Why is it so difficult to fight aging?
Genes, health and microbiota are linked to longevity, but we don't know exactly how yet
Yaroslav Ashikhmin, Post-science
People have always dreamed of delaying old age and living longer, but real scientific successes in this field are not so great: we still know little about the role of genetic predisposition, cell division, protein synthesis and other processes in the body in aging. Cardiologist Yaroslav Ashikhmin told post-science about why aging is so difficult to avoid and whether we have real prospects of living longer.
Why does aging occur?
According to the telomerase theory, the shortening of telomeres – the end sections of chromosomes - leads to aging. Because of this, the cells begin to divide less. But telomere lengthening in many experiments does not give positive results. Therefore, it is not yet possible to say that by lengthening telomeres, we will reverse the aging process. Scientists from Tel Aviv University using a hyperbaric pressure chamber "rejuvenated" telomeres for about 25 years as part of the experiment, but these are intermediate results. There are Italian experiments where telomeres are not lengthened, but affect their safety. This is also important, because telomeres also deform with age.
The main mechanisms of aging, in addition to shortening the length of telomeres, are systemic inflammation, changes in the cellular matrix with fibrosis, aging of the immune system. What is systemic inflammation? Some believe that this is a consequence of some general pathological process that covers the entire body outside of the disease from above, as if with a hood, and it needs to be fought. It turns out the principle "let's extinguish systemic inflammation throughout the body, maybe we will prevent both inflammation and disease."
Aging of the immune system is a process in which a "hole" appears in the immune system, as a result, it does not see certain types of cancer. Over the course of life, the probability that a new type of cancer will appear in the body, whose cells will fall into this "hole", increases. As a result, tumors grow that the immune system does not see.
The change in the extracellular matrix is also related to the function of cellular elements. Its components are synthesized primarily by fibroblasts, they are also responsible for collagen. Over time, fibrosis of organs develops – the number of rigid types of collagen increases, the organs themselves become more rigid, due to the fact that this matrix accumulates in them, like slings. But, again, liver fibrosis is also associated with the fact that a person took alcohol, ate fatty foods, he developed liver steatosis, then fibrosis appeared due to the disease.
You need to understand that aging itself is not a disease. In medicine, there are supporters of healthy aging – healthy aging, in which the quality of life of the elderly increases, so that they remain active, get sick less, and can travel. There are those who believe that the pathological aging process is not relevant for everyone, because they still die from specific diseases. Some people – there are not many of them – are protected from diseases. Relatively speaking, they led the right lifestyle, and at the age of 70 they do not show hypertension, atherosclerosis or oncology, there are no other progressive diseases, and then the aging processes come to the fore.
Diseases of old age
When it comes to prolonging life, we are talking about fighting diseases. We have specific biomarkers, disease stigmas. Biomarkers obtained with the help of radiation diagnostic methods, such as coronary calcium, indicate the presence of a latent disease, pre-pain, subclinical organ damage. "Subclinical" means that there are no clinical manifestations yet. Let's say a person has atherosclerosis, but the heart does not hurt. In this case, we see the disease and prescribe not some abstract geroprotector that affects everything, but specifically a statin, which affects the specifically found risk factor.
Geroprotectors are a common name for a group of drugs that are believed to have a positive effect on life expectancy.
You can go a level further: when there is no coronary calcium, there is no disease yet, but there is already high cholesterol, high stress and a specific set of risk factors. If there are a lot of risk factors, then we can already prescribe statins here – they will prevent death from the most likely developing pathologies and thus prolong life.
Potentially, you can go deeper into the genes and see what mutations there are. There is a big difference between mutations and polymorphisms. We can look at mutations in certain genes in a patient with high cholesterol: if they exist, this further increases the risk of heart disease. Ideally, it turns out to be a fusion of biomarkers and genetics, but we can't look only at genes without biomarkers yet. There are tests for the presence of mutations in the BRCA ½ genes. For example, Angelina Jolie, having learned about a disease that is highly likely to shorten her life, breast cancer, made an intervention for herself: she removed her mammary glands. Medicine works with risk factors.
People look at the most common diseases and learn how to prevent them. But the harsh truth of life is that there is a wide range of diseases from which people die, and not all of them are common and studied. The less common the disease is, the less scientific data we have in order to understand how to prevent it. For example, glioblastoma is one of the most aggressive forms of brain tumor. People die from it all the time. (By the way, there is an opinion that the development of glioblastoma may be associated with the use of mobile phones – this is periodically written about in the scientific community.) But we have no recommendations on how to prevent glioblastoma, no one says with what frequency it is necessary to do an MRI, and we generally do not know how to influence the risk of this tumor.
Some say that aging is a global process and that in fact only the intercellular matrix ages. It gets tougher over time. But we cannot consider the aging process in isolation from the disease. If we had an ideal world in which everyone ran and ate right, received statins according to indications, then perhaps the mechanisms of aging would come to the fore. But for now, this is a beautiful dream, which is irrelevant in relation to the overwhelming number of patients. You can look at the huge number of elderly people who survive by taking medications. My grandfather is 90 years old, he gets eight pills a day. He is a long-lived man, but I do not prevent aging for him, but treat heart failure.
Will medications help?
The most effective measure against aging remains the restriction of food consumption and physical activity. Physical activity and proper nutrition can help win a few years – not decades, but two, three, sometimes five years.
Even in animal experiments, we have not yet been able to find drugs that really solve the problem of aging. Here we can only mention rapamycin. It was discovered as an antibiotic, but in 2009, a study on mice found that rapamycin increased their life expectancy – both in males and females. This is quite a significant discovery in the field of aging, because for the first time a pharmacological agent increased the life of a mammal. Journal Science then called this study one of the main scientific achievements of 2009. In 2019, scientists from the Drexel University College of Medicine tried to use rapamycin in humans. They applied it like a cream to the volunteers' hands and watched the results. Rapamycin blocks the TOR protein complex responsible for cell reproduction. And indeed, the number of wrinkles decreased in the subjects, but these are all very conditional indicators, there are few experiments. At the same time, it is impossible to use rapamycin in practice, since it has a huge number of side effects.
There is an interesting population approach, recently it was described in the journal New England Journal of Medicine: Healthy people were given four medications at once – statin, diuretic, beta-blocker and aspirin. There is personalized medicine, which takes into account the diseases and risk factors of each patient, and in this experiment, without understanding whether there is hypertension or not, there is a violation of lipid metabolism or not, just everyone was prescribed the same drugs. And it turned out that taking them significantly prevents the occurrence of cardiovascular diseases even in healthy people. That is, our population is saturated with risk factors so much that even antipersonalized medicine has worked towards improvement.
It is also observed that radiation in small doses prolongs the life of flies and mice, but this is again controversial from the point of view of the effect on humans.
Why is it difficult to identify the role of heredity?
Life expectancy depends on our genetic background. The Russian company GERO, for example, believes that our aging is controlled by something like a genetic program. They say that in fact, each person has about 60 mutations. They are not so critical as to lead to disease, but they lead to a change in proteins: they trim the protein earlier than necessary. They are working in this direction, but we can talk about some results in twenty years.
Now doctors can study the data and say: "It is especially important for you to eat vegetables and fruits. Everyone needs it, but especially you." However, you will not be able to give a pill. Arterial hypertension is a good example, it still has a hidden heritability of 50%. That is, it would seem an amazing thing: geneticists are capable of a lot, hypertension (hypertension) affects 30-45% of the population, it is a genetically determined disease, but only half of the cases can be explained by genetic polymorphisms. And in the other half, we know that genetics plays a role, but we don't know what specific combinations of genes. This is hidden heritability. We have no idea about it yet, because scientists can count genes, but what happens at a higher level – where mRNA and protein synthesis are – is poorly understood. Proteomics is not developed in our country.
Now our models are based on biomarker data, and genetics is practically not taken into account. For example, if male patients over 40 years of age have a level of "bad cholesterol", that is, low-density lipoproteins higher than 4.9 mmol / l, then the appointment of statins reduces mortality. But in most cases, we do not know such genes, the presence of polymorphism in which would make it possible to prescribe an effective medicine.
Genetic polymorphisms are genetic markers that can show a predisposition to a particular disease.
It is possible to analyze how much the same genetic polymorphisms increase the risk of developing a particular disease, but this knowledge does not yet allow changing the treatment strategy. Let's say we have a person, he is 18 years old, the doctor finds all known polymorphisms in his blood pressure, but cannot prescribe a drug to reduce pressure until it rises. And when it has increased, the drug is prescribed, but it would have been prescribed anyway. That is, a specialist can only say: "Dear patient, I understand why your blood pressure has increased, look how many polymorphisms you have." But the tactics of patient management will practically not change.
And how should I? It is necessary to conduct a study that will allow people with a large number of genetic polymorphisms predisposing to hypertension to prescribe a blood pressure lowering drug at an early age. If we prove that this affects mortality, then we will be able to prescribe drugs based on genetics, but not now. Therefore, the genetic test so far does not bring any really useful information to people. It may be necessary when planning pregnancy to search for rare mutations in parents, but it is of little use outside of this area.
What medicine is already strong in is neurodegenerative diseases: we can estimate the risk of developing Alzheimer's disease with a very high proportion based on genetics. But we can't do anything to prevent it. If suddenly we can extract information about the probabilities of developing diseases from genetic analysis, the world will change. Because genetic analysis, unlike the expanded "biomarker", using radiation methods, is done simply and cheaply.
The earlier we want to catch the disease, the more expensive the technology is needed. So there is a risk that success in increasing life expectancy will divide humanity into two large populations: the one that will have access to diagnostic and therapeutic technologies, and the one that will not have it. Africa, for example, will remain Africa for a long time, neither genetic testing nor molecular diagnostics will be carried out there. Although, if genetic tests are cheap, they will eventually come to conditional Africa.
How is the microbiota related to aging?
The future of aging science lies in the link between the emotions of the nervous system, the immune system, on which the risks of cancer and cardiovascular diseases depend, and the microbiota, which, in turn, strongly affects the immune system. The question is that we are not good at studying it: even in the best research universities, it is not possible for one person to simultaneously evaluate the result of fMRI, the state of the "lymph nodes" at once intestine (peyer's plaques), immune system, microbiota. In the immune system, we need to look at the cells that are in the lymph nodes. What is on the periphery and what can be detected with the help of blood sampling very poorly characterizes what is happening inside. It's as if people are sitting in a concert hall, listening to the violin, and those who leave the hall do not know what is happening at the concert, but they give an assessment based on the applause.
There is a promising study when children were enriched with lactobacilli and bifidobacteria from an early age. From 4 to 10 years, we watched these children, waited for great results, but so far they have only decreased the frequency of type I diabetes. I must say, even this is already a great result.
Microbiota – all microorganisms (bacteria, viruses, fungi) inhabiting the human body.
Will cryopreservation help?
Cryopreservation seems to be a way to prolong life for a long time, a lot of people fantasize about it in the movies. But most often people are frozen at too late a stage, their body is far from being in the condition in which they can be thawed in 100 years, even if there are technologies. It is necessary to freeze significantly earlier than it is being done now, but here an ethical question arises. And yet: the shelf life of the body is still limited. We see this in stem cells that are frozen and thawed. You can't freeze it now, but defrost it in a thousand years: it's unlikely that something will work out.
Is it even necessary to live forever?
A doctor should strive to prevent death so that people live as long as possible. But a reasonable question arises: do we need so many people? How will they work, how will the provision of the unemployed take place? Medicines will become more expensive, the burden on the healthcare system will increase. These social issues provoke social challenges. It is unlikely that humanity will reach some kind of consensus, because, on the one hand, people like to live for a long time, and on the other hand, there is nature, there is COVID, which has already reduced the population of elderly people. It is still unclear what we will do if we get a very elderly population, how much we will be able to provide them with resources, how we will solve the issue of overpopulation of the planet. People are not very socially responsible creatures: they cannot put on masks in the subway, pollute the oceans, harm the ecology as a whole.
Our social intelligence, most likely, has not grown to the level that is necessary for a long life. Our limbic system, our "reptilian brain" is still extremely immature. Metaphorically speaking, "we have a powerful engine, but a weak gearbox." It's true: a person has strong problems with emotional regulation, they ultimately oppose the fact that we consciously value life. Impulsive actions, self–destruction, depression - these factors need to be taken into account. On the other hand, we see how powerful a factor in prolonging life is the presence of a goal in life, this is shown in serious scientific research. That is, the hypotheses of Fromm and Frankl are confirmed. Therefore, I believe it is the understanding of the connection of psychological and social factors with genetic and microbiomic characteristics that will allow us to achieve significant longevity in the future (exceptional longevity).
About the author: Yaroslav Ashikhmin – Candidate of Medical Sciences, therapist, cardiologist, advisor to the Director General of the International Medical Cluster Foundation.
Portal "Eternal youth" http://vechnayamolodost.ru