Free radical theory
"Counterclockwise: What is aging and how to deal with it"
Why are we getting old? And is it possible, if not to stop, then at least to slow down this process? In the book "Counterclockwise: What is aging and how to deal with it" (Alpina non-fiction publishing house) biologist, scientific 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 has included this book in the "long list" of 25 books, among which finalists and prize winners will be selected.
N+1 invites its readers to familiarize themselves with an excerpt dedicated to the free radical theory of aging and the reckoning for a temporary victory over old age.
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The most important poison
Adherents of theories of aging as wear and tear like categorical statements. For example, Suresh Rattan, a gerontologist from Aarhus University, describes his vision of the problem as follows: "Every time I inhale," he says, "I kill myself. Every time I eat, I kill myself."
However, these are not just beautiful words. In fact, this 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 reason for the disintegration of the body lies in the damage of macromolecules. In turn, free radicals are to blame for them, and they owe their appearance in cells to a terrible poison – oxygen.
Despite the fact that the digestive and respiratory systems exist separately from each other in the human body, nutrition and respiration are parts of a single process for the cell. Oxygen, which is supplied to the body by the respiratory system, is needed by 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 measured in the "energy currency" of the cell, ATP molecules. Therefore, a cell can live on one glycolysis for a short time – for example, muscle fibers do this when they contract, when energy is urgently needed.
If the cell has time to get more energy, then it goes a longer way: what remains of glucose after cleavage is sent to the mitochondria. There, the breakdown of glucose continues until only carbon dioxide (which we exhale) remains from the molecule, as well as individual protons and electrons on special carriers, the main one of which is NAD (it is designated as NAD · H when there is hydrogen on it, and as NAD + when it is "free").
The long path of glucose breakdown in mitochondria gives 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. In order 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 chemically active molecule, from time to time it enters into unplanned chemical reactions. For example, it captures not four electrons, as it should, but only one – and turns into superoxide. Meeting with protons, superoxide turns into hydrogen peroxide. And it already, in turn, decays, forming a hydroxyl radical. All these are reactive oxygen species that give rise to other free radicals in the cell, reacting with the molecules surrounding them, and then damaging 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. That's what they call it –the mitochondrial theory of aging – and that's what Aubrey de Grey was doing before he came up with his "engineering approach." According to this theory, the attack of free radicals prevents mitochondria from extracting energy from food, which leaves the cell without resources.
In addition, with age, mitochondria in cells become smaller. Reactive oxygen species introduce mutations into mitochondrial DNA, and then the mutant mitochondria compete with each other in the cell and gradually die. Recently, Japanese scientists have calculated that every year 0.36% more mitochondria die in human cells than are formed. This figure seems small, but if a person lives long enough, the difference becomes significant: for 104 years of life, only 685 out of 1000 mitochondria remain. Accordingly, they can supply less and less energy and it ceases to be enough for intracellular repair.
Anyway, the more radicals there are, the higher the stress level. Mild oxidative stress occurs every time oxygen enters the cell. A strong one develops less often – for example, if there is too much oxygen or if the cell is not able to resist a weak one. 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 has been called stress-induced aging (SIPS, stressinduced premature senescence). That is, in order to age the cell, a lot of time is not needed: a large dose of oxidative stress is enough.
Thus, free radicals become an unavoidable byproduct of respiration and the payment of the cell for the opportunity to receive energy. We could live by glycolysis and related processes alone, as yeast does, but then we would not have enough resources for muscle contraction and the work of neurons of 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, consequently, 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, do not think that cells are completely defenseless in the face of free radicals. Simultaneously 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 "skip" a certain amount of reactive oxygen species every now and then, so some molecules still suffer from them. The cell also has a rule for 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 lumps 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 life without stress
It is logical to assume that it is possible to prolong life by reducing the level of oxidative stress. Probably, the longevity of naked diggers is also connected with this: 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, underground oxygen concentration in the air is slightly lower than on the surface: about 20% instead of the required 21%. Probably, having got deeper, naked diggers hid not only from predators, but also from sources of oxidative stress.
There are also some animals that know how to get rid of stress 100%. To do this, they fall into anhydrobiosis, that is, they almost completely dry out. Roundworms, some crayfish, tardigrades and other invertebrates are able to do this, but this form of existence is best studied in the African mosquito, Polypedilum vanderplanki. It lives in sub-Saharan Africa. The four rainy months of the year when animals can breed are followed by eight months of fierce heat. Mosquito larvae are usually hatched 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 the water from the body, up to 98% or more. Water is replaced by the carbohydrate trehalose, which fills the entire inner space of the cells. It is made up of two glucose molecules, but in such a way that it cannot enter into a chemical reaction with it. Therefore, trehalose acts as a filler: it maintains the shape of the cell and does not allow the membrane to collapse and stick 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 drying.
The result is something like a mummy or an ancient animal stuck in amber, which are still found all over the world. However, this comparison is not entirely accurate. Most of all, anhydrobiosis resembles the technology of plasticization, with the help of which people are now preserving the bodies of the deceased for further research: a solidifying polymer is allowed through the blood vessels of the body, which fills the cavities and freezes, not allowing the structure to disintegrate.
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. If necessary, they can do this trick several more times. 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 ° C.
The secret is that, being 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 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 after eight months of anhydrobiosis, the animal does not age? Strictly speaking, this has not yet been proven for the bell mosquito larvae themselves. But there is data on the tardigrade – the more famous superhero – which is also resistant to a variety of life adversities and also falls into anhydrobiosis. Here, apparently, during the time spent in a state of total dryness, there are no signs of old age, and the years pass unnoticed for her. Some authors even compare invertebrates in a state of anhydrobiosis with a Sleeping Beauty from a fairy tale, for which time has stopped 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 mastery of the Celestial Empire is always carried out through non-action. Those who act are not able to master the Celestial Empire." To paraphrase his words in relation to aging, we can say that only those who do not live are immortal.
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