Does aging look like cancer and can it be turned off, why does the body need inflammation, where did viruses come from and did they appear before cells, who can live longer fasting, and who - ketogenic diets? All this is discussed in the report by Indicator. Ru from the lectures of the section “Life Sciences” at the forum “Science of the Future - Science of the Young”.
Conflicting signals
Ruslan Medzhitov, a professor at the Yale University School of Medicine, was the first to give a lecture on inflammatory processes and homeostasis (in the body this is how the maintenance of constant conditions of the internal environment is called). The scientist asked the audience to imagine the state of homeostasis as a ball inside the parabolic "pit" of the norm. When some factors try to unbalance the system, then under the influence of regulatory forces homeostasis will "roll" back - like a ball under the influence of gravity. But too much acceleration of the ball (even for the sake of its stabilization "at the bottom") will lead to the fact that it will fall out of the curve and the system will no longer be able to return to its normal state. “The same is with the inflammatory response: it is needed in order to restore balance. But in case of severe pathology, it will only push the system further from the norm or lead to its stabilization in a state of chronic pathology,”the biologist noted.
Inflammation can develop in response to allergens and poisons, tissue damage, stressful conditions for the body (environmental factors, unhealthy lifestyle) and, of course, infection. In all these cases, such a reaction evolutionarily and physiologically makes sense (except, perhaps, inflammation in response to unfavorable conditions): it protects the body, getting rid of harmful substances, influences or "conquerors", restores damage. But it is worth overdoing it - and problems begin: due to excessive hostility to unfamiliar (albeit harmless) foreign substances, allergies appear, an irreconcilable fight against infections leads to autoimmune reactions and even sepsis, the pathology of tissue healing entails fibrosis and cancer.
Medzhitov spoke about the four components of the process: what causes, what is detected, the regulator of the inflammatory response, and what acts. “These components are not unique to inflammation. Even in a thermostat, the principle of operation is the same: there are sensors and something that changes the value of a variable. The concentration of glucose in the blood, other homeostasis processes are also regulated in this way, all these are control systems,”Medzhitov cited examples. The scientist proposed to look at homeostasis simultaneously from the perspective of dynamic systems and control systems. In any controlled system there is a quantitative parameter, as well as processes that increase and decrease it. In a dynamic system, many elements change their position depending on time, and the whole whole assumes one of the permissible states. Some signals that are not associated with a parameter may come from outside. It is also known that if two teams contradict each other, then the green light for inflammation will be a priority. We also have mechanisms of negative feedback, when the system will actively resist changing the parameters of the environment. Some components do not affect the value of variables, but they help to adapt to new values.
Hungry life and well-fed death
“This leads to very diverse variations in biology. In an inflammatory response, the sensors produce cytokines, but they also act on system components that do not play a direct role in protection. This is necessary to adapt the system. The existence of two types of effects (elimination of pathogens and adaptation to them) leads to different defense strategies - resistance or habituation (resistance vs tolerance). For example, our body is tolerant to a huge number of bacteria in the intestines and on the skin, but in case of illness it will fight microorganisms,”the scientist explained. The same thing happens with an excessive inflammatory response: the body reduces its strength or adapts. However, for the patient, the latter means that the process can become chronic and cause a lot of problems.
A somewhat curious biology of survival is at work here: from an evolutionary point of view, the system is stable when the benefits exceed the costs. What looks like a disease to a patient or a doctor turns out to be a stable system, but with enormous costs. The behavior of unhealthy animals deviates from the norm: there is a loss of appetite, lack of communication, fatigue and lethargy, unwillingness to take care of themselves, suppression of libido. But, paradoxically, life can be bought at the cost of this suffering.
Studying these features, Medzhitov found that mice with sepsis stopped eating in order to survive, but died if they were force-fed (including simply from the injection of glucose). This happened even with "sterile" inflammation, experimentally caused by bacterial polysaccharides. “When the mice didn't eat, they changed their metabolism: they absorbed fats and produced ketonic acids. This is necessary for sepsis from lipopolysaccharides, Medzhitov said. - 30 seconds before death, the mice had convulsions - this may explain why, in some diseases, the risk of convulsions can be reduced by ketogenic diets. We also found that valporic acid leads to survival."
"Viruses infect everything"
We talked at the section not only about reactions to infection, but also about infectious agents themselves - the second lecture was devoted to the most ubiquitous of them. The world of viruses is inhabited by amazing creatures (or objects - depending on whether these portions of hereditary material in a symmetrical protein capsule-capsid are considered alive). “There are 10 million times more viral particles on Earth than there are stars in the observable Universe: if there are 5 * 1030 bacteria on Earth, there are 1031 viruses. In all habitats, there are 10-100 times more viruses per cell. Viruses infect everyone, and they are surprisingly diverse,”began Evgeny Kunin, a leading researcher at the National Library of Medicine at the US National Institutes of Health. All organisms have the same pattern of replication (reproduction) of genetic material. But viruses alone have several ways that no one else uses. RNA or DNA, single-stranded or double-stranded, and even in different polarities - all forms of nucleic acids have become genetic material. Only one of the Baltimore classes of viruses (depending on the type of hereditary material) practices replication, like all normal people.
Knowing where viruses came from and how they got so unusual would take science to a new level of understanding of evolution and the origin of life. The three supposed patterns of virus origin are about 100 years old. Viruses could be the first genetic systems in nature to emerge from self-replicating replicon elements. Perhaps all variants of genetic cycles were tested on them, and then the most reliable and effective one, which allows us to create more complex organisms, won (and we got it). The second group of hypotheses - early ideas, where viruses were represented by reduced cells (regression). Indeed, having switched to a parasitic way of life, organisms often discard the functions necessary for their existence in freedom as unnecessary ballast so as not to waste resources on them. Finally, the third group of hypotheses states that viruses are "mad" escaped genes that have acquired autonomy.“All this may seem like empty speculation, which there is no way to check. And in the first decades it was,”notes Kunin.
It is very difficult to understand who is right here (if at all it is possible to resolve this issue completely). Unlike cellular organisms, which definitely have a common origin and which have preserved genes that belonged to their common ancestor, viruses for similar processes did not find ancient homologous genes, according to which it would be possible to build an unambiguous related tree. Although viruses do not have universal genes, they do have conservative genes that are very widespread and encode the basic proteins required for replication or the construction of symmetric capsid envelopes. An attempt by Kunin and his colleagues to understand this topic led them to unusual conclusions. According to scientists, a wide variety of polymerases come from the same type of domains and may be of precellular origin. But the "relatives" of genes encoding capsid proteins were found in cells. It is possible that viruses have stolen the master's genes. This data is an argument in favor of the "chimeric" scenario of the origin of the virus, according to which the precellular replicative machine has merged with the "mad genes".
"Coronavirus is more different from flu than we are from bacteria."
It is curious that representatives of different classes of viruses according to Baltimore choose their hosts differently: in bacteria and archaea, viruses with double-stranded DNA dominate, animals and plants are more often attacked by RNA viruses. But it is impossible to study the entire variety of organisms (and the viruses inhabiting them) using the old methods: among the bacteria and archaea known to us, one of thousands of strains is able to grow in culture. The solution to this problem was the approaches of metaviromics and metagenomics in general, which led to a "tectonic shift in the understanding of the evolution of viruses." These methods allow you to isolate genetic material from environmental samples, read genetic sequences and learn about new objects without ever seeing them "live". “This shift in science is officially recognized. Today it is possible to register new families, groups of viruses sequenced only by metagenomics. More than half of the RNA virus sequences are now known from metaviromics,”Kunin emphasized.
By studying the conserved gene for RNA-dependent RNA polymerase, it was possible to construct a tree for RNA viruses. As noted by the virologist, the connections in it look rather unusual: “Relatives of SARS-CoV-2 are simple RNA viruses that infect plants. Influenza and Ebola viruses also have negative polarity, and symptoms of the disease may resemble COVID-19. But they are generally found on different continents of the world of viruses and are more different from each other than we are from bacteria. It is interesting that coronaviruses have one of the largest and most complex RNA genomes: their size reaches 30-40 thousand nucleotides. " The ancestral branches were viruses with single-stranded RNA with positive polarity. Of these, double-stranded ones arose, from double-stranded ones - RNA viruses with negative polarity. “We analyzed one water sample from the Yangtze estuary and as a result, we doubled the variety of known RNA viruses. About 5,000 sequences were known, now 10,000. And most of this diversity, in principle, falls into the groups identified by us, "said Kunin.
The DNA viruses that have recently been united into the Duplodnaviria empire have also prepared many surprises for researchers. The largest part of it turned out to be representatives with the familiar double-stranded DNA genome. They did not have common conservative genes, but the networks of common genes made it possible to distinguish two huge groups of relatives: the first includes bacteriophages with "tails" and relatives of herpes, the second includes bacteriophages without "tails" and giant viruses that attack eukaryotes (like smallpox or mimivirus). The controversy surrounding the origin of giant viruses seems to have been resolved against reduced cells: the ancestry of huge viruses can be traced back to smaller ancestors, acquiring genes from the host. Well, small viruses with single-stranded DNA genomes, apparently, several times originated from replicating agents-plasmids - single-stranded circular DNA.
To date, scientists have managed to obtain a clear and not too complex megataxonomy of the viral world with four empires, each of which includes separate kingdoms and types. Such a proposal from researchers was officially accepted by the International Committee on Virus Taxonomy, and more recent findings fit into this scheme. But the twists and turns in the evolutionary history of these creatures remained a lot - to study and study. This information, of course, helps not only to answer existential questions, but also to look for new ways to fight infections and use viruses for their own purposes.
Defeat something, I don't know what
However, human life and health are threatened not only by danger from the outside: as Vadim Gladyshev, professor of medicine at Harvard Medical School, professor at the Faculty of Bioengineering and Bioinformatics of Moscow State University named after M. V. Lomonosov, often the main risk factor for death (and non-communicable diseases too) is age. For centuries, humanity has been struggling to defeat aging, but there is still no general opinion about what it is. “Last year we had a debate with Aubrey De Gray in Berlin on this topic. And when at the conference of gerontologists in Canada 35 professionals were interviewed at the end, they all gave different definitions,”Gladyshev recalled.
The lack of attempts to explain this mechanism cannot be complained about. So, the idea of programmed aging by Weismann (originally from the 19th century) says that aging was originally laid down somewhere in the body, possibly encoded in genes. “But there is no such situation that the owners of some mutation suddenly stopped aging,” Gladyshev notes. According to the evolutionary theories of Medawar and Williams, there is an accumulation of mutations and antagonistic pleiotropy in the body. Genes are good at first, then damage builds up. But how many genes are there, how important is their role? No one knows". According to Harman, aging is due to free radicals, this approach does not consider all other causes of damage. Leslie Orgel attributed transcriptional and translational errors to the multiple copying of genes during cell division. But then again - why are they more important than the rest of the mistakes? The list goes on. The lecturer himself defined aging as the accumulation of harmful changes. “During reactions within the body, the enzyme converts the substrate into the product, but there is a non-zero chance that the enzyme will create (damage) a by-product. It is not accidental, and it can be called programmed, but it has no purpose. " One-sidedness remains the main problem of various approaches to the study of aging. There is no major damage, no major gene that could be turned off to enjoy eternal life: the entire body is involved in aging. The notorious telomeres are one small element, and their lengthening is not enough: you need to study all the elements together.
Thus, it will most likely not work to disable the process for good. But, from the point of view of Gladyshev, it is not necessary to remove all damage from the cell: you can simply dilute them. “It had to be a key strategy for life from the beginning. But then aging is a more complex process than life itself! If dilution is not possible when there are non-renewable cells, then aging is inevitable. But it can be slowed down, cells or structures can be rejuvenated,”the scientist believes. Gladyshev and his colleagues studied genetic changes in cancer cells as a model of aging and found several interesting features. For example, if a tumor originated in a child, then she had fewer opportunities to accumulate mutations, while the old man had more time. At the same time, the rate of accumulation in different crayfish is different. Every eight years, the probability of mortality doubles (cancers of the reproductive organs go away from dependence, since the body loses these functions faster than others). The difference was observed between representatives of different sexes - and this corresponds to the fact that men live less and age faster.
"There is no known intervention that extends life expectancy."
It is also important to understand that mutations not only accumulate with age, but are also present in the original organism. For some ultra-rare mutations, they may be associated with longevity or healthy life. Scientists also found a connection with the age of death of the mother (but not the father - although fathers may have died earlier due to risky behavior or war, and not for natural reasons). “Each person initially has about six harmful mutations on average. Even if followed for ten years, those with additional mutations die faster. Each such mutation shortens life on average by six months. So, some lead to long life, others vice versa. In the future, editing the genome could change the situation,”Gladyshev suggested.
More promising studies are possible on other organisms. But animals use different strategies, and not all of them are, in principle, applicable to humans. Work on 33 species of mammals has shown that in "centenarians" some genes of the central metabolism in the liver are strongly suppressed (in the kidneys - less, in the brain their work does not change). Several animal studies have shown a link between life span and nutrition. In one of them, yeast growing on a medium supplemented with "young" yeast lived longer than yeast growing on a medium supplemented with old yeasts. In another, mice fed with old deer meat lived longer than those who ate young.
In humans, alas, not everything is so simple, and similar patterns have not been proven. So far, it has not been possible to find a substance that would immediately change all these indicators in different organs "as it should" (assuming that we know how it should be). Growth hormone receptor knockout, food every other day, metformin, rapamycin, methionine restriction and even hypoxia - all these and other interventions continue to be studied, but success does not go beyond model organisms. “There is not a single known intervention for a person that increases life expectancy. We only know how to shorten it,”Gladyshev summed up. However, new approaches are already making it possible to quantify aging. Perhaps they will point the researchers in the direction in which to move.
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