Alternatives to death

How to Beat Aging

Mail.Ru Group, Geektimes

How does modern molecular biology look at the phenomenon of aging? How are they trying to study aging, are there any hopes for slowing down or even stopping this process? These issues were the subject of a lecture by biologist Alexander Panchin, which he delivered at the last in the office Mail.Ru In the popular science lecture Set Up.

Aging is a decrease in life expectancy with age. Starting from a certain age, the probability of a person's death increases every year. After 20 years, every eight years of life, the risk increases approximately twice. People die from heart disease, cancer, stroke, emphysema, pneumonia, kidney disease, Alzheimer's disease, accidents. But the good news is that scientific and technological progress has already made it possible to defeat many diseases and increase human life expectancy.

Over the past 60-plus years, life expectancy has increased in all countries, and in some people have begun to live about 20 years longer. In Australia, Canada, Japan, and some European countries, the average life expectancy exceeds 80 years. This is about the importance of good medicine in the country, the reasonable use of scientific achievements, the use of effective medicines, and not some kind of homeopathy and so on. But in general, progress is noticeable all over the world.

When the question arises whether we can beat this growing schedule of increasing mortality, I recall the words of the Wright brothers: "If birds can fly, then we can achieve controlled flight." Biologists say that if the hydra's risk of death does not increase with age, then we can probably achieve this. There are no fundamental restrictions that do not allow a living organism to live for a very long time.

At the end of the XIX century, a hypothesis was put forward about the theoretical immortality of hydra. In 1997, Daniel Martinez proved the hypothesis experimentally.

A classic example of a long–lived organism is a naked digger that lives ten times longer than its relatives – mice and rats. Scientists are already investigating the genome of the naked digger in the hope of understanding what makes this creature so special and long-lived.

If we evaluate the diversity of life on a global scale, then life expectancy in mammals can differ by almost a hundred times, and in animals as a whole – by tens of thousands of times. What could this be related to? It is obvious that genes play an important role in the aging process and longevity. From an evolutionary point of view, some shrew or vole is not particularly interested in living for a long time. In nature, few of the representatives of these species live to an advanced age, they are eaten by predators early enough. Even if some kind of life-prolonging mutation appeared, it would be of little use in terms of increasing reproductive success. And in species that have got rid of the threat from predators, we are just seeing an increase in life expectancy. The same naked digger living underground can live for 31 years. Another example of protection from predators is the ability to fly, as in the case of bats and birds. People can protect themselves with the help of science and technology.

There are organisms in whose genome death programs are already embedded. For example, in some salmon species, females die immediately after spawning. But there is a more interesting example – this octopus:

The female octopus lays eggs, stops eating and dies on average in a month. This is programmed death. But it turned out that this program can be canceled, and surgically – by simply cutting out a couple of glands, after which the octopus can live not a month, but 6-9 months.

There are examples of programmed cell death, when individual cells can kill themselves. This process is called apoptosis: when a cell accumulates a large number of mutations in order not to become cancerous, not to pose a threat to the body, it destroys itself, and reasonably enough – the cell does not just splash all its contents out, but falls apart into compartments, which can then be captured by neighboring cells and disposed of.

Interestingly, there is a transition from the death of cells to the death of the whole organism. The gut of the roundworm Caenorhabditis elegans (nematodes) slightly fluoresces. And when the worm dies due to natural causes or as a result of some damage, then an hour before death in the anterior part of the intestine, the glow increases and the wave gradually passes to the end of the intestine. After that, the worm departs to another world. This phenomenon has been called the "blue death wave". The wave can be induced artificially, for example by freezing and defrosting a worm. Scientists have also found a way to stop this wave. The worm's lifespan does not increase, but if it is damaged, it does not die from it. With the appearance of the wave, the process of cell death is triggered, but then this blue glow fades, and the worm continues to live on. The glow itself is just an indicator, but in fact it is a wave of cell death along the intestine, which leads to death.

Why did this mechanism arise? Apparently, as a result of such a "death in an hour", the worm gets to its own descendants as food. Worms bear babies, die and become food for the next generation. A symbol of sacrificial motherhood.

No such mechanisms have been found in humans, at least in adults. In our country, aging is a combination of numerous diverse processes. One of them is the aging of cells.

Old cells can damage neighboring ones, they can secrete substances that lead to inflammation. Old cells can become cancerous, and therefore it would be good to get rid of them. Recently, the results of studies on the removal of old cells of a certain type in genetically modified rodents with the help of a special drug have been published. And these rodents lived longer. That is, it is quite realistic to find an approach to aging cells.

Shortening of telomeres

Cell aging is associated with some processes. One of them is the shortening of the telomere. Nature is so arranged that with each cell division, the DNA molecule is shortened. At the ends of the chromosomes there are areas called telomeres, which are shortened, thereby protecting the rest of the chromosome. Telomeres are shortened from generation to generation, and in old cells they become very short. That is, the cells of an old and a young person can be distinguished by the length of the telomere, taking into account some variations in these signs.

However, the problem of shortening has already been solved in our stem cells. They have the enzyme telomerase, which is able to complete telomeres. Therefore, some cells are said to be immortal.

Another great news is that we can lengthen telomeres with gene therapy. Experiments were conducted in which telomerase was delivered to rodents by means of a special virus, and telomeres were completed in cells. Such rodents, as experiments show, live longer.

Similar experiments inspired Elizabeth Parrish to try such gene therapy on herself. It is clear that she is doing this as part of a PR campaign, because she owns a large biotech firm. There was information in the news that her telomeres seemed to have lengthened. But this is not really a scientific experiment, there is no control group, there is nothing to compare it with. Although this story inspires many and suggests that the shortening of telomeres is not an insurmountable problem of aging.

Accumulation of damage

Another thing that happens in cells is the accumulation of damage. They are different. One of the types of damage is the accumulation of all kinds of garbage in the cells. For example, poorly folded proteins, as is the case with Alzheimer's disease. Or improperly functioning organelles like corrupted mitochondria. With each cell division, these damages seem to be diluted, and for each of the two resulting cells, they account for half as much. That is, with active division, cells could rejuvenate.

But division also has a dark side – cancer. There are genetic mutations that are not diluted. A cancer cell is a cell that has accumulated a large number of mutations that can lead to unlimited division, disabling apoptosis. Today, there are more and more modern methods aimed at fighting cancer. Previously, it was a completely incurable disease, now in some cases it is being treated.

Fasting

One of the most beautiful experiments on life extension was associated with the study of the effects of partial starvation. The experiment was conducted on rodents. This is a graph of mortality:

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Green color shows those who ate from the belly, blue ate 25% less, purple – 55% less, and red – 65%. As you can see, the maximum life expectancy has increased by about 1.5 times. The greens died somewhere in three years, and the rest lived much longer. When all the greens have already died, the reds are still alive. An impressive result. It turned out that the mechanism of prolonging life through starvation is relevant for very different organisms, although not for everyone. There are those in whom partial starvation shortens life expectancy. But in many species it works. For example, the roundworms Caenorhabditis elegans, rats, some lines of mice, dogs, have conflicting data regarding macaques. It is very difficult to put such experiments on people.

When they found out how partial starvation prolongs the life of the worm, they found hormones that are released in response to food consumption. These hormones affect the DAF-2 receptor located on the cell surface, and this somehow contributes to aging. If this receptor is damaged, then such worms live about twice as long.

When the DAF-2 receptor is activated, it triggers a cascade of cellular processes leading to the inactivation of a protein called DAF-16. DAF-16 is a very important protein that regulates the work of the cell as follows. If food is available and DAF-16 is inactivated, then the cell thinks: "Oh, great, there is plenty of food, everything is fine, you can relax, nothing threatens me, you can multiply, share – everything is fine." If this signal is not present, that is, DAF-2 is spoiled, or if there is no food, then DAF-16 is activated, the cell thinks: "What a horror, I'm dying, stress, nightmare! We need to save ourselves!" – and launches a bunch of defense mechanisms: from mutations, from oxidative stress, heat shock, everything in a row. That is, DAF-16 makes hundreds of other genes work, protecting the cell from various problems.

It turned out that humans have proteins similar to DAF-16 and DAF-2. But a mutation was found in a protein similar to DAF-16. There are people with one variant of this protein, and there are people with another variant. Owners of the first option (FOXO3) are much more likely to live to 90 years or more. That is, by studying the molecular mechanism of aging in worms, we better understand how the mechanisms of aging in humans work.

Of course, not everything we learn about worms can be broadcast to people. For example, if we remove the germ cells from the gonads of a worm, this will also activate DAF-16 and it will live longer. But if you castrate yourself, it will not prolong your life.

Body weight

Dwarf bats can live up to 40 years. Organisms with a larger body weight live longer. But there are those whose life expectancy greatly exceeds the calculated based on their body weight. For example, humans live much longer than other species with the same mass. Dwarf bats and their relatives are also long-lived. These bats were found to have a protein similar to DAF-2, but with specific mutations.

In addition to model organisms, scientists are also investigating mutations that occur in humans.

This young man died at the age of 17, he had a premature aging syndrome called "progeria". This is a genetic disease that causes the early appearance of signs of aging. At a young age, senile diseases occur, and such people live on average for 13 years. This disease is caused by a mutation in the gene that is responsible for the synthesis of the protein lamin. This protein is responsible for the organization of the nucleus, the so-called nuclear matrix, the structure of the nucleus. In worms, with age, the nuclear matrix is destroyed in cells, and the slower this happens, the longer the worms live. Maybe the destruction of the nuclear matrix plays an important role in human aging.

Growth Hormone

Growth hormone indirectly leads to an amplification of the signal that is transmitted through our analog DAF-2. To simplify it a lot, the cells of dwarfs feel some effect of starvation. Here is the dwarf mouse Yoda and his girlfriend Princess Leia:

Yoda's gene regulating the synthesis of growth hormone was corrupted. He lived in the laboratory for four years – translated into human age, this is more than a hundred years.

In Ecuador, there is a population of people with a certain form of dwarfism, which is called Laron syndrome, there are about a hundred people. We don't know how long they live yet. Scientists have been observing them for more than 20 years, and there was a publication that these people have a reduced risk of certain senile diseases, including cancer and diabetes. Maybe they really live longer, compared to other residents of the same region.

The God of TOR, the lord of garbage

Our cells are able to remove garbage from themselves not only during division. They can absorb it. This is called autophagy – cells digest all sorts of filth inside themselves, then somehow dispose of it and throw it away. This process can promote cell rejuvenation, but it is hindered by the TOR protein.

What is he doing? He says, "Everything will come in handy. This rotten sandwich that you have here will come in handy. There will be hunger, there will be a blockade, and he will go into action." Our ancestors lived in conditions of regular food shortages. There were no genetically modified organisms, there was no green revolution, normal agriculture, there was nothing. Hunger could come at any time, and therefore TOR played an important role. But now this garbage accumulates and damages the cells. Fortunately, there are inhibitory substances that can crush this protein.

TOR inhibitors trigger autophagy through this protein. TOR itself is named after rapamycin: Target Of Rapamycin (target of rapamycin). Rapamycin is an antibiotic produced by fungi, it is also used as an immunosuppressant. This substance is used in organ transplantation to reduce the risk of rejection. Rapamycin also prolongs the life of various organisms, in particular mice, and quite strongly.

Rapamycin is very expensive, so in many cases a much cheaper TOR inhibitor, caffeine, is used. Animal studies have confirmed that it improves autophagy and prolongs life. There are also results of epidemiological studies, according to which in human populations, where it is customary to drink several cups of coffee a day, mortality is reduced by 10%.

There is a concept of "French paradox": the French live a long time and rarely suffer from cardiovascular diseases. At one time, this was explained by the consumption of resveratrol contained in red wine. This substance prolonged the life of rodents. But then they recalculated how much wine a person needs to consume in order for resveratrol to have the same effect – two barrels a day. Apparently, the French paradox is rather related to ethanol itself, which in a certain small concentration prolonged the life of nematodes. People who drink a glass of wine a day also have a reduced risk of cardiovascular diseases, such as coronary heart disease, coronary heart disease, and so on. But ethanol has negative side effects: alcoholism, cirrhosis of the liver, and the risk of certain cancers increases. Therefore, whether ethanol can be recommended as a geroprotector is a moot point.

Scientists are also interested in metformin, a cure for diabetes. It has some side effects related to the gastrointestinal tract. There is a study confirming that metformin prolongs the life of worms.

But nematodes live the longest – by 50% – thanks to alpha-ketoglutarate. It is remarkable because it is present in humans in large quantities and has low toxicity. But research on rodents has not yet been conducted, because it is very difficult for scientists to get funding to study this anti-aging drug, because aging is not considered a disease. Alpha-ketoglutarate, by the way, athletes use as a dietary supplement to accelerate the growth of muscle mass. But there is very contradictory data on whether it really helps in this.

Young blood

In a number of studies, scientists surgically connected the bodies of two rodents – old and young, combining their circulatory systems. Under these conditions, the old rodent lives longer, and the young one lives less, while the plasticity of the nervous system increases in old rodents, that is, the ability of nerve cells to form new nerve connections. They even improve the regeneration of muscle tissue. It is clear that no one suggests stitching pensioners and young children together so that pensioners live longer. But maybe we will find some factors that are present in young blood plasma, or we will find cells that prolong life, and we will be able to synthesize them and give them as medicine to elderly people. Tony Wyss-Coray told us about this wonderfully. Currently, technical tests are being carried out on the use of plasma from young organisms for the treatment of Alzheimer's disease. Let's see what they get.

Live long

Another story is connected with the researcher Aubrey de Grey, who also spoke at the Ted Talk. Aubrey said: "Some people say, 'Well, if we prolong life for 20 years, we will die not at 80, but at 100. But it's still not very comforting. Can we expect something more?“». Aubrey replied, "Yes, we can." Why? He cites a metaphor with universal gravity. If you take the ball and throw it, it will fall. If you throw it hard, it will fall a little later. But if you throw it so that it reaches the first cosmic velocity, then the ball will fly into space and never return to Earth. "Look, scientific and technological progress is developing faster and faster, and maybe in the 20 years that you still live, they will come up with a drug that prolongs life for another 25 years, and in these 25 years they will come up with a drug that prolongs life for another 30 years, and so on. And maybe, starting from a certain age, some people will be able to live for a very long time, thousands of years." Many scientists are skeptical about this. But there are no serious arguments why this is impossible in principle.

We see that scientific and technological progress prolongs people's lives, and all over the planet, in all countries, even in the poorest, and life expectancy is steadily increasing. And this means that for the sake of prolonging life, science needs to be developed.

Finally, I want to recommend a wonderful website geroprotectors.org – there are collected publications on the results of studies of various substances from the point of view of prolonging the life of experimental animal organisms.

Portal "Eternal youth" http://vechnayamolodost.ru  14.06.2016