Old men, robbers
Cancer and aging: two sides of the same coin
Polina Loseva, "The Attic"
The relationship between cancer and old age is difficult to call unambiguous. Aging is considered the main risk factor for the development of tumors and at the same time the main strategy of protection against them. But this contradiction disappears if we imagine that old age and cancer, like Dr. Jekyll and Mr. Hyde, are not complete opposites, but the same thing.
The dark side of the cellular soul cannot be eradicated: every peaceful cell in the body strives to capture the maximum amount of resources. General prosperity lasts until one of the equals randomly becomes stronger than the others. With rare exceptions, tumors are found in all multicellular organisms, from plants and fungi to "immortal" hydra and naked diggers. And regardless of which cellular "state" something goes awry, all cancer cells violate the five basic rules of peaceful coexistence.
1. Demographic control. Tumor cells are deaf to the reproaches of neighbors and continue to multiply, despite the tightness in the tissue. Sometimes they even secrete growth factors – signaling substances that stimulate division, and water themselves with them.
2. The Code of Honor. A cellular sociopath is not able to admit his mistakes and virtuously commit suicide, realizing that he has gone too far. In tumor cells, the mechanisms of programmed cell death (apoptosis) are disabled or anti-apoptotic signals are too strong.
3. Rules of catering. Cancer cells often have damaged mitochondria, and this is a sure path to apoptosis. In order not to injure them further, malignant cells switch to eating "fast food", that is, glucose. From it, you can quickly get energy bypassing mitochondria and oxygen respiration, and oxygen in the tumor is also not always enough. But such "nutrition on the run" is ineffective, so you need a lot of glucose, much more than the average citizen should. And, in accordance with the principle of "to everyone – according to their needs", the crook turns into a bottomless mouth for glucose, eating his neighbors.
4. Division of labor. In the tissues of the adult body, idlers are not liked: the cell is either specialized and works for the common good, or multiplies and gets a profession, or sits on maternity leave and prepares to leave offspring. However, "maternity" stem cells, freed from the need to work, do not enjoy other public benefits: they do not grow and practically do not eat. Cancer cells try to combine all these statuses: they rest like stem cells, multiply like progenitor cells, and eat like real hard workers.
5. Cleaning schedule. No matter how the relationship between cells in the tissue is built, they live in a common space – the extracellular matrix, which must be kept clean. The matrix is something like a large web with niches for individual cells. The longer the protein strands from which it is woven, the stronger the fabric and the more stable life: the sense of support allows cells to survive, and the protein barrier prohibits the immune police from deploying military operations in the tissue. Therefore, the inhabitants of the web continually digest broken proteins and secrete new ones. Gluttons, on the contrary, dissolve the matrix, which prevents them from moving and settling their offspring.
Aktipis et al. / Philosophical Transactions of the Royal Society B.
Now imagine that there is a potential pest in the slender cell rows. He has not yet begun to deceive the system and has not seriously harmed anyone, but he is already expressing seditious thoughts, for example, about a large family and dozens of children, like two drops of water similar to their father.
The easiest way to pacify his impulses is to forbid him to reproduce, to hand over to a monastery, as a girl who has disgraced the family. At the molecular level, the "monastery" looks like two proteins, p16 and p21, which tightly bind the proteins that trigger cell reproduction and their corresponding genes. This is quite enough for a disordered citizen to stop threatening the existence of the organism.
And so we blocked the division program in a suspicious cell. Now we have a sterile citizen who, however, has not lost his arrogant manners: he still does not want to work, hunts for glucose, litters right and left and refuses to die.
In this description it is not difficult to recognize a typical old cage. Old age at the cellular level is not so much a sign of an organism's age as a set of specific properties. Old cells, just like cancer cells, prefer glucose to any other food, do not succumb to apoptosis, lose their former functions, but secrete proteins that trigger inflammation and restructuring in the tissue, that is, they actually destroy it.
The similarity of criminals with old people turns out to be so strong that even the drugs act on them the same.
Most of the senolytics (drugs against old cells) that are currently undergoing clinical trials have been obtained on the basis of long-known antitumor agents.
The tumor cell, of course, is quite an unsympathetic character, a kind of Mr. Hyde, who allows himself what others cannot. But upon closer examination, the old cell is not much better. Presumptuous gluttons, in fact, indulge in a free cellular life, the dream of which every second decent citizen cherishes. And the old cell differs from them only in that it is able to recognize bad changes in itself in time, like a conscientious Dr. Jekyll, and use the rest of its will to solve this problem on its own.
Stevenson's character took a magic serum to get himself back on the right track and not give free rein to base instincts. Inside each cell there are also several mechanisms of self-discipline. The most famous of them are telomeres, the end sections of DNA, a measure of cellular reproductive abilities. With each division, they become shorter and shorter, and when they reach a critical length, they stop cell reproduction, and reproductive aging occurs.
This is not the most reliable way to protect yourself from an outbreak of crime – the cellular Hyde manages to produce the first few generations of offspring – but perhaps the most economical. In the end, the "cancer attempt" may fail on its own – most cells with oncogenic mutations never become a tumor, but commit suicide, unable to accept changes in their worldview, that is, numerous breakdowns in DNA. And only when the next attempt to create a state within a state begins to show signs of success, the mechanism of replicative aging comes into play and it turns out that the length of telomeres is not enough for the rebels to arrange a full-fledged sovereignty.
Sometimes cells come to their senses earlier – at the stage when thoughts of domination over the world are just emerging in them. In order for a cell to become cancerous, several seditious ideas, that is, oncogenic mutations, must be born in its head at once. This may be a mutation in the gene of telomerase, an enzyme that prolongs the reproductive capabilities of the rebel, as well as breakdowns in the genes that control cell division and death – oncogenes. But if a young separatist moves along his path with timid steps, gaining key mutations one by one, then sometimes he has time to come to his senses – oncogene-induced aging becomes a response to excessive activity of genes that stimulate reproduction.
The most prudent and law-fearing citizens go into voluntary exile long before the manifestation of seditious intentions. This is how stress-induced aging works: the cell stops multiplying in response to the action of toxins, radiation, temperature changes and other stressful factors. Each of them can lead to mutations in DNA, which means it makes sense to protect yourself in advance, at the first signs of mental instability.
However, this does not mean that in the absence of stress, bad thoughts and someone's "liberation movement" in the neighborhood, cells indulge in idyllic coexistence. If we look at what happens in human tissues with age, we will see that decent citizens are increasingly harmful.
With age, suspicious individuals accumulate in the tissues, who work worse, die less often and eat more. Most often, they do not declare their claims to hegemony, but remain simple crooks, slightly parasitic on their honest neighbors.
The reason for this stratification in the fabric is again competition. During life, each cell acquires a set of unique mutations. Some of them randomly give her a small advantage – for example, they allow her to work a little less and react less to signals from neighbors. Lazy cells leave more descendants in the tissue than honest and hardworking ones, and therefore they begin to dominate with age. This apparent degradation of society has its advantages: there are fewer ardent separatists in such a situation. Why, indeed, raise a fuss, if you can steal from your neighbors with impunity? Tumor cells are the product of fierce tissue competition, these are the citizens who have to break the system to meet their needs. "Lazy" mutant cells are intermediate winners in the competition, who have no incentive to move on and become even more malicious.
Dr. Jekyll did not stop turning into Mr. Hyde when he realized what abominations he was capable of. Instead, he sponsored his nefarious alter ego with money and let him into his house. Old cells similarly support the existence of a tumor: they secrete growth factors that stimulate the reproduction of vile types, and split the intercellular substance, allowing those to spread around. Therefore, in particular, the risk of developing tumors increases with age: tissues become less resistant to the criminal collusion of old people with bandits. In turn, cancer cells complicate the lives of others and expose them to stress, which makes them age faster. In this sense, tumors are not only a consequence of aging, but also accelerate it additionally. Even antitumor therapy does not save: mass killings of cells in the body do not contribute to the rejuvenation of survivors and patients who have survived oncological diseases often turn out to be much older biologically than they were before treatment.
Old age and cancer go hand in hand for a long time in life. And only at a respectable age, after 70 years, the incidence of tumors decreases, and in centenarians (100 years and more) they are almost not detected at all.
You can come up with different explanations for this phenomenon. For example, it can be assumed that after a certain age people go to doctors less often and look for new diseases, because they have enough old ones. Or you can imagine that at some point the body runs out of resources - there are fewer dividing cells, and inflammation, on the contrary, increases – and theft ceases to be profitable. But it may also be that everyone who had an increased risk of developing a tumor has already died (or been cured) from them before, and only the most persistent remained afloat.
The strategy of fighting and preventing crime, which our body has chosen, is certainly quite economical, but it seems to be a losing one. With age, tissues are filled with marginals: some of them are socially dangerous, some are generally harmless, but none of them directly benefits the body. Neither mafiosi, nor humble infertile old men, nor lazy parasites improve the welfare of the state. Meanwhile, it continues to fight the threat of disintegration, sacrificing its citizens. Sooner or later, citizens come to an end, and along with this, the life of the state ends. But if everything goes well, it dies unconquered, not succumbing to internal enemies, like Dr. Jekyll, who was lucky to die as Dr. Jekyll.
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