Take care of your fire
What if old age is an inappropriately prolonged youth?
Polina Loseva, "The Attic"
"They've been looking for a long time, but they can't find it" is about aging research. There are already a lot of individual factors that accelerate the extinction of the body. I would like to identify one key reason that drives this complex process, eradicate it and finally find eternal youth. However, upon closer examination, it turns out that the same programs work in the old body as in the young one, just too long their work leads to disastrous results. So, it is with eternal youth that we have to fight.
Who started it first
Any thoughts about aging inevitably end in metaphysical speculation. No matter what aspects of it we study, we still want to understand why it is needed or at least why it happens.
Surprisingly, the first question is easier to deal with. One can imagine aging as a way to clear the population of individuals who have left the reproductive period. It can be assumed that the rapid change of generations allows the species to evolve faster. Or simply conclude that there are no biological considerations that would justify the eternal life of organisms.
The question "why" is much more controversial. First of all, because we know too many answers to it. Everyone is blamed for aging – free radicals, mutations, incorrect functioning of genes, excessive DNA methylation, retrotransposon migration, and depletion of the immune system. And the further away, the weaker the hope of finding the instigator among these criminals. At the same time, it seems that the members of this gang cannot act independently, their mastermind must exist somewhere. In other words, I want to cut off unnecessary entities and determine the specific root cause of aging.
In an attempt to explain everything in one fell swoop, a theory of programmed aging arose: it's not that something breaks in the body, but that some program prohibits repairing breakdowns. One of the main arguments of this theory was the existence of long–lived animals, and a classic example is a naked digger. Since they age more slowly than we do, the authors of the theory claim, and their breakdowns accumulate at the same rate as ours, it means that they somehow managed to disable this program. But time is passing, and it is not yet possible to bring it to light.
But another interesting observation has appeared: many mechanisms (genes, proteins and signal transmission pathways) that are active in an aging organism are also active in a young one. This allowed Professor of Oncology Mikhail Blagoslonny to formulate the theory of the quasi-program: there is no separate program leading to aging; it is caused by the work of the same mechanisms that keep the young body afloat. And, unlike his predecessors, Benevolent presented a list of suspects and brought specific charges against them.
The three-headed Dragon of Aging
What is the difference between a young organism and an old one? The first one produces a resource (work, body weight, offspring), the second one protects the accumulated over a long life. Therefore, the metabolism at different life stages should differ. The task of a young creature is to consume the maximum amount of energy, build a house, plant a tree, raise a son, and stock up the rest of the food for hungry times. After the end of growth and reproduction, such an intensive metabolism is completely unnecessary and even harmful – it is quite enough for a pensioner to live in a small house and cultivate his garden.
But there is no switch in our body that would signal to the cells that youth is over and it's time to moderate the ardor and tame the metabolism. Therefore, the mill wheel continues to spin, but it already does more harm than good. There are three names on Benevolent's list of suspects. All three are proteins, signaling molecules that stimulate intracellular metabolism in response to energy intake.
The first of the trinity is the most famous, his name is insulin. Its main function is to force cells to capture glucose from the extracellular environment, that is, to increase energy consumption. In addition, it enhances the production of a number of hormones associated with growth and development, and the deposition of fat reserves.
The second, obviously related to the first, is growth hormone. Confirmation of its important role in aging is Laron syndrome, a form of dwarfism caused by a mutation in the growth hormone receptor. People with Laron syndrome do not grow to the required size, but they are less likely to develop diseases that accompany aging (for example, cancer and diabetes).
And finally, the third, most mysterious, is mTOR. This is a protein that has been talked about in connection with the benefits of fasting. It supports the processes of glucose breakdown and protein synthesis, but blocks autophagy – the digestion of unusable proteins and organelles. During starvation, there is a shortage of energy, mTOR stops working, autophagy starts and the cell updates its contents and "working tools". This, apparently, is due to the fact that limiting calorie intake prolongs the life of a variety of organisms.
Give the adults a break
The demonic trinity smells food from afar and gives harsh orders to the cells: absorb, store, build! But what is good in youth leads to the opposite effects in older age. Another principle formulated by Blagoslonny was called the theory of hyperfunction: if a cell is stimulated longer than it should be (for example, when it has already lost the ability to divide), it prematurely ages. Imagine that you are going home late at night waiting for the well-deserved hours on the couch. But instead of letting you go from work, they keep throwing tasks at you. It is not surprising that sooner or later you will break down, start doing a bad job and harm others.
This theory can be applied to whole tissues and physiological processes. At the beginning of life, the human body faces a variety of tasks. For example, to increase blood pressure (in a newborn, blood pressure is about two times lower than in an adult), learn how to curl blood (all broken knees are still ahead) and regularly rebuild bones (destroying old tissue for this). Then the child grows up, the body copes with all the tasks, and there is no reason to stop there – but the cells, with perseverance worthy of better use, continue to follow the original program. The result is high blood pressure (and with it a lot of cardiovascular diseases), excessive blood clotting (hello, thrombosis) and osteoporosis (systematic destruction of bones).
The principle of hyperfunction is confirmed not only in human diseases. A group of British scientists working with C. elegans use it to explain the most common causes of aging and death of roundworms. So, nematodes often die from a tumor of the uterus.
The reason, scientists say, is as follows. The eggs of worms are fertilized in the uterus with the help of sperm, which is stored in a special pocket. When the sperm runs out, the eggs, once in the uterus, begin to divide, as if they were fertilized. But the result is not a fetus, but a huge tumor.
Another example is death as a result of intestinal atrophy, the cells of which are filled with fat droplets. This process is nothing more than an untimely accumulation of yolk (and is regulated by the same genes); but what is good for the nematode – the expectant mother, is fatal for the nematode-pensioner.
Life is out of place
It would seem that the culprits have been found. But the questions don't end there. How did it happen that in our body (as well as in the body of the roundworm, and many other animals) there was no cherished button that would turn off the destructive processes in time? The explanation of this unfortunate fact was found in the theory of antagonistic pleoitropism, formulated 60 years ago.
Its essence is that the same mechanism – a gene, a protein, or a whole biological process - may have several functions (pleiotropism), but their effect on the body may be the opposite. This is the same double–edged sword: it helps with one side, kills with the other. In the case of the demonic trinity – insulin, growth hormone and mTOR protein – the opposite effects are spaced out in time: everything that happens to the young body is only on hand, and he begins to suffer only later, after retiring to reproductive retirement. But natural selection supports only those mechanisms that allow for more efficient growth and reproduction. The better these mechanisms work at the beginning of life, the more they hit the viability of the body later. Thus, one can consider decrepit old age as a payment for a stormy youth.
There are many examples of antagonistic pleiotropism in humans, even if we do not take into account the demonic trinity. Thus, the protein p53, widely known as a cancer blocker, prevents stem cells from fully dividing and renewing. Therefore, people who have it functioning well rarely get cancer, but they age biologically quickly. And those who got a worse working version of the protein get cancer more often, but if they survive, they live a long time. The story is similar with the aroE protein: it improves cognitive functions and increases fertility in youth, on the one hand, but increases the risk of developing Alzheimer's disease in old age, on the other.
Scheme: Anatoly Lapushko
If we now look at the original problem with new knowledge, it takes on a new philosophical meaning. From the point of view of the quasi-program theory, aging is not just an integral part of life, but an inevitable consequence of youth. Unbeknownst to us, the body is trying to stay forever young while we dream about it. And it is these attempts that result in cell aging and the development of age-related diseases.
But now we can guess where to look, if not the main button that turns off the inappropriate program, then at least a few key levers. Timely blocking of the demonic trinity – insulin, growth hormone and mTOR – according to many scientists, can, if not cancel aging, then at least slow it down. That is why the healing effect of fasting and its medicinal analogues are being actively investigated now.
The answer to one of the most confusing questions of biology turns out to be surprisingly simple: we can either live in a big way, but not for long, or save resources and gain time. We face a painfully familiar dilemma: what kind of fire to burn? Take care of your fire or burn everything down in an hour? Evolution has made its choice for us, but perhaps there is still time to disagree with it.
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