Evolution doesn't need "longevity genes"

We talked with chemist Mikhail Shchepinov about what scientists now know about aging, what unsolved problems there are and how the transition from the simplest organisms to multicellular ones provoked a decrease in life expectancy.

– Are there any technologies in the fight against aging?

– Of course, there are no technologies. If there were – we would have seen other people on the streets with you.

– What are the main approaches to explaining aging in science?

– If we draw some kind of demarcation line, then at the scientific level, thoughts about aging are divided into two large camps. One camp believes that aging is encoded in genes, and the second – that it is not encoded, that it's all a matter of chance: something broke here, something worsened there. And so these breakdowns accumulate. The fact is that these breakdowns are starting to grow exponentially. There is such a term – "stochastic", it means that damage can occur randomly anywhere. Of course, there are some weak nodes in which the probability is more frequent. And two or three injuries are not terrible, say, in youth, and when these injuries gain some threshold value, they already begin to grow exponentially at an accelerating rate, and, accordingly, the weakening of the body also begins to go exponentially, and the person is already dead rather than alive.

The first line of demarcation that I would like to draw is that there are supporters of coded aging, and there are supporters of uncoded aging. I myself adhere to the point of view that it is not encoded. Why? The fact is that there is evolution, natural selection, it goes on an unpredictable path. If a child has some small difference that turned out to be genetically accidental, which the parents did not have, it is easier for him in some conditions than for others - for example, to get food for himself. So, he has more chances to leave offspring. It's like the mites that Darwin noticed on the Galapagos Islands. There were trees with different nuts growing there, and the pincers were divided into different types: some had a beak for some nuts, others for others. Small changes lead to the fact that some individuals feel better in some environment, and since they can get more resources in this way, they are more likely to leave offspring. And this parameter of theirs is inherited, and, accordingly, their offspring are the same as them. And individuals who either do not have such an advantage, or, on the contrary, something bad has appeared, will die out, because it is harder for them to survive. And this is how everything works randomly, because evolution is blind.

– Because, if you look, the selection is based only on those genes that can increase the chance of leaving offspring. And offspring are influenced by things that manifest themselves in the area of reproductive age, early in life.

One can cite the example of Arnold Schwarzenegger as a generalized image of male power. He is healthy, his bones are wide, his posture is correct, and so on. So, he needs these genes in order to leave offspring in the range from 15 to 55 years. But then, when his reproductive age passes, there can be no selection of genes for a later part of life, in which there is no reproduction at all. That is, no gene that will allow you to extend your life, say, up to 150 years, can work. So what if you live to be 150? You can't leave offspring. Thus, I want to say, there is no mechanism that evolutionarily selects a gene that allows you to live for a long time.

People who can really live to an advanced age are often very calm.

Perhaps this is the only common denominator among them, because there are centenarians who drink, there are centenarians who do not drink, who smoke and do not smoke, eat meat or fish, there are vegetarians. There are centenarians who live at sea level, and there are in the mountains. And many people pay attention to this and come to the conclusion that the most important unifying factor among centenarians is that they don't care about anything. Nothing can get them out of themselves. And I'm not just talking about a football match, but about much more tragic things: the war, the death of close relatives.

– You touched on the theory of evolution. What other theories do I need to mention to tell you what aging is?

– This echoes both evolution and the emergence of life on the planet. No one knows how life originated. Either some molecules came from outer space, or there was some set of unique circumstances here that has not been reproduced since. In short, it has arisen. And initially, when it appeared, there was no oxygen in the atmosphere.

I will make a small digression. The human body works in much the same way as an internal combustion engine: we have fuel, this fuel is burned in oxygen, which is in the atmosphere, and energy is released from this process through special small molecules into which it is converted, which are then used as energy sources in the body in all reactions. And not only in man, but absolutely in all living things, there is the same small molecule called ATP. It provides energy to all processes in the body. This molecule is obtained due to the fact that in the cells of the body, or rather, in the mitochondria of cells (these are such energy stations), fuel, such as sugars or fats (lipids), is burned with oxygen, so we breathe. This fuel produces energy that is used everywhere.

Initially, when the cells first appeared, life arose, there was no oxygen. Oxygen is in itself a product of the fact that cyanobacteria and other (later plants) began to use light energy for their needs, and exhale oxygen from themselves. So in the end, a high level of oxygen in the atmosphere accumulated, to such an extent that all living organisms that existed at that time had to take it into account. It was no longer possible to ignore oxygen, because it is an active gas, it oxidizes everything.

And they needed to react to it somehow. Some of them went deep under the water, where there has been no oxygen since then. And the other part decided to use oxygen to their advantage, because oxygen gave them the opportunity to produce the oxidation process much more efficiently. Similarly, oxygen enabled them to obtain energy much more efficiently from available power sources.

Other organisms like them have become one of the interesting and affordable food sources. Before that, they could not eat each other, because for this they needed a strong oxidizer so that all the energy that is in the other could be effectively converted into energy for themselves. And there was no oxidizer, there was no oxygen, so there was nothing to oxidize those sources of potential energy that were in another cell. Therefore, they only slowly dissolved some minerals at the bottom. And with oxygen, it became possible to devour your own kind. And a very interesting thing happened from this: organisms suddenly became multicellular, and before that they were unicellular.

Now it became important to them who was bigger, and they began to grow uncontrollably. So evolutionarily there was an interesting thing – multicellularity. They began to grow into some kind of conglomerates, actively adapted to everything and completely did not notice one interesting moment: all this progress had a flip side of the coin, namely, when oxygen appeared at such levels, they became mortal. This oxygen gave them advantages, but inevitably some small percentage of this oxygen did not get to where it was needed, because enzymatic reactions are not 100% accurate, but, say, 99.9%. And where the remaining 0.1% will jump out and what it will do is not clear to anyone. It was precisely these by-products of oxygen metabolism that began to spoil everything and accumulate everywhere. This is the essence of aging.

Returning to evolution. Evolution has only one goal, if it can be so animated and expressed, – to leave offspring.

And the only thing that can really be tracked is whether the genes from the previous one have been passed on to the next generation. Therefore, the push with oxygen was so powerful – organisms suddenly had access to such an immense amount of new energy that they were able to leave more offspring. Accordingly, they, without looking back at anything, utilized oxygen and since then they have been tormented by what to do with these products of secondary oxygen metabolism, which in the form of free radicals spoil everything everywhere, and nothing can be done here.

– What attempts have been made to overcome this and understand the mechanisms of aging?

– Naturally, there were various attempts, at first primitive, how to fix this whole thing and lengthen life. Firstly, there is such a thing as the Hayflick limit. This scientist discovered that cells can only divide a certain number of times and after that they no longer divide. And now, whatever theory of aging arises, it must also explain this fact. The second important case was when an experiment was conducted with the diet of mice. It is believed that the mouse eats from 3 to 6 grams of dry food per day. And they noticed that if you remove 40% of the amount of food that she herself would eat uncontrollably and feed her all her life with such a reduced amount, then you can extend her life by 15-20 percent. This is called calorie restriction.

There are many interesting points for and against. For example, opponents of this theory say that this experiment is wrong, because mice in cages are very much gorged compared to how they would live in the wild. And if you feed her like that all the time, then this is not the norm for her. Therefore, there are people who say that if you reduce the amount of nutrition by 40%, the mouse will not be malnourished, but, on the contrary, it will be normal compared to what it eats in the cage. Therefore, the experiment is an incorrect statement of the question. And the "reduced" amount is her amount of food if she lived in natural conditions.

There are also other critics who ask: how is it normal? After all, mice never die of old age in the wild. They always die one way or another. How do we know what would be the norm? The case is complicated by the result of recently completed experiments with primates. This restriction of caloric intake as a way of prolonging life was very interesting to everyone, and therefore, in the end, they decided to conduct an expensive and long experiment on monkeys.

NIH (National Institute of Health), one of the main organizations in America that funds and conducts research in the field of life science, has found funding for the experiment. The results are as follows: the life of a monkey is not prolonged by calorie restriction, but others are prolonged (this works on different flies, for example). There were some positive results – for example, there were fewer types of oncologies, which are often observed in old age, wool was better, but life expectancy did not increase.

And primates are monkeys and we are with you.

The modern approach, which began in the last century and continues now, is an attempt to look at cellular mechanisms and from these mechanisms to understand which parts of the cell, which aggregates and nodes in the cell are most important for the aging process and most quickly become unusable.

They agree that mitochondria – those factories that make energy from food and oxygen – are very important because they wear out very quickly, they work like motors in a cell. Scientists are now trying to understand the mechanisms at the molecular level. And here, naturally, the field of activity begins to expand.

It is important to tell about telomerase, which was originally invented by our compatriot Olovnikov.

We have all the information contained in DNA. DNA is two chains in which genes, in which all the information. These DNA must be copied: when a cell divides, exactly the same must pass into the daughter cell. But this is done by enzymes. There are four letters: A, T, G, C. And the letter A always sticks to the letter T, and the letter G always sticks to the letter C. Therefore, when you copy a chain, one of the two, the enzyme learns that it has stumbled upon the letter A, and immediately builds a parallel chain, complementary to this one, and puts the letter T there. If he recognizes the letter C, he inserts the letter G. And so, like a zipper, it comes to the end. The result of this is that he was traveling along one chain of these two, and built a second, complementary thread to it, because there should be duplicates in the cells. Unless we are talking about germ cells, sperm cells and eggs, in which there is a single copy, in all other cases it is double.

It turns out an interesting thing. The enzyme is very large, it does a complex job. The problem is that due to the fact that there is a small physical distance between the place that the tip of the DNA recognizes and the place of this enzyme that begins to make a copy, and this piece is lost every time.

That is, each time a cell divides, the resulting DNA will be a small piece shorter.

And Olovnikov predicted the existence of an enzyme, which he called telomerase, which completes these tips without any principle of complementarity. Without him, life would have ended long ago.

This enzyme telomerase adds tips all the time, but then, when it more or less reaches the shape, it turns off. And this is a very important mechanism, because otherwise, if it did not turn off, 100% of people at a young age would die of cancer.

Please note, a cancer cell is a normal cell that needs to undergo several changes. Some cells always have some genes working, and other cells have other genes. And here the balance is important. So, in all cells, telomerase is turned off. But cancer cells undergo several changes, and all these changes are in one direction – so that they can multiply uncontrollably and quickly. And one of the interesting changes that cancer cells must achieve in themselves, otherwise they will not be cancerous (they can be pro–cancerous) is the process of turning on telomerase in them. Then they can share as much as they like. And the reduction of chromosomes will not occur. And, accordingly, this case will not stop.

– What does this have to do with aging?

– Here we need to recall the Hayflick limit, one of the first observations when people sat at microscopes and just made observations: the cell divided 30 times or 100 times and no longer divides. Why? Maybe she has scars on the membrane or something. In fact, if you look deep into the mechanism, telomeres are at a deeper mechanistic level just an explanation of the Hayflick limit: cells divide, and telomerase does not work for them. And when the tips of the chromosomes have shrunk to such a level that the place of recognition for the enzyme to count and start copying them has already disappeared, then everything stops.

This resonates with aging in a very interesting way. Therefore, we have several organs in which cells do not divide. The technical term here is "postmitotic cells" (mitosis is division, postmitotic cells that have stopped dividing).

Imagine a brain, it has neurons. No one knows how the brain works, but it is known for sure that information is contained in the contacts of neurons. Neurons are brain cells. And each neuron has tens of thousands of branches. For example, you have learned a new foreign word – you have a contact formed between two neurons in the area that is most likely responsible for the language, then another and another. Maintaining these contacts is, strictly speaking, the storage of information. Therefore, by definition, neurons cannot divide. Because if neurons were divided, then all the clever ways of their contacts, which are all our information, would disappear. Therefore, neurons do not divide, they are postmitotic. When they talk about brain cancer, it's not a cancer of neurons, but something starts in the blood vessel, and it begins to germinate. There are also indivisible cells in other parts of the human body. For example, the heart cells do not divide, everything connected with the eyes does not divide, there are still such places in the main blood vessels, in the arteries. That is, there can be no repair by cell renewal in principle.

And one of the most important tasks in the field of aging is to figure out what to do with telomeres. If you are looking at cancer, and not aging, then it is clear: it is better to have some substance, roughly speaking, a pill that causes telomerases to turn off, telomeres do not grow, and cancer cannot go on. But this is in contradiction with the desire to live forever. Because if you do, what should the unfortunate cells do that would just like to be renewed because the organ is wearing out?

In the mucous walls of the stomach, cells are updated once every two weeks. So quickly damage happens to them due to the fact that there is a caustic, active environment. Therefore, there is the highest probability of cancer: the faster it is updated, the easier it is for cancer cells to switch mechanisms. And from the point of view of aging, this is an unsolved problem.

– How can you even determine what the aging process is?

– This is a process of uncontrolled, gradual, under the influence of external and internal factors of wear and tear of the body. But when people say "aging", what does it mean? After all, there has never been such a thing in history that someone has died of old age. How do you imagine? Always the cause of death is that some one component has become unusable and is no longer compatible with life. And this suggests an interesting conclusion. This means that it's probably a little wrong to try to beat aging, because people don't die from it.

People die mainly from three causes: neurological diseases, cancer and cardiovascular.

Then you can just continue, as pharmaceutical companies do, to work on these three main topics, and people will live longer.

People used to die from infections. When taps with water and a bar of soap were introduced, life expectancy instantly jumped by 15 years. And what happened? Suddenly they saw: it turns out that there are cardiovascular diseases, and no one knew about them before, because they did not live to see it. Or they saw: there is Alzheimer's with Parkinson's. Alzheimer's was discovered only at the beginning of the twentieth century, there was some kind of genetic case in a woman who had everything started earlier, but did not live up to it.

If we somehow take these things under control and slightly improve the situation on them, then we can make such a prediction: firstly, life expectancy will last - say, people will live up to 120 on average; but, secondly, at the same time completely new causes of death will appear – and this is a separate problem in the field of aging research.

About the author: Mikhail Shchepinov – PhD in bioorganic chemistry, founder and director of Retrotope.

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23.06.2015