Cellular tragedies, part 5
Where do the years go?
Polina Loseva, "The Attic"
The inner life of the cell is eventful no less than the human one. It is full of passions and dangers and just as inevitably ends in death. Polina Loseva understands what plots occur in the fate of cells and how their development affects you and me. The following story is sad, but not without optimism – about aging. By what signs can it be recognized, can it be prevented and when to wait for the pills of eternal youth?
"Cellular tragedies" is a large series of articles about cells, which continues to be replenished. Read other texts about the difficult life of cells: they tell about deaths and suicides, stress, shock and self-determination.
Before falling into the inevitable accompanying despondency of the stated topic, let's decide on the hero of our story. It's not difficult to imagine an old man, but how can I describe his condition? If we assume that old age is only an age characteristic, then it is unclear what to do with people who age prematurely as a result of various diseases. What, in fact, are the criteria for aging? Inability to reproduce, depletion of cellular resources, or organ malfunction? And is it true that old age is inextricably linked with age?
Looking for the root of evil
Let's first look at what we know about the causes of aging at the cellular level. The phenomenon of cell aging was discovered in 1961. Before that, it was believed that cells in culture (that is, outside the human body) can divide indefinitely. But careful experiments by Leonard Hayflick showed that sooner or later the cell population stops growing, regardless of the availability of free space and nutrients. This is how the replicative theory of aging arose: a cell ages when it can no longer divide.
But wait, attentive readers will object to me, not all cells in the body divide. Let's take a neuron or a cell of the pancreas, which are normal and should not multiply. Are they considered old too? In addition, in 1961, they did not yet know that there are stem cells in almost any human organ, in which the division limit is more difficult to detect.
However, even cells that do not multiply die more often with age and begin to work worse (for example, they can synthesize fewer proteins). This fact is intended to explain the free radical theory of aging. Its main idea is that an extremely active molecule, oxygen, is constantly present in the cell. From time to time, extra electrons sit on it and free radicals are formed. Due to their increased reactivity, they damage different molecules on their way (when they accumulate in the cell, oxidative stress occurs). The longer a cell lives, the more it collects such corrupted molecules and the more difficult it is for it to perform its functions in the body.
But the cell's troubles do not end there either. If free radicals reach the nucleus, then errors can occur in the DNA under their action. In this case, the repair system is activated – a group of multifunctional proteins. They not only repair breakdowns in DNA, but also stop cell division and, if there are enough breakdowns, start the process of cell death. Therefore, the theory of DNA damage explains aging through the accumulation of mutations and the work of repair proteins. Numerous studies of premature aging syndromes speak in favor of this theory. The most well–known of these diseases is childhood progeria, or Hutchinson-Guilford syndrome, but there are also many syndromes that manifest themselves in adulthood. In all cases of progeria, the same disorders occur in the body as with aging. And for all these diseases, it was possible to establish a connection with defects in the DNA repair system or improper DNA stacking in the nucleus.
Nine Faces of old age
Most likely, all three theories of aging are true at the same time and there are several reasons for cellular aging. However, this knowledge does not allow us to reliably distinguish an old cell from a young one. How many free radicals or mutations must accumulate in order for us to recognize the cell as old? We would really like to be able to determine the "degree of old age" of a cell, especially if we want to look for ways to prolong life. It would be nice to selectively color old cells with something and calculate the change in their number during, for example, contact with different substances. But, unfortunately, we don't have such a dye yet. At the moment, the old age of the cell is determined by the sum of the signs. That's what should make you suspicious if you're a cage:
1. You have memory problems. When dividing any cell, there is a problem of DNA doubling, or rather the end sections of chromosomes. In order to copy a DNA molecule, a special enzyme – DNA polymerase - must sit on the DNA chain and travel along it to the end. But if she sat down at the end of the chain, then she will not be able to copy the end sequence itself. The zipper on clothes works approximately on the same principle: at the beginning there is always a metal plate that cannot connect to anything. But, unlike lightning, DNA must be double-stranded along its entire length. Any fragment of single-stranded DNA is broken down by special enzymes (what if it is the DNA of a virus and it needs to be fought?). Therefore, chromosomes lose their ends and shorten with each division. Until some time, this does not pose a danger, since telomeric repeats are prudently placed along the edges of DNA – a set of TTAGGG sequences (thymine-thymine-adenine-guanine-guanine-guanine) in a row. They are needed precisely in order to lose them. But sooner or later telomeres come to an end, and the semantic part of the chromosome is under threat. And useful genetic information in the cell begins to be gradually lost. At first you forget what you did in early childhood, then school years are remembered with difficulty, and the student days fade from memory day after day. So it's not long to forget what just happened. And if memory loss is not always critical for a person, then the cell can thus forget about how to eat or breathe, and then it cannot avoid imminent death. Cells that divide frequently (stem and cancer) have a way to solve this problem. The enzyme telomerase works in them, which completes telomeres at the edges of chromosomes. Such cells are not threatened with memory loss. However, as cells specialize, they lose their "stemness" and stop producing telomerase. And then each new division brings them closer to imminent death.
2. You are not ready for change. With age, not only the length of DNA changes, but also the areas of information available for reading. As we age, more and more of the DNA is covered with methyl tags that cause it to twist. This is called epigenetic aging. The cell can no longer read the folded genes. This means that its adaptability to the environment is reduced. The further you go, the more familiar your home and lifestyle are, and if something happens, you will not be able to move, change your job or diet. The years are not the same anymore.
3. Your digestion has changed. Disturbances in the work of individual proteins lead to global changes in physiology. Even your favorite food you begin to digest in a different way. For example, the functioning of the enzyme that breaks down carbohydrates, beta-galactosidase, changes: it begins to activate in a less acidic environment. At one time, it was with her help that they tried to selectively dye old cells. You can offer beta-galactosidase a colorless carbohydrate, which after cleavage is oxidized and turns blue. If you do this in an acidic environment, then young cells are stained, and in an almost neutral environment – old ones. Unfortunately, later it turned out that this method is not accurate enough.
4. Self-criticism is difficult for you. It is possible to fight the accumulation of spoiled or superfluous proteins with the help of autophagy – the digestion of individual molecules and organelles. This allows, for example, to get rid of poorly functioning mitochondria. And stem cells should remain stem cells and not specialize ahead of time. In old cells, autophagy is significantly reduced, and proteins accumulate, which makes it difficult for the cell to function. The more difficult it becomes to look at yourself from the outside, the less likely it is to cope with your problems.
5. Your daily routine has gone astray. Individual cells, as well as the body as a whole, obey daily biorhythms. This is of practical importance. For example, we have skin stem cells that divide regularly. Therefore, they need to copy DNA often, and this requires energy. That is, it is more convenient for cells to divide in the daytime, when a person is active and absorbs food. But in the light, DNA is more often damaged, so it needs to be actively repaired. It turns out that in the stem cells of the skin, division genes and repair genes should work simultaneously during the day. Over time, the repair begins to take more and more time, the energy is absorbed worse and the rhythms are lost. Imagine that you have worked all your life, say, as a trolleybus driver, from 9 am to 6 pm. And then you got older, started waking up earlier and now you work well only from 5 am to 2 pm, and then you fall asleep. You are out of sync with the general work schedule and wait a long time in the morning for the depot to open, and in the evenings you sleep right behind the wheel. It is not difficult to guess what all this threatens – both you and those who depend on your actions.
6. You are not able to reproduce. An old cell can be identified by a reduced number of proteins that trigger division. As a rule, cells maintain a balance between proteins that stimulate and inhibit division. But in old cells, due to errors in DNA and the active work of the repair system, the scales of these scales lose their balance. What kind of reproduction, in fact, can we talk about if you don't even find your way home the first time?
7. You often move things from place to place. Aging cells more often than young ones secrete proteins that destroy the intercellular substance. But at the same time, they also produce components of this substance. The protein framework of the tissue ages along with its inhabitants and needs to be rebuilt. Here to wipe the dust, there to glue, here to patch up – maybe the old house will be suitable for young people.
8. You provoke conflicts. Aging of the body as a whole is accompanied by an increase in the general inflammatory background – that is, the amount of proteins stimulating inflammation increases in the blood. The cells themselves are partly to blame for this. As they age, they more often secrete interferon and some interleukins, thereby attracting immune cells. In case of death of old cells or the appearance of a tumor, this will be useful – an immune response will immediately develop. This is a rather unexpected logic for a person: regularly call the police and ambulance in case you suddenly go crazy while they are driving.
9. You continuously give advice. Not so long ago it turned out that old cells have a significant effect on young ones. They secrete a whole spectrum of substances, but their effect depends on the intensity and duration of contact. If a young cell is not near the old one for a very long time, then the effect is rather positive: old cells stimulate the division and activity of young ones. But with prolonged contact, the consequences are unfavorable: young cells "become infected with old age" and begin to function worse or turn into tumor cells. This effect is familiar to everyone who has adult children: if you give something to young people once, there is a chance that they will listen. But if you impose your opinion for a long time and persistently, then either they will lose the desire to do anything at all, or they will become aggressive and then you can expect anything from them.
Old people don't belong here
And what about the recipes of eternal youth? The more we know about how we age, the more rejuvenation strategies should arise. The problem is that aging, as we now know, is a very multifactorial process, and the more difficult it is to influence all its mechanisms simultaneously. At the moment, attempts to prolong life are developing in the following directions. Remember everything. If we assume that life expectancy decreases along with the ends of chromosomes (which is not confirmed in all experiments), then we can assume that people lack telomerase, an enzyme that restores these ends, for eternal youth. We have already said that it exists in stem cells, but is lost during specialization. And what happens if it is artificially activated?
In the USA, the drug TA-65 is already being sold, containing an extract of astragalus (a plant from the legume family). Its creators claim that it activates telomerase, but the US Food and Drug Administration questions the efficacy of this drug. But even if we assume that we will learn how to activate telomerase, this does not solve the problem of damage to cellular proteins and DNA yet. Calm, and only calm.
The second theory of aging puts all the blame on free radicals and oxidative stress. In addition, the phenomenon of premature aging of cells caused by stress is known. When stress factors (for example, hydrogen peroxide or excess oxygen) act on the culture, they quickly acquire the characteristics characteristic of old cells. Does this mean that it is enough to reduce the level of oxidative stress in cells to achieve eternal youth? Alas, there are no such results yet. Even the well-known Skulachev ion SkQ has only a small effect on animals. In most cases, antioxidants (substances that reduce the level of free radicals) help prevent cell death in degenerative diseases when oxidative stress is significantly higher than normal. But this does not mean that they will be useful to people without degenerative diseases.
On the contrary, the concept of hormesis – a weak effect that stimulates the cellular response - has recently become popular. Under the influence of small doses of radicals, the cell enhances the antioxidant response, which allows it to respond better in case of real difficulties. Old people don't belong here. The third strategy, being projected onto human society, causes more horror than enthusiasm. If there is so much harm from old people and if old age, as we already know, is contagious, then you can simply remove them from the population. It sounds intimidating. However, at the cellular level, this method seems to work. By eliminating old cells, we reduce the level of inflammation, the risk of developing cancerous tumors and "old age infection" of young cells.
For example, last year, scientists selectively caused the death of cells with one of the characteristic markers of aging in mice. The result was an increase in life expectancy and an improvement in the functioning of the circulatory and excretory systems. Two senolytics are currently being tested – drugs that kill old cells – dasatinib and quercetin. Individually, they have already shown good results on mice. And dasatinib is even officially approved as a cure for leukemia. But their joint action has not yet been studied.
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The search for the miraculous "old age pill" continues. But taking into account the fact that aging is a multifactorial process, it is not necessary to count on speedy success. Nevertheless, numerous articles suggest that we consider aging as a protective reaction against tumor transformation. The more errors accumulate in the cell, the faster it will stop its division cycle. The longer oncogenes work in a cell – genes that usually stimulate the development of a tumor – the more often the aging mechanism is activated. Therefore, in the pursuit of eternal youth, one should not forget about the risk of developing cancer – the inevitable companion of dividing cells. Apparently, we have to solve these problems in parallel.
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