Mechanisms of aging
What Science knows about Life extension
Alexey Moskalev, Post-science
Over the past 100 years, the average human life expectancy in developed countries has almost doubled. There are objective reasons for this: a decrease in child mortality, treatment of most acute diseases, an increase in the quality of life, a significant decrease in the number of deaths due to non-biological causes, such as war. But over the past few decades, life expectancy has not increased so much, since humanity has exhausted all simple methods of increasing life span: hygiene, vaccines, antibiotics, a healthy lifestyle. In some countries, life expectancy has even decreased because people have started eating cheaper high-calorie food, which leads to epidemics of obesity. In addition, an increase in the life span does not guarantee its quality at all. Previously, people died from infections at an early age. Now a lot of people have a chance to live to a very old age.
But not everyone will be able to live an active and full life at this age. According to the World Health Organization (WHO), age-dependent diseases are currently leading among the ten leading causes of death: coronary heart disease (CHD), stroke, cancer, diabetes mellitus. Aging is the main risk factor for these and many other socially significant chronic diseases, including neurodegenerative, namely vascular dementia, Alzheimer's and Parkinson's diseases. On average, by the age of 50, a person has two chronic diseases, and by the age of 70 there are already seven. And if these diseases were not fatal, a person in a very old age would acquire the whole possible bouquet of age-dependent diseases. Therefore, aging can be considered as a hidden, preclinical stage of the occurrence and course of these diseases.
The beginning of aging
To defeat aging and learn to lead a full life in old age, it is necessary to understand what exactly we are fighting. And there is no simple unambiguous answer.
From a fertilized egg, we grow into an organism, are born and develop to leave offspring. This process of physiological, reproductive and psychological maturation of an individual is called adulthood. The period of optimal human productivity falls on about 20-40 years: at this time, he gives life to children, ensures their survival, educates them and educates them. After that, from the point of view of evolution, we are no longer needed and can die in peace.
There is a hypothesis about the "grandmother effect": women live longer, since they were selected to help the next generation – the cultivation of grandchildren. It seems that at this moment aging should start – a degenerative process that leads to a gradual loss of adaptive capabilities and the ability to maintain the constancy of the parameters of the internal environment.
In fact, aging begins in the womb. A living organism constantly "puts itself in order" with the help of special enzymatic "nanomachines": they repair DNA, dispose of damaged proteins, patch cell membranes, and so on. But over time, the repair mechanisms themselves break down. And then the cascade of breakdowns becomes exponential, and the body gets chronic diseases.
Aging is a multi–level process. We lose many functions at once and age at all levels: molecular, cellular, tissue, functional, psychological. It is impossible to single out one cause or consequence of aging. There are no special genes, hormones or organs aimed by evolution at implementing the aging program. Aging, like diseases, is only a consequence of the deregulation of the mechanisms of self-maintenance of the living system and does not bring anything fundamentally new to the organization of our body.
Causes of aging
Previously, the idea was popular that we live in an oxidizing environment, which is the main engine of aging. According to this idea, the cells of the body simply cannot help but accumulate oxidative damage, and it is they who cause various diseases associated with aging. In the late 1990s, many believed that if protection was established against oxidative damage and damage by free radicals (any molecules or atoms containing one or more unpaired electrons at the external electronic level), it was possible to protect against aging. The stores still sell nutritional supplements-antioxidants. But in the 2000s, this theory was experimentally tested on animals by adding antioxidants to food. The theory turned out to be wrong: although oxidation does occur, it does not play a role in the aging process.
Let's consider the main mechanisms of aging.
Gene mutations. In the course of human life, many generations of cells of the body are replaced. They reproduce by division. In the nuclei of cells there are chromosomes designed to store, implement and transmit from generation to generation the genetic program of the development and functioning of the organism. Chromosomes consist of double-stranded DNA molecules. DNA chains are constructed of four letters (nitrogenous bases) according to the principle of complementarity: against adenine (A) there is always thymine (T) and vice versa, and against guanine (G) there is always cytosine (C). Each section of DNA – a gene – determines how proteins that perform certain functions in the body will be built. functions. During life, some genes accidentally or damaged under the influence of external adverse factors change their structure and activity. These changes in the genome are called mutations. Over the years, mutations gradually accumulate, which leads to malfunctions in the body.
But some genes change their activity without changing the primary structure – these changes are called epigenetic. For example, a methyl group can join cytosine, one of the nitrogenous bases of DNA, and this will affect the production of a particular protein at a certain point in time. This is a natural process by which liver cells, for example, have their own profile of active genes compared to brain neurons, despite the fact that the DNA sequence of all body cells is the same. However, in response to stress, inflammation, shortening or damage of chromosomes during cell division, the epigenetic profile of the cell may change, which leads to an age-related change in the activity of genes, including vital ones.
In 1957, the evolutionary biologist George Christopher Williams suggested that some genes at different ages have different effects: if at a young age they are extremely important for survival, then in old age they only harm. For example, a gene that increases calcium fixation in bones reduces the risk of fractures in youth, but increases the risk of osteoarthritis in old age due to excessive calcification of the joints. This idea is known as antagonistic pleiotropy.
Shortening of telomeres. When a cell divides, the daughter DNA chain formed on the parent DNA matrix becomes somewhat shorter due to the peculiarities of the enzyme - DNA polymerase. The fact is that DNA polymerase cannot start from scratch (connect two free nucleotides). For her, an RNA seed is specially created at the very tip of the DNA, to which she begins to attach DNA nucleotides. Subsequently, the RNA seed is split, and the genetic information about the tip of the chromosome is lost. In a series of cell divisions, the ends of chromosomes become shorter and shorter and at some point are perceived as DNA damage that stops cell division.
A cell with damaged DNA normally does not divide, so as not to be reborn into a tumor. This phenomenon of the inability of cells with short telomeres to divide is called cellular aging. Therefore, at the ends of mammalian chromosomes there are meaningless repeats forming telomeres, which are periodically completed by the enzyme telomerase. However, telomerase is turned off after birth in all cells, except for sex and some stem cells. Therefore, with each cell division, telomeres shorten. By the end of human life, they become so short that each subsequent division jeopardizes genetic information. When this happens, the division of, for example, stem cells stops and, as a result, tissue regeneration.
"Attenuation" of mitochondria. With age, mitochondrial cells lose their function of "energy stations". This is due to the accumulation of errors in mitochondrial DNA and enzymes, weakening the culling of damaged mitochondria. There is no longer enough energy for the process of recovery and growth, which also becomes one of the causes of aging. In addition, protective barriers are broken inside the cell over time. Mitochondria are overloaded with calcium and open the pores of temporary permeability. Through them, ring mitochondrial DNA enters the cell, which in the cytoplasm of the cell, where they normally should not be, are perceived as an infectious invasion (some viruses and bacteria have similar DNA). Interferon response and chronic inflammation are activated, which contributes to the development of diseases.
Deterioration of protein quality. Over time, there is a violation of the circulation of intracellular proteins: damaged proteins cease to be replaced by new ones and accumulate in the body. And extracellular proteins, which are practically not updated, eventually form crosslinking. Because of them, the tissues become rigid and inelastic. Hence the appearance of wrinkles, pulmonary insufficiency, high blood pressure.
Aggregates (clots) of proteins that disrupt intracellular traffic in the cytoplasm gradually accumulate in non-dividing cells (heart muscle cells, neurons that are not replaced by others for almost the entire life), and some of these cells are quite extensive. Proteins also accumulate in the endoplasmic network – the internal transport and sorting system of the cell. The stress of the endoplasmic network (it's like a traffic jam on the road), in turn, triggers cellular aging or death. It is not uncommon for proteins outside cells to become aggregates, amyloid plaques and tau protein strands in the intercellular space of the brain are associated with Alzheimer's disease, an incurable form of age-related neurodegeneration.
Weakening of biological barriers. Biological barriers that are located in the intestine, vascular wall, skin, between the brain and blood flow play a key role in maintaining the constancy of the parameters of the internal environment. With aging, these barriers are broken, and infections, unwanted molecules or toxins penetrate through them. This causes a variety of diseases: inflammation in the wall of the gastrointestinal tract, atherosclerosis, and so on.
Fight against aging
Although we know quite a lot about aging, this is not enough to effectively and safely interfere with these processes. However, some successful experiments were set by nature itself. So, the polar shark lives 400 years. A naked digger has almost no cancer, is insensitive to pain and lives up to 30 years in captivity, which is unusually long for a rodent of its size (13 cm): a laboratory mouse lives about three years (10 cm). It is quite clear from a person how old he is, which cannot be said about a naked digger: it is extremely difficult to determine by his appearance how long he has lived. It is believed that the longevity of the digger is due to the active restoration of damaged DNA bases. Moreover, there is an assumption that the naked digger is a neotenic animal – the development of his body stops at the newborn stage. And the most amazing long–lived bat is considered to be Brandt's moth: with a body weight of only 5 grams, it lives up to 40 years in the wild - usually those animals that have the largest mass live for a long time. Scientists decode the genomes of long-lived animals, which allows us to establish new genetic causes of longevity.
You can also study the genetics of diseases that resemble accelerated human aging. For example, with Hutchinson –Guilford syndrome, children live up to about 15 years old: their hair falls out, a large number of wrinkles appear, osteoporosis. This syndrome is caused by a mutation in the LMNA gene: because of it, a defective protein accumulates in cells, which leads to deformation of the membranes of cell nuclei (where chromosomes are stored) and the failure of many epigenetic processes. If we take the accumulation of this protein under control, it may be possible to slow down some degenerative processes.
In 2009 , the Nobel Prize in Physiology or Medicine was awarded Elizabeth Blackburn, Carol Greider and Jack Shostak for the discovery of telomerase, an enzyme capable of completing telomeres. Only germ and stem cells have access to telomerase. There was an idea that if you give other cells access to active telomerase, they will be able to complete telomeres, and aging will slow down. But this strategy didn't work. It turned out that the shortening of telomeres is a barrier to the growth of cancerous tumors: due to the establishment of a limit on the number of possible cell divisions of the incipient tumor, it is more difficult to turn into a truly malignant one. As soon as a cell gets unlimited access to telomerase, it begins to divide indefinitely, and the risk of becoming cancerous is high.
One of the possible ways to prolong life is genome editing. In experiments with animals, scientists activated individual genes or made changes to them, which sometimes led to a significant increase in life expectancy. Experiments on mice have shown that genome editing based on factors that lengthen telomeres or reprogram ordinary cells into stem cells can prolong life. The banking of bone marrow stem cells at a young age, followed by their introduction in old age in mice, also contributed to the prolongation of life.
There is no single cure for aging today. Even experiments on animals do not give reliable results. We know that it is necessary to have a complex effect on various body systems in order to prolong life and at the same time improve its quality. It is possible to increase the body's resistance to some kind of stress. You can remove some damage in the DNA. Individually, these interventions will be ineffective, but together they can improve the quality of life. Therefore, it is necessary to systematize our knowledge about aging, evaluate the contribution of each of the mechanisms of aging known today to the longevity of the whole organism and create a mathematical model of aging and human longevity on this basis. We need more accurate and safe methods of editing the human genome. Large-scale clinical studies of pharmaceuticals, dietary supplements, diets, lifestyle with a comprehensive assessment of biological age, age-dependent diseases and mortality from various causes are needed.
About the author:
Alexey Moskalev – Doctor of Biological Sciences, Head of the Laboratory of Molecular Radiobiology and Gerontology of the Institute of Biology of Komi National Research Center Ural Branch of the Russian Academy of Sciences, Head of the Department of Ecology of Syktyvkar State University, Head of the Laboratory of Genetics of Life Expectancy and Aging at MIPT.
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