It's not about wrinkles

Why does science not know if old age exists

Polina Loseva, N+1

It is becoming fashionable to deal with the problem of aging. A dozen years ago, the search for "pills for old age" was limited to theoretical developments and experiments on animals, and now some of the candidates for "pills" are sneaking up to the second or third phases of clinical trials. Since the beginning of the decade, the number of such tests has doubled, and the budget of startups to develop new methods to combat old age 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.

Border 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 more closely, it turns out that among the many similar definitions, there are quite a few that coincide. 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.

Imagine that we decided to find a cure "for old age". It is logical to assume that the desired medicine should help ensure that young people do not age, that is, do not turn into old people. Therefore, it is necessary to draw up a protocol for a laboratory assistant who will monitor whether old people have appeared among the subjects or not.

Let's say we have collected an approximate sketch of an old man, as we see him: this person, most likely, walks badly and often gets sick, gray-haired and hunched, with wrinkles and without teeth, forgets a lot and is not able to reproduce.

But even if we have worked carefully and prescribed the number of wrinkles that the subject should have and the teeth that he should lose in order to be ranked among the elderly, our laboratory assistant will inevitably have difficulties. What about those who lost their teeth, but kept perfect posture? And with those who 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 did not work well enough on the definition of old age. There are two other important circumstances that make the appearance of such a criterion unlikely.

Firstly, aging, as well as the development of which it is a continuation, is a gradual process. No change in it is made simultaneously: teeth fall out in turn, physical strength decreases gradually.

Even the ability to reproduce, which, it would seem, can be measured by the "is/is not" principle, does not disappear overnight. Therefore, there is no clear boundary between old age and youth.

Secondly, old people 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 over it among the elderly members of the population will be no less, or even more, than among the young.

With age, the variation in the values of physiological parameters only grows, as can be seen by the example of the concentration of thyroid hormones in the blood of elderly people and centenarians. (Ostan et al. / The journals of gerontology: series A, 2018).

And this has its own logic: used cars of the same model are less similar to each other 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", which determine how much one or another of its organs will eventually give up.

That is why the average value, or "norm", that we could calculate for the elderly, is unlikely to be indicative and will allow us to reliably distinguish them from the young.

The old man and roulette

The paradox of the hapless laboratory assistant has an obvious solution: let's measure not the absolute state of a person – aged or not aged – but the speed with which he moves from one state to another, that is, the rate of aging.

Even if we don't know where to draw the line, we can measure the average rate at which age–related changes accumulate and try to reduce it - preferably to zero.

But here another problem arises: it is not very clear exactly what changes need to be monitored. Among the many cells and molecules in the body that are affected in one way or another by the passage of time, it is necessary to single out some one parameter that will serve as an indicator of old age.

Such parameters are called markers of biological age – it is believed that they, in contrast to the chronological (passport) age, more accurately reflect the degree of aging of the body.

However, it is not an easy task to identify a single marker that allows you to judge the state of the body as a whole. In 2004, aging researchers put forward a list of criteria that such a marker should 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 marker of biological age should:

1. Be easily measurable. In addition, these measurements obviously should not harm the health of the subject. Therefore, it will not be possible to determine the 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 probability of death. After we have come up with a marker, it needs to be verified somehow, that is, to 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 does not fully reflect the real rate of aging. So, some kind of independent verification is needed.

Currently, the risk of death from natural causes (i.e. diseases and pathological conditions, not wars and catastrophes) is used as an independent criterion. This is one of the modern definitions of aging: the growing risk of death.

Despite the fact that there are many questions about this definition, it is quite simple to measure the risk of death – it is enough just to calculate what percentage of people of a certain age live to the next year.

Thus, the marker of biological age must 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 the best idea: people who work a lot in the sun, the skin shrinks faster, but almost no one dies from it.

3. Be relevant to the biological causes of aging. This is another problem with estimating 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 pugnacity.

But the biological causes of aging lie deep – in every sense of the word – and as soon as we decide to count, 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 on humans. Since the starting point for the development of markers of biological age is the search for an "old age pill", it is useful to immediately think about how it will undergo clinical trials.

Before such a pill is released to humans, it will have to show its effectiveness on laboratory animals – and it would be nice to check its effect by the same criteria, that is, by the same marker of biological age.

There is no single token that would satisfy all these requests today. Those that are easy to measure, such as external signs, are rarely associated with the 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 tags on DNA that determine the degree of its twisting. They have learned to easily measure them by taking cells from the skin or blood (although 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 you to predict the risk of dying. But at the same time, the epigenetic age of a person is not uniquely related to the age of laboratory animals: for each species, it is necessary to calculate its own scale for converting epigenetic years into human ones, and it is not always linear – it has recently become clear, for example, that for dogs it is logarithmic and uneven.

The epigenetic age of a person and a dog are related non-linearly: at the beginning of life, dogs age rapidly relative to humans, and then, on the contrary, slowly. (Wang et al. / bioRxiv, 2019).

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 key cause does not exist. This means that each parameter that we come up with will measure some reason of its own, ignoring the rest.

For example, the epigenetic clock gives an idea of the working capacity of cells, but it does not say anything about the number of mutations in their DNA, nor about the state of their proteins, much less about the amount of hormones and nutrients in the blood.

It is not surprising that the markers also do not agree well with each other. One works better for children, the other for adults, one predicts the risk of dying well, and the other the risk of developing age–related pathologies. This specialization allows us to solve specific tasks, but does not move us closer to understanding what aging is and how to measure it.

Detour maneuver

So, we want to look for a pill for old age, but we don't know what it is or how to measure it. To find a way out of this situation, gerontologists decided to look at the problem from the other side.

Let's say we can't figure out what aging is, but we know exactly what people usually die from. And this is not old age itself, but a specific set of age-related diseases: heart failure, atherosclerosis, cancer, Alzheimer's and Parkinson's diseases, osteoporosis, diabetes, chronic obstructive pulmonary disease, and so on. And they are already much easier to diagnose and track.

So the paradigm appeared geroscience, which suggests considering aging – at least at the level of clinical trials – as a set of age-related diseases and thereby drawing a clearer outline of our enemy.

This idea has a specific scientific justification. Today there are several officially recognized mechanical causes of aging: inflammation, depletion of cellular reserves, 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 occurrence of tumors increases under the influence of stress, reacts to the metabolism in the body, and also causes inflammation in the tissue and damage inside cells, both tumor and healthy. For example, diabetes develops against the background of metabolic disorders and is often accompanied by inflammation and accumulation of protein tangles.

In addition, all 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 deprive stem cells of the ability to multiply.

Thus, the hierarchy of causes of aging and death turns out to be not vertical, but network: there are many causes 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 connected to each other, forming not a vertical hierarchy, but a network. (Kennedy et al. / Cell, 2014).

The way out of this situation today seems like 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. Then these drugs can 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, it will mean that they eliminate several causes of death at once, that is, they struggle with old age in general.

If gerontologists are really going to stick to this technique, then we should hardly wait for the loud results of the tests 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 "antiaging") will disappear from scientific discourse: after all, if we equate old age with a set of specific diseases, does it exist as an independent phenomenon?

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