Dealing with the problem of aging is becoming fashionable. A dozen years ago, the search for a "pill against old age" was limited to theoretical developments and experiments on animals, and now some of the candidates for "pills" are sneaking up on the second or third phases of clinical trials. Since the beginning of the decade, the number of such trials has doubled, and the budget for startups to develop new methods of dealing with aging has increased eightfold. But as we get closer to the enemy, its outlines blur more and more. Surprisingly, the longer we study old age, the worse we can determine what it is.
Borderline difficulties
Whatever article on gerontology you open today, it begins with the words "aging is …". Such a beginning may seem strange: why explain seemingly obvious things?
However, if you look closely, it turns out that among the many similar definitions, there are quite few coinciding ones. Therefore, the authors of the articles are reinsured and from the very beginning explain in detail what exactly they are going to study, measure or win.
The fact is that the intuitive definition of aging, which each of us uses in everyday life, is completely inapplicable in an experiment.
Let's imagine that we decided to find a cure for “old age”. It is logical to assume that the desired medicine should help to ensure that young people do not grow old, that is, do not turn into old people. Therefore, it is necessary to draw up a protocol for the laboratory assistant, who will track whether old people appeared among the subjects or not.
Let's say we have collected an approximate sketch of the old man, as we see him: this person, most likely, walks poorly and is often sick, gray-haired and hunched over, with wrinkles and no teeth, forgets a lot and is not able to reproduce.
But even if we worked carefully and prescribed the number of wrinkles that the subject must develop and the teeth that he must lose in order to be considered old, our laboratory assistant will inevitably have difficulties. What about those who have lost their teeth, but retained the perfect posture? And with those who have turned gray or bald at the age of 30?
The problem awaiting our hapless laboratory assistant is not caused by the fact that he or we have not done enough to define old age. There are two more important circumstances that make the appearance of such a criterion unlikely.
First, aging, like development, of which it is a continuation, is a gradual process. No change in it occurs at once: teeth fall out in turn, physical strength decreases gradually.
Even the ability to reproduce, which, it would seem, can be measured according to the principle "is / no", does not disappear overnight. Therefore, there is no clear boundary between old age and youth.
Second, the elderly are a very diverse group. Whatever parameter we undertake to measure, be it the strength of the grip of the hand, the concentration of some substances in the blood or a set of microbes in the intestine, the spread in it among the elderly members of the population will be no less, if not more, than among the young.
With age, the spread in the values of physiological parameters only grows, as can be seen from the example of the concentration of thyroid hormones in the blood of the elderly and centenarians.
And this has its own logic: used cars of the same model are less alike than a fresh batch from the assembly line. Over a long life, the human body manages to break and repair individual parts so many times that it accumulates a unique set of molecular and tissue "scars", on which it depends on how strongly one or another of its organs over time.
That is why the average value, or "norm", which we could calculate for the elderly, is unlikely to be indicative and will allow us to reliably distinguish them from the young.
Old man and roulette
The paradox of the unlucky laboratory assistant has an obvious solution: let's measure not the absolute state of a person - whether he is old or not old - but the speed with which he moves from one state to another, that is, the rate of aging.
Even if we do not know where to draw the line, we can measure the average statistical rate at which age-related changes are accumulating and try to reduce it - preferably to zero.
But then another problem arises: it is not very clear which changes should be monitored. Among the many cells and molecules in the body, which are affected in one way or another by the passage of time, it is necessary to single out one parameter, which will serve as an indicator of old age.
Such parameters are called biological age markers - it is believed that, in contrast to the chronological (passport) age, they more accurately reflect the degree of aging of the body.
However, it is not an easy task to single out a single marker that makes it possible to judge the state of the organism as a whole. In 2004, aging researchers put forward a list of criteria that such a marker must meet.
Despite the fact that they all look absolutely justified, it is almost impossible to come up with a parameter that satisfies them. Try it yourself. So, the ideal biological age marker should:
1. Be easy to measure. In addition, these measurements, obviously, should not harm the health of the subject. Therefore, it will not work to determine age with the help of an autopsy or even a biopsy of internal organs, but a blood test or scraping of mucous membranes is quite suitable.
2. Predict the likelihood of death … After we have come up with a marker, we need to somehow verify it, that is, make sure that it makes sense. You can, of course, see how well his predictions correlate with chronological age. However, this is not enough, because the very idea of biological age is that chronological age does not fully reflect the real rate of aging. This means that some kind of independent verification is needed.
Now, the risk of death from natural causes (that is, diseases and pathological conditions, not wars and disasters) is used as an independent criterion. This is one of the modern definitions of aging: an increasing risk of death.
Despite the fact that there are many questions about this definition (we talked about them recently), measuring the risk of death is quite simple - you just need to calculate what percentage of people of a certain age survive to the next year.
Thus, the biological age marker should correspond to some extent to the probability of death. Therefore, for example, using the number of wrinkles on the face as it (and such ideas have already arisen) is not a good idea: people who work a lot in the sun wrinkle their skin faster, but almost no one dies from this.
3. Be relevant to the biological causes of aging. This is another problem with assessing age by wrinkles: since this is an external manifestation, it can be caused by many reasons - just as the number of teeth depends not only on age, but also on the type of diet, brushing habits and pugnaciousness.
But the biological causes of aging lie deep - in every sense of the word - and as soon as we decide to calculate, for example, the number of mutations in cells or the number of aged cells in tissues, our measurements become much more traumatic for the subject and begin to contradict point 1 of this list.
4. Work on model organisms, not just humans. Since the starting point for the development of biological age markers is the search for a "pill for aging", it is useful to immediately think about how it will go in clinical trials.
Before such a pill is released for humans, it will have to show its effectiveness in laboratory animals - and it would be nice to check its action according to the same criteria, that is, according to the same biological age marker.
There is no single marker that would satisfy all of these requests today. Those that are easy to measure, such as external signs, are rarely associated with underlying causes of aging. And they, in turn, require expensive and often traumatic measurement methods. Finally, even those that pass the first three criteria often fail on the fourth.
For example, an epigenetic clock is a set of labels on DNA that determine the degree of its twisting. They learned how to easily measure them by taking cells from the skin or blood (however, they do not always reflect the degree of aging of other body tissues).
They seem to be really related to the degree of aging and allow predicting the risk of dying. But at the same time, the epigenetic age of a person is not unambiguously associated with the age of laboratory animals: for each species it is necessary to calculate its own scale for converting epigenetic years into human years, and it is not always linear - it has recently been found out, for example, that for dogs it is logarithmic and uneven.
The epigenetic age of humans and dogs is not linearly related: at the beginning of life, dogs age at an accelerated rate relative to humans, and then, on the contrary, at a slower pace.
Finally, the main problem with markers is that we still do not know which of the known causes of aging is most important, and even suspect that such a root cause does not exist. This means that each parameter that we come up with will measure its own reason, ignoring the rest.
For example, the epigenetic clock gives an idea of the performance of cells, but does not say anything about the number of mutations in their DNA, or the state of their proteins, and even more so about the amount of hormones and nutrients in the blood.
It is not surprising that markers agree poorly with each other. One works better for children, the other for adults, one well predicts the risk of dying, and the other - the risk of developing age-related pathologies. This specialization allows us to solve specific problems, but does not move us closer to understanding what aging is and how to measure it.
Bypass maneuver
So, we want to look for a pill for old age, but we do not know what it is, nor how to measure it. To find a way out of this situation, gerontologists decided to look at the problem from a different angle.
Let's say that we cannot define what aging is in any way, but we know exactly what people usually die from. And this is not old age in itself, but a specific set of age-related diseases: heart failure, atherosclerosis, cancer, Alzheimer's and Parkinson's, osteoporosis, diabetes, chronic obstructive pulmonary disease, and so on. And they are much easier to diagnose and track.
This is how the geroscience paradigm appeared, which proposes to consider aging - at least at the level of clinical trials - as a set of age-related diseases and thus draws a clearer outline of our enemy.
There is a specific scientific basis for this idea. Today, there are several officially recognized mechanical causes of aging: inflammation, depletion of cell stores, molecular damage, epigenetic changes, metabolic shift, protein aggregation, and the body's response to stress. All of them are somehow involved in the development of any age-related disease.
For example, the onset of tumors is enhanced by stress, reacts to the body's metabolism, and also causes inflammation in tissue and damage within cells, both neoplastic and healthy. For example, diabetes develops against the background of metabolic disorders and is often accompanied by inflammation and the accumulation of protein tangles.
In addition, all the known causes of aging do not exist in the body alone, but reinforce each other. As a result of inflammation, metabolism changes, stress leads to protein aggregation, and epigenetic changes make it impossible for stem cells to multiply.
Thus, the hierarchy of causes of aging and death turns out to be not vertical, but network: there are many reasons at once, and then they add up to one or another age-related disease (and often more than one).
All mechanical causes of aging are linked to each other, forming not a vertical hierarchy, but a network.
The way out of this situation today seems to be this: let's look for a cure for age-related diseases separately, because the presence or absence of each of them is a sign that is easy to measure. These drugs can then be tested for effectiveness against other age-related diseases.
And if some methods or drugs turn out to be the right remedy for several ailments at once, this will mean that they eliminate several causes of death at once, that is, they are fighting old age in general.
If gerontologists are really going to adhere to this technique, then we should hardly expect high-profile test results of "pills for old age." All of them will be "disguised" as drugs for various age-related diseases, and their ability to prolong life will depend on how many targets they can hit at the same time.
Following this, we can imagine that the very concept of "pills for old age" and "anti-aging" (and at the same time the fashionable word "anti-aging") will disappear from the scientific discourse: after all, if we equate old age with a set of specific diseases, does it exist as independent phenomenon?