When old age comes from the point of view of biology

Who can be called an old person? Someone over 50? Or someone who suffers from "senile" ailments? Biologist and science journalist Polina Loseva believes that everything is not so simple. Lifehacker, together with Alpina Non-Fiction Publishing House, publishes an excerpt from the chapter “In Search of Definition: Who Really Is Old” from the book “Counterclockwise: What is Aging and How to Fight It”.

Drawing the border

Let's start with my childhood definition: old is someone who is many years old. But "a lot" is not the most strict concept. I'm 30 - is that a lot? And 40? Or 60? It would be possible to introduce a uniform age threshold for all, beyond which a person begins to automatically be considered old. Such a threshold can be considered, for example, the retirement age - but in many countries it does not coincide, and in some countries they have not heard of pensions at all. In addition, this threshold has to be constantly moved in line with the average life expectancy: for example, in Romania it is raised by a year every four years, and in Belgium - every five. And how, then, to understand when and how much to move the border of old age? To do this, we still need to rely on some other signs not directly related to age.

With any age threshold, there is one more problem: as soon as we establish the boundary between old and young people, we close our eyes to the aging process, and we designate the onset of old age as a specific event. A person turns, say, 60 years old - and exactly on the anniversary of his birth he becomes an old man at the snap of his fingers. This is a good plot move for a fairy tale, but in real life it looks incredible.

In our view, aging is still a gradual process that takes years and does not occur instantly.

And if we consider aging as a part of development, then, like most development processes, it is logical to consider it continuous.

Besides, it is not clear what to do with animals. If we expect to test our tablet of eternal youth on model organisms, before moving on to people, then our criterion of old age should also work for them. And their lifespan is very different: from a few days to hundreds of years, and in the laboratory they often live longer than in the wild. Therefore, you will either have to set your own threshold for each species and constantly refine it, depending on the circumstances, or come up with some point of reference common to all organisms.

Judged by looks

Since the age limit turned out to be an inconvenient criterion, you can try to push off from the external signs of old age. In the end, each of us can identify an old man on the street without looking at his passport: gray hair, hunched figure, wrinkled skin, uneven gait, memory impairments.

At the same time, it is not difficult to give a counterexample to any of these signs - that is, to find a person who would possess him and would not be an old man in the eyes of others. For example, some people start to go gray when they are young, or even go bald before their hair loses pigmentation. Posture problems plague not only the elderly, but also many office workers. And wrinkled skin can be found among residents of southern villages who spend a lot of time in the open sun.

Therefore, if we decide to calculate old people by their characteristics, then people of all ages who accidentally acquired a gray strand or a crooked posture will fall into this category. In addition, among the "old people" there will be many disabled or mentally ill people who have lost their memory. And wealthy people who can afford to monitor the condition of their skin and hair, on the contrary, will seem younger than their poor and unkempt peers.

The most obvious criterion for us turns out to be inaccurate, and this is no accident. The fact is that it is not directly related to the mechanisms of aging. Composing a portrait of the average old man, we evaluate the process by its final manifestations - as if we were determining the readiness of porridge by the escaped milk. But the cereal can be cooked without leaving the limits of the pan, if you handle it carefully, or it can fill the entire stove at the very beginning of cooking, if you turn on too high a fire. Therefore, in order to grab the tail of old age, we have to look inside the pan, that is, go in search of the causes of aging and its first manifestations.

Checking in battle

Turning to the main source of folk wisdom - "Wikipedia" - we get the answer: "Old age is the period of life from the loss of the ability to procreate and to death." This definition looks logical, because, unlike the previous ones, it reflects specific changes within the body. In addition, it seems pretty clear - unlike the outward signs of old age, the ability to reproduce can be easily measured: allow an animal to mate with other individuals and see if it produces offspring.

But a person is not very convenient to evaluate by this criterion.

First, not all people strive to reproduce continuously, demonstrating their reproductive potential.

Secondly, it is not very clear by what parameter it is necessary to determine this potential: by the ability to give birth to offspring or by the number of germ cells in stock. Modern reproductive technologies allow a woman to bear a child and give birth to it at 50 or even 60 years old (the Oldest person to give birth record is almost 67 years old in the Guinness Book), but eggs, at least healthy ones, usually run out of them somewhere in the 40-45 years.

Third, the reproductive criterion will work differently for men and women. Spermatozoa, unlike eggs, are constantly formed, and a man's body can produce them until his death, even when his peer has no germ cells left for a long time. At the same time, external signs of old age like gray hair and wrinkles appear in men and women almost simultaneously, and women, as a rule, live longer.

Measuring old age in terms of reproductive potential turns out to be just as inconvenient as in appearance. Modern 40- and 50-year-old women look young in all the parameters that we have already listed, but most often they no longer dare to bear children - and we cannot check whether they are capable of this. And with the care of cosmetologists and plastic surgeons, some manage to preserve external youth even at 70.

We count mutations

When at lectures I ask the listeners what old age is, they often answer me: these are breakdowns and disorders in the body. The reproductive criterion also fits into this definition: the inability to reproduce is one of these breakdowns. But, since it can arise in each specific person sooner or later, out of connection with other signs of aging, it is unreasonable to make it a measure of old age if we want to find a single point of reference for all.

You can make a list of the problems that are typical for the old organism. This is the principle used by Searle S. D., Mitniski A., Gahbauer E. A., Gill T. M., Rockwood K. A standard procedure for creating a frailty index // BMC Geriatrics. 2008 Sep; 8. (we will return to them in the chapter on biological age), which are often used by physicians studying aging. The fragility index is a set of symptoms and age-related diseases that a particular patient has accumulated. The higher the index value, the closer to old age.

The same nuisance can happen to the index as to the external signs of old age: when we focus on the effect, not the cause, rich people are, on average, younger than their poor peers.

This, however, does not mean that the problem of aging can simply be “flooded with money”: in the end, the rich die just like the poor, and are no less interested in extending their lives.

Therefore, we will have to look deeper - into individual cells and molecules, and look for signs of aging already at the microscopic level.

A point mutation in DNA, that is, the replacement of one “letter” (nucleotide) in its “text” (sequence) with another, can be considered an example of a molecular sign of old age. In most cases, such single substitutions do not affect the life of the cell, since the genetic code is redundant and insured against accidental errors. However, a breakdown can also occur in a significant place in a gene - then it either stops working completely, or the protein that it encodes will turn out to be deformed. A mutant protein sometimes performs its functions better or worse than usual, and in both cases this can lead to unpleasant consequences for the body, such as the development of a tumor.

Not all point mutations affect the life of an organism, but it is rather difficult to determine the effect that each of them produces individually. Therefore, for simplicity, any point mutation can be considered a breakdown. In the end, any of them makes the DNA in the cell different from the "original", the original carrier of genetic information.

In 2018, articles were published by two Bae T. et al. Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis // Science. 2018 Feb; 359 (6375): 550–555. groups Lodato M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons // Science. 2018 Feb; 359 (6375): 555-559. scientists who believed point mutations in the nerve cells of humans. The researchers wondered at what point these mutations arise, and how many of them accumulate during their lifetime. To do this, they took several neighboring nerve cells from the brain of adults - and the rudiment of the brain in embryos (scientists worked with material obtained as a result of abortions) and read their DNA. Ideally, in all cells of our body, the sequence of nucleotides in DNA should be the same. But during life, each cell independently of the others accumulates "one-letter" substitutions. Therefore, if we compare two cells with each other, the number of point differences in the DNA text will be equal to the number of mutations in each cell.

The results of the calculations turned out to be frightening. At the very beginning of the development of the embryo, when the fertilized egg is split into the first cells, it divides approximately once a day. Each such division, as it turned out, already brings with it an average of 1, 3 new mutations. Later, when the nervous system begins to form - by the 15th week of development - each day adds about five more mutations to the cells. And by the end of neurogenesis, that is, cell division in most areas of the developing brain - this is about the 21st week - each cell already carries 300 unique point mutations. By the time a person is born, up to 1,000 mutations accumulate in those cells that continue to divide. And then, during life, DNA mutates more slowly, at a rate of about 0.1 errors per day, and by the age of 45 the cells contain approximately 1,500 mutations, and by the age of 80 - 2,500 each.

Illustration from the book "Counterclockwise"

If we, as agreed, consider each mutation a breakdown, that is, a sign of old age, then it turns out that a person begins to age immediately after conception, from the moment of the first division of a fertilized egg. But how can a structure that has not yet formed become decrepit?

At the molecular level, our intuitive understanding of aging is confirmed: it is not an event, but an ongoing process.

Mutations do not appear suddenly, but accumulate from the first day of development until the end of life. And where to draw the line of "youth DNA" is completely incomprehensible. If old age is counted from the appearance of the very first mutation, then a heap of several cells will have to be recognized as old. And if we try to set a threshold value for the number of mutations, then we will face the same problem as in the case of retirement age: so that the border does not surprise us, we will have to rely on other signs of old age - appearance, the ability to reproduce, or something else., - which, as we already know, are unreliable.

It would be possible to focus not on the moment of appearance of errors, but on the rate of mutation - for example, to call the old one whose mutations begin to appear faster. But here, too, a catch awaits us: nerve cells accumulate errors before birth faster than after. By the time they are born, they already contain more than a third of all mutations that they will manage to get in their entire life. One could decide that this is a feature of the cells of the nervous tissue, which are almost completely formed in the embryonic period, and then, after the birth of the child, they hardly multiply. But no, dividing cells of the intestine or liver in an adult mutate Blokzijl F. et al. Tissue-specific mutation accumulation in human adult stem cells during life // Nature. 2016 Oct; 538: 260-264. at about the same rate as the nervous ones - about 0.1 mistakes per day. And this means that counting errors does not bring us closer to the definition of old age.

We make a diagnosis

It seems that we will not be able to unambiguously define old age and an old person: aging is a gradual process, with an end, but without a beginning. However, there are people who continue to fight aging despite the lack of definitions - these are doctors. They recognize old age by specific manifestations: age-related diseases, and fight - when possible - directly with them. Everything a doctor can do today for an elderly patient: replace teeth, insert a hearing aid, heal the heart or transplant the cornea - minor body repairs, replacement of individual parts. Therefore, old age from the point of view of a doctor is a collection of the most common defects that can be corrected.

It is worth giving the medical approach its due: so far, this is the most effective way to prolong life that we have.

Whatever the underlying mechanisms of aging, we still do not know how to deal with them, but we can easily defeat many of the immediate causes of death: residents of developed countries no longer die en masse from infections, paralysis has long ceased to be a sentence, but to cope with high blood pressure or blood sugar can now be done with a pill. The average life expectancy has increased over the past century. Federal State Statistics Service. Statistical Bulletin 2007. almost doubled. In this sense, the battle with old age, despite the lack of a clear definition of the enemy, is already in full swing.

But when we talk about reversing aging, we can hardly imagine the eternal struggle with age-related diseases. We would most likely like them not to even arise. Therefore, a pill for old age, if we come up with one, will probably need to be taken even before the onset of alarming symptoms. This means that the pill will have to fight a disease that does not yet exist. What is now called "old age" in the International Classification of Diseases (a document that is published every 10 years by the World Health Organization to unify medical diagnoses in different countries) describes a standard set of age-related symptoms: "senile age, senile weakness, senile asthenia." But modern medicine itself does not consider aging to be a disease.

Good or bad is a moot point. On the one hand, this state of affairs seriously hinders the development of science. Even if gerontologists Specialists who treat and study the health of people over 60 years old. agree on who is considered old and who is young, now they cannot conduct clinical trials of a single pill for old age and check whether it works or not. For such a test, they will not receive either money or permission from ethical committees. To work around this problem, they try drugs for an age-related disease, such as joint inflammation. If the patients no longer have joint pain, it will be good in any case. And if at the same time they live longer than average, it will be even better.

On the other hand, let's imagine that old age is still officially classified as a disease. Then it will immediately become clear that a significant part of the world's population is sick, and incurable. And if you measure aging by the number of mutations, then everyone will be sick. From the point of view of a physician, this is absurd: a disease is a deviation from the norm, but where to look for a norm when healthy people do not exist?

So far, gerontologists and doctors have not been able to agree: the first publish Bulterijs S., Hull R., Björk V., Roy A. It is time to classify biological aging as a disease // Frontiers in genetics. 2015 Jun. calls to recognize aging as a disease, the latter stubbornly resist. However, I suspect that sooner or later the doctors will have to give up: here and there, individual biohackers begin to experiment on themselves, and courageous researchers launch private clinical trials of pills for old age at the expense of the subjects themselves. Fighting this chaos is useless, so one day the medical community will have to lead it and recognize old age as one of the many diseases of mankind, and at the same time agree on a single definition.

Polina Loseva is a biologist by education, graduated from the Department of Embryology, Faculty of Biology, Moscow State University. Writes articles for the portals "Attic", "N + 1", "Elements", OLYA and popularizes science. In Counterclockwise, she talks about the mechanisms of aging, attempts to create a "pill for old age" and ways to delay the inevitable.