I breathe in,” he says, “I kill myself. Every time I eat, I kill myself."
However, these are not just nice words. In fact, it is a paraphrase of the most powerful of the "wear and tear" theories - the free radical theory of aging, which was proposed by the American chemist Denham Harman in 1955. From the point of view of this theory, the cause of the disintegration of the body lies in damage to macromolecules. They, in turn, are to blame for free radicals, and they owe their appearance in cells to a terrible poison - oxygen.
Despite the fact that in the human body, the digestive and respiratory systems exist separately from each other, for the cell, nutrition and respiration are part of a single process. The oxygen that the respiratory system supplies to the body is needed by the cells in order to eat, that is, to receive energy from food.
The main food for our cells is glucose. It is possible to extract energy from it directly in the process of splitting into parts, this process is called glycolysis. But at the same time, little energy is obtained - if you measure it in the “energy currency” of the cell, ATP molecules. Therefore, the cell can live on one glycolysis for a short time - this is what, for example, muscle fibers do during contraction, when energy is needed urgently.
If the cell has time to get more energy, then it goes a longer path: what remains of glucose after splitting is sent to the mitochondria. There, the decomposition of glucose continues until only carbon dioxide (which we exhale) remains of the molecule, as well as individual protons and electrons on special carriers, the main of which is NAD (it is designated as NADH when there is hydrogen on it, and as OVER + when it is “free”).
The long pathway of glucose breakdown in mitochondria provides 18 times more energy (ATP) than glycolysis. In addition, with the help of mitochondria, the cell can receive energy from other molecules - for example, proteins and fats - that cannot participate in glycolysis.
But the cell has to pay for highly efficient mitochondrial respiration. To release the carriers in time, the cell uses oxygen: it reacts with protons and electrons to form water molecules. Thus, the cell becomes dependent on the supply of oxygen, and in its absence it quickly dies.
At the same time, oxygen has one unpleasant property: since it is a reactive molecule, from time to time it enters into unplanned chemical reactions. For example, it captures not four electrons, as expected, but only one - and turns into superoxide. When superoxide meets protons, it turns into hydrogen peroxide. And it already, in turn, decomposes, forming a hydroxyl radical. These are all reactive oxygen species that give rise to other free radicals in the cell, reacting with the molecules around them, and then damage proteins, fats and, in extreme cases, even DNA, causing oxidative stress in the cell.
Since mitochondria are the first to be hit by reactive oxygen species, one of the branches of the free radical theory suggests that it is their damage that drives aging. It's called the mitochondrial theory of aging, and that's what Aubrey de Gray was doing before he came up with his "engineering approach." According to this theory, free radical attack prevents mitochondria from extracting energy from food, leaving the cell without resources.
In addition, with age, mitochondria in cells become smaller. Reactive oxygen species introduce mutations in mitochondrial DNA, and then mutant mitochondria compete with each other in the cell and gradually die. Recently, Japanese scientists calculated that every year in a person's cells, 0.36% more mitochondria die than are formed. This figure seems small, but if a person lives long enough, then the difference becomes significant: after 104 years of life, only 685 mitochondria remain out of 1000. Accordingly, they can supply less and less energy and it is no longer enough for intracellular repair.
One way or another, the more radicals, the higher the stress level. Mild oxidative stress occurs every time oxygen enters the cell. The strong develops less often - for example, if there is too much oxygen or if the cell is unable to withstand the weak. In response to severe stress, cells age, that is, they stop dividing, begin to secrete SASP (a set of pro-inflammatory proteins) and acquire other signs of senescence. This phenomenon was called stress-induced aging (SIPS, stress-induced premature senescence). That is, in order to age a cell, it does not take much time: a large dose of oxidative stress is sufficient.
Thus, free radicals become an inevitable byproduct of respiration and the price the cell pays for energy. We could live on glycolysis and related processes, as yeast does, but then we would not have enough resources for muscle contraction and the work of neurons in the nervous system. The complex structure of our body does not allow it to do without oxygen. And in this sense, Rattan is certainly right: every piece of food and every breath increases the amount of reactive oxygen species and, therefore, increases oxidative stress in cells (accumulation of free radicals and damage to proteins).
The free radical theory of aging, like other theories from the “wear and tear” group, implies that aging is inevitable. Since we cannot live without oxygen, we will inevitably breathe and burn glucose, and oxygen will supply us with free radicals, destroying cells from the inside. And the more reactive oxygen species, the shorter the life.
However, one should not think that cells are completely defenseless in the face of free radicals. Along with respiration, cells produce antioxidants - substances that neutralize reactive oxygen species. These are, for example, proteins: superoxide dismutase, which fights superoxide, or catalase, which decomposes hydrogen peroxide into water and oxygen. Other substances for which this function is not the main one can act as antioxidants, for example, vitamins C and E.
Nevertheless, antioxidants now and then “pass” a certain amount of reactive oxygen species, so some molecules still suffer from them. The cell also has control over the damaged molecules - we already talked about it in the second part of the book - these are garbage collection systems: repair proteins (which repair DNA), proteasomes (which break down damaged proteins) and autophagy (the process of digesting protein clumps or whole organelles) …However, a small percentage of damage inevitably escapes them, and with age, the number of oxidized macromolecules in the cell increases.
Is there a stress-free life
It is logical to assume that it is possible to prolong life by reducing the level of oxidative stress. Probably, this is also related to the longevity of naked mole rats: in the underground tunnels where they live, there is no sunlight, and with it ultraviolet rays - a source of free radicals in cells. In addition, the concentration of oxygen in the air underground is somewhat lower than on the surface: about 20% instead of the prescribed 21%. Probably, having climbed deeper, naked mole rats escaped not only from predators, but also from sources of oxidative stress.
There are animals among animals that know how to get rid of stress by 100%. To do this, they fall into anhydrobiosis, that is, they almost completely dry out. Roundworms, some crayfish, tardigrades and other invertebrates can do this, but this form of existence has been best studied in the African bell mosquito Polypedilum vanderplanki. He lives in Africa, south of the Sahara. The four rainy months of the year, when animals can reproduce, are followed by eight months of brutal heat. Mosquito larvae usually hatch in puddles on the surface of granite rocks, so they have to wait out the hot two-thirds of the year in the form of a dried “mummy”.
Falling into anhydrobiosis, the mosquito larva loses almost all water from the body, up to 98% or more. The water is replaced by the trehalose carbohydrate, which fills the entire inner space of the cells. It is composed of two glucose molecules, but in such a way that it cannot be chemically reacted with. Therefore, trehalose acts as a filler: it maintains the shape of the cell and prevents the membrane from collapsing and sticking together. In addition, the larva produces a large number of special proteins that envelop the cells' own proteins so that they do not change shape when they dry.
The result is something like a mummy or an ancient animal stuck in amber, which is still found around the world. However, this comparison is not entirely accurate. Most of all, anhydrobiosis resembles plasticization technology, with the help of which people are now preserving the bodies of the dead for further research: a solidifying polymer is sent through the blood vessels of the body, which fills the cavities and solidifies, preventing the structure from disintegrating.
Anhydrobiosis makes mosquito larvae practically superheroes. They survive eight months of heat without the slightest consequences and resurrect back in half an hour in the water. They can do this trick a few more times if necessary. In addition, when dried, they withstand the effects of many toxins and radiation, as well as being in space and temperature drops from –270 to +102 ° С.
The secret is that, deprived of all their water, the larvae stop the chemical processes in the cells. The macromolecules that fill the cells enter into chemical reactions only in solution - they need to move around the cell in order to get to each other. In the absence of water, this is impossible, so the dried larva does not eat or breathe, does not build proteins and does not copy DNA, and no stress acts on its cells.
Does this mean that the animal does not age in eight months of anhydrobiosis? Strictly speaking, this has not yet been proven for the bell mosquito larvae themselves. But there is data on the tardigrade - a better-known superhero - which is also distinguished by its resistance to a variety of life's adversities and also falls into anhydrobiosis. For her, apparently, during the time spent in a state of total dryness, signs of old age do not increase, and the years pass unnoticed for her. Some authors even compare invertebrates in a state of anhydrobiosis with the Sleeping Beauty from a fairy tale, for which time has stood still for a hundred years.
However, this temporary victory over old age is given to animals at a difficult price: by stopping aging, they also stop the course of their own life. As Lao Tzu said, “the conquest of the Celestial Empire is always carried out through non-action. Whoever acts is not able to take possession of the Celestial Empire”. To paraphrase his words in relation to aging, we can say that only those who do not live are immortal.