Medicines for aging
Where do they live?
Mikhail Tyumentsev, "First-hand Science"
Time does not directly kill people, aging is a biological process. There is a group of diseases that are called age-associated, or senile. The main risk factor for their development is age, and they account for a significant proportion of the causes of mortality. These are strokes, heart attacks, oncological diseases, Alzheimer's disease, type 2 diabetes... It is these diseases that are killing us. Scientists working in the field of aging biology are looking for what unites them, a single mechanism, if, of course, it exists
Causes of death in the United States in 2010-2015 Age-associated diseases – cardiovascular, oncological, stroke, Alzheimer's disease, diabetes, make a huge contribution to it. By: (de Magalhães, Stevens, Thornton, 2017)
I would like to talk about whether there are actually any successes in the "heroic" fight against aging. The media tell us from time to time that scientists have discovered the aging gene, but there are still no pills for old age in pharmacies. I would like to know how things really are. To do this, we need to decide what we consider a success in the fight against aging. For people to live up to a hundred years? Or up to one hundred and fifty? Then it will be possible to talk about success or not yet?
It should be understood that the biology of aging is a very exciting topic, and it is a double–edged blade, because any conversations on this topic are easy to sell both literally and figuratively. This topic requires scientists, on the one hand, correctness and restrained optimism, and on the other – the ability not to rush to extremes in their ideas. There are two opposing points of view. One is that nothing can be done with aging at all: as it is written in the genus (in the genes), so it will be. The other implies that immortality should come just the other day. The latter is used by some pharmacological companies that are starting to sell jars with a "cure for old age". But if there was a jar with such a medicine somewhere in secret laboratories, then we would already be living in another world.
Where are they looking for "medicines for old age"?
One of the obvious directions of the search for anti–aging means is to replace organs that decline during the aging process with new, specially grown ones. Now it is more or less clear in which direction to move in order to achieve this. There are techniques that allow reprogramming specialized, terminally differentiated cells into induced pluripotent stem cells (iPSCs), which can then be directionally converted into almost all types of cells. You can take his own cells from an elderly patient, turn them into iPSCs, during which, among other things, they lose the features characteristic of senile cells (sometimes the term "rejuvenate" is used, but it is recommended to avoid it). Then you can grow a "young" organ from them, or at least a "young" tissue and transplant it to the patient.
Thus, a grown and transplanted young organ will not stay young for long.
However, this effect also works in the opposite direction: old cells, once among the young ones, already acquire their properties! To understand how this happens, and possibly reproduce this effect, it is necessary to find the molecular substrate of the "recognition" by cells of the "young" or "old" cellular environment. This substrate is probably some kind of signaling molecules. The results of experiments using parabiosis, an artificial connection of mice through the circulatory system, as a result of which the muscle and nerve tissues of old mice were "rejuvenated", revealed an alleged candidate for the mediator of this effect. It turned out to be the GDF11 protein (growth and differentiation factor 11) isolated from the blood of young mice (Sinha et al., 2014). However, these works were subsequently criticized, which consisted in the fact that GDF11 is a concomitant find, and therefore research is still ongoing (Reardon, 2015). But I believe that it is only a matter of time to discover the true mediator or intermediaries.
Surgically creating a common blood circulation between laboratory mice of different ages, as well as injecting elderly individuals with GDF11 protein obtained from the blood of young ones, led to the same result: signs of aging of the muscular, nervous and circulatory systems decreased in "elderly" mice. By: (Kaiser, 2014)
One of the problems of the method is that it is a tactical retreat that makes sense only as long as it does not come to the brain: after all, it is not so easy to replace it. The second problem is that the cells having the properties of young, being surrounded by senile cells, themselves acquire the phenotype (molecular markers) of senile cells (Acosta et al., 2013).
Another strategic direction of the fight against aging is attempts to directly influence its mechanisms by changing the regulation of the metabolism of nutrients and energy. Growth hormone, which controls the growth of tissue, as well as insulin–like growth factor, a molecule similar to the hormone insulin, necessary for the regulation of glucose metabolism, but having a wide range of effects on the processes of cell growth and development, can be called as substrates of influence.
The molecular systems in question "make decisions" about how actively cells should grow, divide, and use energy. And, although it does not seem obvious, in the course of aging, such systems begin to work not weaker, but stronger, but at the same time inefficiently (Blagosklonny, 2010). As a result, most of the potential tools that change the operation of these systems are aimed at suppressing them. For example, these include the antibiotic and the immunosuppressant rapamycin, which inhibits the so-called signaling pathway of the mTOR kinase involved in synthetic processes in the cell and activated by amino acids. Rapamycin has serious side effects and is not suitable for use to prolong human life, but perhaps more suitable substances will be found in the future. One of them may be the antidiabetic drug metformin, if it is proven that it is safe to use it for preventive purposes.
It should be noted that the aging process is very slow for a long time, and then accelerates. The fact is that there are "quality control systems" in the body that are engaged in "repairing the broken", and what can no longer be repaired is sent for recycling. This is, for example, the proteostasis system, which is responsible for the proper folding of protein molecules; and the process of autophagy, which is, among other things, an important link for sending damaged cellular organelles for processing; and apoptosis (cellular "suicide"). Finally, the immune system itself, which fights not only infections, but also tumor cells. Over time, all these systems begin to work worse, but if they return to their former activity, it may be possible to reverse a number of senile changes, and one of the areas of work is just the search for substances that would increase the activity of "quality control systems".
The proteostasis system is one of the "quality control systems" functioning in cells. Under the influence of a number of unfavorable factors, for example, oxidative stress, proteins can lose their structure, the complex convolution of the protein molecule. Such proteins must either be destroyed by the process of autophagy or the ubiquitin–proteosomal system, or their structure can be restored with the participation of chaperone proteins. Otherwise, they will form aggregates, the accumulation of which leads to disturbances in the functioning of the cell and its aging. Autophagy is divided into micro- and macroautophagy. The first type is called chaperone-mediated autophagy, when these proteins are involved in directing the damaged protein into the lysosome, a cellular organelle containing enzymes for the cleavage of cellular macromolecules. Macroautophagy is associated with the formation of a membrane structure – an autophagosome, which contains a protein to be destroyed, and, merging with the lysosome, ensures its degradation. By: (Lopez-Otín et al, 2013)
Another direction is due to the fact that during aging, a state of weak, sluggish, unable to complete inflammation develops in the tissues of the body – the so-called smoldering inflammation (Salminen, Kaarniranta, Kauppinen, 2012). In general, inflammation is characterized by five signs: redness, swelling, pain, fever and dysfunction. And, perhaps, if we fight inflammation or what causes it during aging, we will be able to restore the lost functionality to the tissues.
It has been known for quite a long time (although it took a long time to confirm this phenomenon) that calorie restriction leads to a slowdown in the development of senile changes and an increase in life expectancy (Colman et al., 2009). In rats, in this way, it was possible to achieve an increase in life expectancy up to 40%. These experiments prove that an artificial increase in the maximum life expectancy is in principle possible. Calorie restriction also affects quality control systems and reduces smoldering inflammation, i.e., apparently, it "hits" very close to the subject of the search - the general mechanism of aging.
Eat less – live longer?
The first experimental data on the effect of dietary restriction on life expectancy were presented in the early 1900s in experiments on rats: restriction of food intake inhibited the growth of animals, but increased life expectancy. The most famous were studies in 1935, when it was shown that limiting the calorie content of food by 40% in rats, starting from the age when they switched to regular food from mother's milk, extended their life by half. To date, the effect of calorie restriction on life expectancy and health has been demonstrated on completely different organisms: roundworms, fruit flies, mice and rats, dogs and cows, and some monkeys.
During this time, many hypotheses have been expressed about the mechanisms of action of calorie restriction on longevity. At first, it was assumed that the effect was somehow related to the slowing down of metabolism. It was also suggested that this is an artifact, that laboratory animals simply overeat compared to wild species, and a return to the natural norm is good for them. These early hypotheses were eventually discarded. Then the idea arose that the rejuvenating effect of calorie restriction is associated with a decrease in the production of reactive oxygen species that attack macromolecules in cells, i.e. with a decrease in the level of oxidative stress. When molecular biology became firmly established in scientific life, they began to look for an explanation in the field of regulation of molecular signals. Now most gerontologists agree that the effects of calorie restriction on life expectancy are associated with nutrients that trigger a number of signaling cascades in cells.
One of the possible mechanisms of action of calorie restriction on life expectancy is mediated by a decrease in the activity of interconnected signaling pathways of mTOR kinase (activated by amino acids), insulin-like growth factor and insulin receptor (activated by carbohydrates). The result of their activity is the activation of a number of proteins involved in the processes of cell division, apoptosis, and response to stress factors. The weakening of the activity of these signaling pathways eventually leads to positive consequences: for example, the inactivation of mTOR kinase enhances the processes of autophagy - degradation of damaged proteins and intracellular organelles.
Other possible mediators of the caloric restriction effect may be an increase in the activity of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and the activity of proteins called sirtuins. AMPK is activated under conditions of energy restriction, regulates the energy balance in the cell and participates in the regulation of carbohydrate and fat metabolism. Sirtuins, on the one hand, are involved in the shutdown of genes, the products of which the cell does not need now, and on the other – in DNA repair.
But all my life since childhood, eating in calorie restriction mode is a difficult task to realize. Therefore, gerontologists and biologists are trying to develop drugs that mimic the beneficial effects of calorie restriction.
According to the results of a number of studies, one of these drugs may be the antioxidant resveratrol, contained, in particular, in grape skins and red wine. The action of resveratrol has long been attributed to the so-called French paradox: a relatively low level of cardiovascular and oncological diseases in French residents against the background of a high-calorie diet. However, it was later shown that the content of resveratrol in wine is too low to cause the desired effect, and in general, the results of research on the effects of resveratrol on health and longevity are quite contradictory.
The signaling pathway of mTOR kinases can inhibit the drugs rapamycin and metformin. But rapamycin, an antibiotic and an immunosuppressor, has serious side effects, and, of course, there can be no question of using it to prolong human life. Whether it is possible to use the drug for the treatment of type 2 diabetes mellitus metformin, which, in addition to affecting mTOR kinase, activates the AMFK signaling pathway, is also questionable.
In fact, the mechanisms of action of calorie restriction of food on life expectancy are still not fully understood. Regarding all hypotheses, there are both confirming and refuting data. Apparently, this is due to the fact that calorie restriction is accompanied by complex systemic changes in the body. The signaling pathways involved in these processes interact closely and flexibly with each other and do not always produce the same result in the end. Thus, despite serious advances in understanding the mechanisms of the aging process, the "anti-aging pill", at least reliable and guaranteed harmless, does not yet exist. But everyone is free to implement the "difficult" way – to monitor their diet and, if they do not live to be a hundred years old, at least feel better. By: (Lee, Min, 2013; Martin et al., 2016)
Problems and ways to solve them
I have described the areas of aging biology in which research is actively underway, but any such list will be obviously incomplete. Many processes are already known, the course of which is disrupted during aging, and, importantly, hundreds of candidate substances are known for potential "anti-aging drugs" – geroprotectors. The abundance of potential targets and techniques, on the one hand, pleases, because it says that the stage at which the search for at least some targets was conducted has been passed. But another problem has arisen: there are now many more potential targets than the scientific community can "digest". Perhaps among several hundred potential geroprotectors there is the most effective one, but how to determine it? The limiting factor is the number of laboratories and specialists.
What can be the way out of this situation? It is possible to involve non-specialists in the work by analogy with the way ornithologists act: they accept observations of people who are in bird-watching communities (this approach is called "citizen science"). Experts on aging suggest involving dog owners in their activities (Kaeberlein, 2016). A dog is one of the very few animal species, the volume of accumulated medical data about which is comparable to the data of "human" medicine. Dog owners, receiving experimental treatment for their pets, could collect data (simple, home-measured indicators) and send reports on the results.
One more possible option for activating data collection can be mentioned, although it is debatable. According to the law recently introduced in many US states, a terminally ill person has the right to receive experimental treatments, if they exist, without waiting for the end of the procedure for their approval. Some such patients believe that they have nothing to lose, and do so at their own risk. Although this is a very specific case, and even it remains the "arena" of heated debates, therefore it is impossible to actively encourage people to use deeply experimental techniques.
It is very difficult to study the aging process in humans. A person ages for a long time, it is inconvenient from a methodological point of view. We must not forget about the ethical aspects. Therefore, aging is studied mainly on nematode worms, yeast, flies, mice - on short–lived organisms. Research on model organisms is a good approach, but a human is not a mouse or a fly, and not everything that is true for models will also be true for humans (de Magalhães, Stevens, Thornton, 2017). There are several hundred yeast and nematode genes whose function is associated with aging, but in humans these genes mostly do not function that way or are absent at all.
According to the GenAge database, several hundred genes are known for yeast and nematodes, the function of which is associated with aging. However, these data are overwhelmingly inapplicable to a person for whom only 7 such genes are known. By: (de Magalhães, Stevens, Thornton, 2017)
One of the ways to get around this problem is to "fit the solution to the answer." There are animals that have overcome the problem of aging and live a long time: life expectancy correlates well with the size of the body, but some animals break out of this pattern. These include rodents – naked diggers and blind mice, some bats, birds, very large mammals. It is possible to study how they differ from non-long-lived organisms and try to imitate the effect of gene variants responsible for long life with pharmacological agents (Gorbunova et al., 2014).
Some small animals (rodents, bats, squirrels) managed to overcome the problem of aging, as well as the development of cancer, as well as very large animals like elephants. Different species use different molecular mechanisms for this. For example, in naked diggers, cells cannot be located near each other as tightly as it happens in the early stages of the development of a cancerous tumor. The protective systems of blind people use the "scorched earth" tactics in relation to cancer, killing not only the cancer cell, but also its entire environment, among which potentially dangerous cells may turn out to be. Having studied these mechanisms, we can try to imitate them by pharmacological methods and apply them to humans. By: (Gorbunova et. al., 2014)
Experiments that "conducted themselves" can also be found in human populations. Today, studies are being conducted on the genomes of people who have lived for more than 100 years (Puca et al., 2017), with the consideration that these people "won the genetic lottery". And the identification of gene variants (alleles) associated with their longevity can tell us which substances are able to reproduce this effect in the general population.
Some potential geroprotectors are medicines that have been used in medicine for a long time (for example, metformin mentioned above), and the study of the course of senile diseases in people taking them for third-party indications can help us identify the most promising substances.
A promising direction is the search for biomarkers of aging – indicators whose rate of change over a relatively short period of time, for example, over a year, fairly reliably reflects the overall speed of this process (Sprott, 2010). The use of biomarkers will make it possible to directly investigate the effectiveness of geroprotectors without requiring lifelong observation.
If aging is a "collection of symptoms", such as type 2 diabetes, strokes, heart attacks, why not give up trying to embrace the immensity and try to treat only these diseases? After all, they have already tried to make a universal medicine, for example, associated with an increase in telomeres, and it did not work out?
The treatment of symptoms does not always justify itself, if we draw analogies with medicine as such. We assume that senile diseases are different facets of a single process. Undoubtedly, the study of senile diseases is an important area of the biology of aging, but we, analyzing different aspects, want to see what they have in common.
On the graph of survival in the population over time, the number of individuals decreases due to their death. If we learn to treat any one group of age-associated diseases, for example, oncological, but we do not learn to influence the mechanism of aging as a whole, the average life expectancy (A) will increase, but the maximum life expectancy, if it changes, will not be much: the place of oncology will immediately be occupied by an expanded share of other senile diseases. (B). But the radical fight against aging implies an increase in the maximum life expectancy. By: (Flurkey et al., 2007)
Telomeres are areas at the ends of chromosomes that protect them when copying and with the number of cell divisions they shorten. When they completely "wear out", the cell dies. Indeed, a few decades ago, the idea was put forward that telomeres could be lengthened to increase life expectancy. Experiments on mice show that with an increase in the activity of telomerase (an enzyme capable of increasing telomeres), the lifespan of mice increases, while the frequency of tumor diseases does not increase (de Jesus et al., 2012). But in mice, as in small animals in general, telomerase always works, and in these experiments its activity only increases. It is difficult to broadcast this to humans and other large organisms. In humans, telomerase works only in embryonic and tumor cells, and its activation can cause oncological diseases. It is believed that telomere shortening and subsequent cell death are a protective mechanism against malignant degeneration. For everything else, we need a high-performance method of testing hypotheses: if we test each one for decades, we will get answers very soon.
And about the future of the fight against aging. I will first give an example of the statistics on the survival of patients with cancer. Although it still seems to us that cancer is a verdict, for many types of tumors, the survival rates and the onset of long–term remission have increased by tens of percent, for example, for prostate cancer – from 30 to 70%. Fundamental research has been going on for a long time, and now we see the fruits of the work that began in the middle of the XX century. Probably, the results of the fight against aging will be the same "silent revolution". We won't wake up and read in the headlines that aging has been defeated. This will be a gradual process, preceded by a gradual accumulation of new data. First we will find out that an increase in life is possible in principle, then we will find an increasing number of working geroprotectors, then life expectancy will begin to grow… And someday we will look back and see that there really is progress.
Literature
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