Blockade genes: details

Alexander Sokolov, XX2 CENTURYAlas, it is not often that news about the research of Russian scientists gets into the world's leading scientific journals.

It is all the more gratifying that in June, not somewhere, but in Science, a news article by Russian authors appeared, entitled "Did good genes help people outlast brutal Leningrad siege?" ("Good genes helped people survive the brutal siege of Leningrad?").

It turns out that although doctors have repeatedly studied the people who survived the blockade, until now no one has thought to look at the blockade from the point of view of genetics. But the Leningrad blockade, in fact, is a monstrous evolutionary experiment. During the 872 days of the blockade, more than a million people died, a significant part of them from hunger. In fact, natural selection took place: carriers of certain genotypes survived, whose body was tuned to economical energy consumption. This hypothesis was put forward by Russian geneticists, and in order to test it, DNA analysis was carried out in 206 blockade runners. The attention of scientists was focused on 5 genes regulating the metabolism of lipids and glucose. For comparison, a control group of 139 people of close age (over 69 years old) who did not live in Leningrad during the blockade was studied. What are the results? The blockade group significantly more often (by 30%) had gene variants associated with economical metabolism. Probably, it was these genetic features that helped the blockaders to survive in extreme conditions of hunger and constant stress.

We talked with one of the authors of the study – senior researcher at the D. O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, leading researcher at St. Petersburg University, geneticist Oleg Glotov.

XX2 CENTURY. Oleg, tell us how the idea of such a study came about?

O. Glotov. We have been studying the genetics of aging for a long time, for 15 years, this is an extremely complex and interesting topic. We started studying centenarians aged 69 to 102 years, analyzed their genomes and compared them with younger people. The goal was to understand the differences in the genome of centenarians, whether there is logic in them, whether the frequencies of alleles of different genes change with age. The genes we studied were related to the risk of cardiovascular diseases. 

It should be clarified that the main way of prolonging life, recognized in the world, is associated with the restriction of caloric intake. There are a lot of works on model objects, starting with ascarids and ending with mice, which show that in order to live for a long time, there should be enough food, but not in excess. This is due to the work of genes that involve carbohydrate and fat metabolism, switch the exchange from slow to fast and vice versa. We thought about the fact that the work of these genes has been little studied. And that there is such a unique object as blockade runners, whose genetics no one has looked at. 

But those of them who are still alive – they not only survived in extreme, stressful conditions, but also became centenarians. There was a hypothesis that some genetic features helped to survive the blockade, thanks to which all the meager food received during the blockade was used by the body to the maximum. As you can see, the hypothesis was confirmed.

XX2 CENTURY. Was there anything unexpected in the results that surprised you personally?

O.G. The first moment. We assumed that depending on the duration of stay in the besieged city, the picture of the subjects will be different. Nothing like that! Groups different in this parameter did not differ genetically from each other. That is, the minimum period in besieged Leningrad was enough to weed out everyone with weak genotypes – the first harsh winter of 1942 did it. By the way, you may know that the blockade certificate was issued even for the minimum period of stay in the blockade. According to our results, this is also true from the point of view of genetics.

And the second point. Genetic features that ensure economical metabolism, in theory, under normal conditions should lead to obesity and type 2 diabetes. Genes that help to accumulate energy are good when living half-starved. And when a person moves a little and eats a lot, then obesity or diabetes occurs.

So, it turned out that the incidence of diabetes in blockaders is not higher than in the usual group. Why? Perhaps those who have survived to the present day, despite everything, have genetic protection against diabetes. There are also few overweight people in our sample – mostly these people weigh 70, maximum 80 kg. 

XX2 CENTURY. Your article says that one of the genotypes contributed to the survival of the blockade only in women. How to explain it?

O.G. Most likely this is due to the fact that men and women have different metabolism, different fat layer, etc.

XX2 CENTURY. Your results are a convincing example of the action of natural selection in the human population. And what are the possible practical applications of the results obtained? For the purposes of longevity, or to combat overweight, for example…

O.G. As I have already said, the genes we are studying are associated with a slowing down of metabolism. In the presence of such genetic features as blockade runners, a person has an increased risk of obesity and diabetes. To correct the effects of these genes, you need to lead an active lifestyle, exercise, and eat less.

In addition – this is interesting from the point of view of sports medicine – these genes play a big role in athletes who want to increase speed and strength indicators. Depending on the genotype, there are three possible options:

Your article says that, according to the results of the study, a certain gene "begins to contribute to longevity after overcoming the "age threshold" of 90 years"…

O.G. Even before the study of blockade runners, studying centenarians, we came to the conclusion that a person has 2 age limits – 75 and 90 years. What are these frontiers?

If a person has a tendency to cardiovascular diseases, for example, an increased risk of heart attack, and at the same time a person successfully lived to 75 years old, overcame this milestone - those genes that were harmful before, increased the risk of heart attack, now become useful. If he did not die from them before the age of 75, now they contribute to a long life! And then – there is another age limit ahead, before which he should not die from cancer. And if this person overcame the milestone of 90 years, then the genes that increased the risk of cancer also become the key to his further longevity. Such an amazing fact: useful becomes harmful, harmful becomes useful. It has not yet been possible to find a solid hypothesis to explain this phenomenon, but not only have we come to such conclusions, colleagues dealing with this topic have similar results.

XX2 CENTURY. Did the study take into account other characteristics of the subjects other than their gender and age? For example, their social status… For sure, not only genetic factors influenced the survival rate during the blockade. For example, someone received a better ration, someone worse…

O.G. Of course, what you say could affect survival. It is not so easy to take this into account. I want to say that we tried to take into account the data that is in our database on blockades (based on the questionnaire that the people studied filled out). The database contains the time spent in besieged Leningrad, age, illness, weight, height, profession, bad habits. But not everything can be found out. Ask everyone what ration they received? Ugly.

Of course, we plan to take into account as many factors as possible, to calculate their contribution to survival.

XX2 CENTURY. The Leningrad blockade is one of the most terrible "experiments" set by life in the XX century. Every year there are fewer and fewer blockaders – soon there will be no one to study. What other research can be done with this unique group of people? What other data can be obtained?

O.G. Yes, there are very few blockade runners left – even of those we investigated in 2006, most are now dead. 

That's why we have to hurry. Of course, even if there are no blockaders left at all, it will be possible to study their children – we also do this. The children of the blockade are also very interesting, they inherited the peculiarities of metabolism from their parents. And they, for example, have different frequencies of certain diseases.

The complete sequencing of the blockade genomes is a golden dream, I really hope that it will come true. If you look not at individual genes, but at the whole genome, many important questions could be clarified. But this requires large sums…

XX2 CENTURY. It seems like a full sequel costs $1,000 now?

O.G. If only! This is in America, and this is only the price of reagents. And in our country, reagents will cost 400 thousand rubles, per person. And this is a "naked" file, which then still needs to be worked with. This is a complex and time-consuming process.

I hope we will find the resources. The main thing is to collect the remaining blockaders and examine them as much as possible. After all, we have suspended the study. I would like to resume it at a more modern level, collect material according to new standards and attract new participants, not 200, but at least 1000 people. And their children, grandchildren, great–grandchildren, the whole family tree - everyone who can be examined.

We also asked for a comment from the scientific journalist Yulia Smirnova, whose efforts brought the news to the pages of Science. Here 's what Julia told:

Yu. Smirnova. I found out a few months ago that Oleg Glotov and his colleagues are engaged in genetic research of blockade runners. When my colleague Angelina Davydova and I had the opportunity to offer Science magazine several topics for an article about Russian research, the first thing I thought about was Oleg's work, because this is an important study not only from a scientific, but also from a social point of view. And seeing the resonance this publication has in the domestic and foreign press, I understand that the choice was made correctly. Fortunately, the editor with whom we collaborated was interested in this particular topic.

After that, a lot of work began, we met with Oleg several times, read a lot of additional literature, contacted experts who shared their opinions on this issue, and it was not without criticism! In general, the experience of working with one of the most prestigious scientific journals is worth a lot, it is a completely different level, a different and much more responsible approach to facts and their presentation than is customary in many Russian media.

There is also a sad moment. It would seem that only last year we celebrated the 70th anniversary of the lifting of the Blockade, and by this date a lot of publications were published, there was a lot of information. When I conceived this article in Science, I thought that in this way it would be possible to tell the Western reader about what the Leningraders experienced in those terrible years. But after reading several domestic publications that appeared after the article was published, it became clear that not all journalists understand what they are writing about. And it's not about genetics, but about the most general data about the Siege of Leningrad.

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06.07.2015