Examples of apoptosis in the human body. Cell apoptosis

Definition of apoptosis. Apoptosis is a phenomenon of hereditarily programmed cell death. Each cell at its birth is, as it were, programmed for self-destruction. The condition of her life is to block this suicidal program.

Apoptosis occurs in cells:

Old ones who have outlived their usefulness;

Cells with impaired differentiation;

Cells with genetic disorders;

Cells infected with viruses.

Morphological characteristics apoptosis.

Cell shrinkage;

Condensation and fragmentation of the core;

Destruction of the cytoskeleton;

Bullous protrusion of the cell membrane.

Features of apoptosis - apoptosis does not cause inflammation in the surrounding tissues. The reason is the preservation of the membrane and → isolation of damaging factors in the cytoplasm until the process is completed (O 2 -, H 2 O 2, lysosomal enzymes). This feature is an important positive feature of apoptosis, in contrast to necrosis. In necrosis, the membrane is damaged (or ruptured) immediately. Therefore, during necrosis, the contents of the cytoplasm are released (O 2 -, H 2 O 2, lysosomal enzymes). Damage to neighboring cells and an inflammatory process occurs. An important feature of apoptosis is the removal of dying cells without the development of inflammation.

Apoptosis process - can be divided into 2 (two) phases:

1. Formation and conduction of apoptotic signals – decision-making phase.

2. Dismantling of cellular structures - effector phase.

1st phase – decision making (=formation and acceptance of apoptotic signals). This is the phase of accepting stimuli for apoptosis. Depending on the nature of the stimuli, there may be two (2) types of signaling pathways:

1) DNA damage as a result of radiation, the action of toxic agents, glucocorticoids, etc.

2) activation of “cell death region” receptors. Cell death region receptors are a group of receptors on the membranes of any cells that perceive proapoptotic stimuli. If the number and activity of such receptors increases, then the number of apoptically dying cells increases. The receptors of the “cell death region” include: a) TNF-R (binds to tumor necrosis factor and activates apoptosis); b) Fas-R (k); c) CD45-R (binds to antibodies and activates apoptosis).

Depending on the type of signal, there are 2 (two) main methods of apoptosis: a) as a result of DNA damage;

b) as a result of independent activation of the “cell death region” receptors without DNA damage.

2nd phase – effector (= dismantling of cellular structures. The main participants in the effector phase:

Cysteine ​​proteases (caspases);

Endonucleases;

Serine and lysosomal proteases;

Ca++ activated proteases (calpein)

But! Among them, the main effectors of the dismantling of cellular structures are caspases.

Classification of caspases - 3 (three) groups:

Effector caspases - caspases 3, 6, 7.

Inducers of activation of effector caspases – caspases 2, 8, 9, 10. = activators of cytokines – caspases 1, 4, 5, 13.

Effector caspases are caspases 3, 6, 7. These are the direct executors of apoptosis. These caspases are in an inactive state in the cell. Activated effector caspases begin a chain of proteolytic events, the purpose of which is to “dismantle” the cell. They are activated by inducers of activation of effector caspases.

Inducers of activation of effector caspases – caspases 2, 8, 9, 10. The main inducers are caspases 8 and 9. They activate effector caspases. The mechanism is the cleavage of aspartic bases followed by dimerization of the active subunits. These caspases are normally inactive in cells and exist in the form of procaspases.

The activation of certain inducers depends on the type of signaling pathway:

1. When DNA damage occurs, signaling pathway No. 1 is activated, caspase No. 9 is activated.

2. When cell death receptors are activated, signaling pathway No. 2 is involved, caspase No. 8 is activated.

Signaling pathway No. 1 (associated with DNA damage)

DNA damage

Activation of the p53 gene and production of the corresponding protein

Activation of proapoptotic genes of the BCL-2 family (BAX and BID)

Formation of proteins of these genes

Caspase 9 activation

Caspase 3 activation

Signal Path No. 2

(associated with activation of the “cell death region”)

Ligand + receptors of the “cell death region”

Activation of caspase number 8

Independent activation of caspase number 3

Activation of other caspases and proteases

Regulation of apoptosis. Research recent years led to the creation of a model of apoptosis. According to this model, every cell at its birth is programmed to self-destruct. Therefore, the condition of her life is to block this suicidal program. The main task of apoptosis regulation is to keep effector caspases in an inactive state, but quickly convert them into an active form in response to minimal action of the corresponding inducers.

Hence the concept of inhibitors and activators of apoptosis.

Apoptosis inhibitors (=anti-apoptotic factors). The most serious inhibitors of apoptosis include growth factors. Others: neutral amino acids, zinc, estrogens, androgens, some proteins.

Example: IAP family proteins suppress the activity of caspases 3 and 9. Remember: one of these proteins (Survin) is found in tumor cells. It is associated with resistance of tumor cells to chemotherapy

Activators of apoptosis (=pro-apoptotic factors). These are proapoptotic genes and their products: a) genes of the BCL-2 family (BAX and BID); b) Rb and P53 genes (trigger apoptosis if the cell is detained by the checkpoint mechanism.

Summary. The pathogenesis of many diseases, including tumors, is associated with a decrease in the ability of cells to undergo apoptosis. Hence the accumulation of damaged cells and the formation of a tumor.

PATHOPHYSIOLOGY OF CELL DIVISION

The main difference between the division of a healthy and a tumor cell:

The division of a healthy cell is regulated in a paracrine and endocrine manner. The cell obeys these signals and divides only if the body needs the formation of new cells of a given type.

Tumor cell division is regulated in an autocrine manner. The tumor cell itself produces mitogenic stimulants and divides itself under their influence. It does not respond to paracrine and endocrine stimuli.

There are 2 (two) mechanisms of tumor cell transformation:

1. Activation of oncogenes.

2. Inactivation of suppressor genes.

ONCOGENE ACTIVATION

First of all, 2 (two) main concepts: = proto-oncogenes;

Oncogenes.

Proto-oncogenes are normal, intact genes that control healthy cell division.

Proto-oncogenes include genes that control education and work:

1. Growth factors.

2. Membrane receptors for growth factors, for example tyrosine kinase receptors.

3. Ras proteins.

4. MAP kinases, participants in the MAP kinase cascade.

5. AP-1 transcription factors.

Oncogenes are damaged proto-oncogenes. The process of damaging a proto-oncogene and transforming it into an oncogene is called oncogene activation.

Mechanisms of oncogene activation.

1. Inclusion (insertion) of the promoter. A promoter is a region of DNA to which proto-oncogene RNA polymerase binds. Prerequisite– the promoter must be in close proximity to the proto-oncogene. Hence the options: a) promoter - a DNA copy of oncornaviruses; b) “jumping genes” - sections of DNA that can move and integrate into different parts of the cell’s genome.

2. Amplification – an increase in the number of proto-oncogenes or the appearance of copies of proto-oncogenes. Proto-oncogenes normally have little activity. With an increase in the number or appearance of copies, their overall activity increases significantly and this can lead to tumor transformation of the cell.

3. Translocation of proto-oncogenes. This is the movement of a proto-oncogene to a locus with a functioning promoter.

4. Mutations of proto-oncogenes.

Production of oncogenes. Oncogenes form their own proteins. These proteins are called “oncoproteins.”

The synthesis of oncoproteins is called “expression of active cellular oncogenes.”

Oncoproteins are basically analogues of proto-oncogene proteins: growth factors, Ras proteins, MAP kinases, transcription factors. But there are quantitative and qualitative differences between oncogenes and proto-oncogene proteins.

Differences between oncoproteins and normal proto-oncogene production:

1. Increased synthesis of oncoproteins compared to the synthesis of proto-oncogene proteins.

2. Oncoproteins have structural differences from proto-oncogene proteins.

Mechanism of action of oncoproteins.

1. Oncoproteins bind to receptors for growth factors and form complexes that constantly generate signals for cell division.

2. Oncoproteins increase the sensitivity of receptors to growth factors or reduce sensitivity to growth inhibitors.

3. Oncoproteins can themselves act as growth factors.

INACTIVATION OF SUPPRESSOR GENES

Suppressor genes: Rb And p53.

Their products are the corresponding proteins.

Inactivation of suppressor genes (hereditary or acquired) leads to the passage of cells with damaged DNA into mitosis, the reproduction and accumulation of these cells. This - possible reason tumor formation.

TUMOR GROWTH: DEFINITION, CAUSES OF INCREASE IN THE NUMBER OF MALIGNANT DISEASES

A tumor is a pathological growth that differs from other pathological growths by its hereditarily fixed ability for unlimited uncontrolled growth.

Other pathological growths are hyperplasia, hypertrophy, regeneration after damage.

Reasons for the increase in the number of malignant diseases among the population:

1. Increased life expectancy.

2. Improving the quality of diagnostics → increasing the detection of cancer.

3. Deterioration of the environmental situation, increase in the content of carcinogenic factors in the environment.

BENIGN AND MALIGNANT TUMORS

Unified classification No tumors have yet been created. Cause:

1. A wide variety of signs characteristic of various tumors.

2. Insufficient knowledge of their etiology and pathogenesis.

At the core modern classifications- main morphological and clinical signs of tumors.

Based on clinical characteristics, all tumors are divided into benign and malignant.

Benign tumors:

1. Tumor cells are morphologically identical or similar to normal progenitor cells.

2. The degree of differentiation of tumor cells is quite high.

3. Growth rate is slow, over many years.

4. The nature of growth is expansive, i.e. During tumor growth, neighboring tissues are moved apart, sometimes compressed, but usually not damaged.

5. Demarcation from surrounding tissues is clear.

6. The ability to metastasize is absent.

7. No pronounced adverse effects on the body. Exception: tumors located near vital centers. Example: a brain tumor that compresses the nerve centers.

Malignant tumors.

1. Tumor cells are morphologically different from normal progenitor cells (often beyond recognition).

2. The degree of differentiation of tumor cells is low.

3. Growth rate is fast.

4. The nature of growth is invasive, i.e. the tumor grows into neighboring structures. Contributing factors:

Tumor cells acquire the ability to detach themselves from the tumor node and actively move;

The ability of tumor cells to produce “carcinoaggressins”. These are proteins that penetrate into surrounding normal tissue and stimulate chemotaxis for tumor cells.

Reduced cell adhesion forces. This facilitates the detachment of tumor cells from the primary node and their subsequent movement.

Reducing contact braking.

5. Demarcation from surrounding tissues – no.

6. The ability to metastasize is pronounced.

7. The effect on the body is unfavorable, generalized.

Programmed cell death is an integral process of the life of any organism. When this process is disrupted, a number of serious diseases develop.

What is apoptosis?

Apoptosis is cell death that occurs as a result of programmed processes occurring in the cell at the molecular level. During apoptosis, the cell divides into several parts surrounded by a cell membrane, after which the cell fragments are digested within a few minutes (usually up to 90 minutes). special cells macrophages.

The phenomenon of programmed cell death is characteristic of all living beings, including humans. Every day, several tens of billions of cells die in the human body. The destroyed cells are subsequently replaced by new cells formed through cell division (mitosis).

What is the role of apoptosis?

Self-destruction of cells that the body does not need is an extremely important process for the normal functioning of any organism. One of the main functions of apoptosis is to maintain the constancy of the cell population. When forming a new cell population (for example, some immune cells), it must be taken into account that a number of cells will necessarily be defective. That is, the body needs to carry out cell selection to preserve only those cells that will fully cope with their functions. In the remaining, defective cells, a self-destruction program is launched.

Apoptosis also plays an important role during infection with infectious agents, in particular viral ones. When the virus enters a cell, it begins to multiply vigorously, after which the cell ruptures and millions of viral particles attack other cells. In the course of evolution, living organisms have learned to deal with this phenomenon. Thus, a number of viruses cause a number of changes in the cell, which are perceived as a signal for self-destruction. Thus, by destroying the infected cell, the body does not allow the virus to spread.

When apoptosis doesn't work

The regulation of apoptosis involves many molecular processes, the coordinated action of which leads to the death of cells “unwanted” by the body. However, for certain reasons, which are not yet completely clear, apoptotic regulation is disrupted. A failure in the system can be caused by insufficient synthesis of apoptotic proteins and enzymes, as well as exposure to specific substances that lead to a decrease in the apoptotic activity of the cell.

Today it is known that one of the regulators of apoptosis is the p53 protein. If there are a number of defects in a cell, in particular breakdowns of genetic material, the p53 protein triggers a chain of molecular processes leading to the development of apoptosis. Mutation of the p53 protein makes it impossible to perform its main function - triggering cell death.

Viruses can also prevent programmed cell death. For example, in genetic The material of some viruses may encode specific proteins that inhibit cell apoptosis. In other cases, a viral infection stimulates the production of anti-apoptotic proteins by the cell itself. Thus, the virus turns off the cell apoptosis program and can multiply uncontrollably.

There are several variants of apoptosis disorder:

• Excessive apoptosis is a pathological phenomenon that leads to excessive death of a cell population. This phenomenon is observed in HIV infection, some forms of hepatitis, chronic myocardial ischemia, neurodegenerative and other diseases.
• Insufficient apoptosis, in which the number of dying cells is clearly less than the number of newly formed ones.
• Incomplete apoptosis, in which the destruction of apoptotic fragments by cells of the immune system does not occur.

What does impaired apoptosis lead to?

Activated protein C may inhibit apoptosis

Regulation of programmed cell death processes may be the key to creating new effective remedy for the treatment of stroke.

American scientists have successfully tested a substance on mice that has already found use in

It is now known that dysregulation of apoptosis can lead to a number of immunological and tumor diseases. Under normal conditions, the human body undergoes a strict selection of newly formed immune cells, since some of them may be reactive towards the body’s own cells. If the process of self-destruction of such immune cells is disrupted, then diseases develop.

Dysregulation of apoptosis of cell populations leads to the development of a number of tumor processes. In particular, it has been proven that mutation of the p53 protein or disruption of its synthesis in the body can lead to the development of hormone-dependent carcinoma of the breast, ovaries and prostate gland. Similar disorders have also been identified during the development of lymphomas.

The possibility of influencing the apoptotic system is one of the directions in the search for drugs against cancer. However, in some cases, stimulation of apoptotic activity, on the contrary, is detrimental to the body. In this regard, scientists and doctors are actively studying the nature of this phenomenon, hoping in the future to obtain a tool with which to control apoptosis.

The term “apoptosis” should be understood as the physiological process of cell death, which is triggered in response to physiological signals or is ensured by the inclusion of a special genetic program. Morphologically, this process is characterized by compaction of chromatin, division of DNA into fragments and changes in the structure of the cell membrane. As a result, the cell is destroyed and phagocytosed without signs of inflammation, which has virtually no effect on surrounding tissues.

Biological role

Programmed cell death is extremely important for normal functioning body.

Programmed cell death plays an important role in the normal functioning of living organisms, it ensures:

• development during embryogenesis;
• regulation of the number of cells and their composition in a mature organism;
• cell differentiation;
• destruction of old cells that cease to perform their functions;
• hormonal changes;
• suppression of tumor growth;
• culling of cells with genetic defects;
• elimination of foreign agents (viruses, bacteria, fungi, etc.).

Dysregulation of cell death leads to the development of:

• viral infections;
• neurodegenerative diseases (,);
• blood pathologies (,).

It should be noted that in some of them the apoptosis function is reduced, while in others, on the contrary, it is increased.

• It is believed that suppression of apoptosis has great importance for tumor progression. Cancer cells can become resistant to it due to increased expression of anti-apoptotic factors or as a result of mutations in genes.
• A decrease in apoptosis is observed in autoimmune processes, when autoaggressive T cells are not destroyed immune system. This leads to damage to the body's own tissues.
• Increased apoptosis also negatively affects human health. This may be associated with increased death of bone marrow precursor cells of the red and white hematopoietic lineage, which results in aplastic anemia.

Thus, apoptosis acts common mechanism cell death, both during physiological and pathological processes.

Development mechanisms

Programmed cell death occurs in a succession of 3 stages:

1. Inductor.
2. Effective.
3. Degradation.

At the first stage, signal reception and the initial stages of its transmission occur. This is carried out using a receptor mechanism under the influence external factors or by internal activation.

Receptors that trigger apoptosis are called death receptors. They have special domains within them, interaction with which induces special intracellular signals.

The internal pathway of activation of this process is associated with changes occurring in mitochondria. It is sensitive to deficiencies of growth factors, hormones or cytokines. It can also be affected by:

• hypoxia;
• hypothermia;
• virus invasion;
• irradiation;
• free radicals.

All these factors can cause restructuring of the inner mitochondrial membrane, as a result of which pores open and pro-apoptotic substances are released. By their structure, these are proteins that trigger the caspase-dependent apoptosis pathway and induce the division of DNA into fragments with condensation of peripheral chromatin regions.

During the effector stage, the main apoptotic enzymes, caspases, are activated. They have proteolytic activity and break down proteins at the aspartic residue. As a result of their activity, massive protein destruction occurs in the cell and irreversible changes develop.

At the last stage, the basic mechanisms of cell death are realized. This activates endonucleases, whose activity leads to DNA degradation. After this, the cytoskeleton is reorganized and the cell is transformed into apoptotic bodies, on the surface of which markers for phagocytosis appear. On last stage such cells are engulfed by macrophages.

Regulation of apoptosis

Impaired apoptosis is one of the factors that increases the risk of developing AIDS.

Each of the mechanisms of apoptosis has its own regulation:

• The mitochondrial pathway is regulated by proteins from the Bcl-2 family. They affect mitochondrial membrane permeability and can attenuate or stimulate apoptosis. This is done by controlling the release of cytochrome C.
• Regulation of the cell death receptor mechanism occurs by controlling the activity of caspases.

Apoptosis allows the body to maintain physiological balance and resist various external influences. Thus, every day in the human body, tens of billions of cells die as a result of programmed death, but these losses are quickly compensated for by cell proliferation. The total mass of cells that are destroyed annually by apoptosis is equal to the weight of the human body.

Birth and death are often perceived by us on an everyday, and sometimes on a philosophical level - as two sides of the same coin. One phenomenon is supposedly inseparable from the other. Birth inevitably entails aging and death. However, this is not entirely true. A living cell, as a kind of molecular factory, is capable of working and reproducing without any signs of fatigue or aging indefinitely. Good one example - all single-celled creatures that reproduce exclusively in asexual way. Of course, the well-known amoeba can be easily deprived of life - poisoned, boiled, dried, crushed, finally. However, if you feed, groom and cherish it (that is, regularly change the culture medium to a new one and add food), then it will divide tirelessly and will never grow old. In this sense, the amoeba is immortal. If the cells of our body were like amoebas, we might not be talking about retirement age.

Apoptosis is a natural and necessary process for maintaining homeostasis in tissues and the normal development of a multicellular organism. Apoptosis, more commonly called programmed cell death, is an energetically active, genetically controlled process that rids the body of unwanted or damaged cells. This process was first described in 1972 by Kerr under the name “programmed cell death.” The origin of the term itself dates back to 1993, when Greek proposed it in accordance with the semantic association with the word “leaf fall.”

Apoptosis is an evolutionarily developed, physiological, in contrast to necrosis, mechanism of cell death that regulates cell mass and architecture of many tissues. There are four main characteristics of apoptosis:

Reducing the volume of apoptotic cells;
condensation and fragmentation of chromatin in the early stages of apoptosis with the formation of so-called apoptotic bodies;
a change in the membrane of an apoptotic cell, leading to its recognition by phagocytes;
the association of apoptosis with active protein synthesis.

Today, 3 types of cell death are known: necrosis, apoptosis and terminal differentiation.

Necrosis (Greek nekros - dead) occurs as a result of direct exposure to a pathogenic factor (microorganism, ischemia, etc.) that violates the integrity of the cell membrane. This leads to a massive release of inflammatory inducers and migration of immune cells to the lesion. As a result, septic or aseptic (depending on the cause) inflammation develops in the area of ​​the damaged cell. In this case, characteristic changes occur both in the nucleus and in the cytoplasm. The nucleus shrinks, condensation of chromatin is observed (karyopyknosis), then it breaks up into clumps (karyorrhexis) and dissolves (karyolysis). Denaturation and coagulation of proteins occur in the cytoplasm. Membrane structures disintegrate. Redox processes and ATP synthesis in mitochondria are disrupted, and the entire cell begins to suffer from a lack of energy. Gradually, the cell breaks down into separate clumps, which are captured and absorbed by macrophages. In place of the formerly functionally active cell, connective tissue is formed.

Apoptosis (Greek aro - separation and ptosis - fall) is significantly different in morphological characteristics from necrosis and has a number of specific features. Factors that initiate apoptosis are an increase in the expression of genes that induce apoptosis (or inhibition of inhibitor genes) or an increased intake of calcium into the cell. The cell membrane remains intact. Despite the external preservation of the mitochondrial membrane, redox processes are disrupted mainly due to blocking of the 1st mitochondrial complex. The result of the processes described above is an increase in the synthesis of proteases, which gradually begin to break down internally cellular structures. Small vesicles filled with cytoplasmic contents (mitochondrions, ribosomes, etc.), surrounded by a membrane lipid bilayer, are pinched off from the cell membrane. The cell accordingly decreases in volume and shrinks. The detached vesicles are absorbed by neighboring cells. The nucleus shrinks at the final stages of the process, the chromatin partially condenses, which indicates the preserved activity of a number of DNA sections. The elements remaining from the cell are phagocytosed by tissue macrophages without the development of an inflammatory reaction and the formation of connective tissue. Terminal differentiation, according to some authors, is apparently a form of apoptosis.

Apoptosis plays a particularly important role in embryogenesis, when it is important to gradually get rid of cells that have fulfilled their function, and active phagocytosis with the development of an inflammatory reaction can disrupt fetal maturation.

Apoptosis is actively involved in the development of one or another morphofunctional system of the body. This can be most clearly demonstrated by the maturation of the immune system. On initial stage all immunocompetent cells undergo “training” in the thymus and lymph nodes, and each cell clone acquires the ability to recognize a specific antigen. During this process, “pathological learning” is possible, followed by recognition of one’s own body’s antigens as foreign and the formation of an immune response to them. In this case, apoptosis is defense mechanism, destroying cells that have become dangerous. At the same time, lymphocytic clones that recognize antigens that are not encountered during a person’s life have no functional significance and apoptose. Apoptosis is also necessary for the elimination of cells that have fulfilled their functional significance at a certain stage of development and have become unnecessary. In addition, apoptosis is actively involved in the processes of destruction of cells that have undergone mutation; To a greater extent, this applies to actively dividing tissues (hematopoietic, lymphatic system, etc.).

Disturbances in the natural process of apoptotic cell elimination are one of the main causes of cancer and the development of degenerative diseases.

Factors that induce physiological cell death can be divided into specific and “nonspecific”. Specific ones include polypeptide cytotoxic molecules (tumor necrosis factor, lymphotoxin) and some others. “Nonspecific” include a wide range of physical and chemical factors, in particular, increased temperature, radioactive and ultraviolet radiation, oxidative stress and many others. The “nonspecificity” of these effects lies in the fact that they do not have a targeted target in the cell and induce multiple damage to the genome, proteins, and/or cause a bioenergetic catastrophe. The result of these influences at the cellular level is often described by the concept of "stress". Having received a specific “deadly” signal or damage incompatible with life, a living cell embarks on the path of implementing the apoptotic program. Apoptosis is active, regulated, requiring energy costs process, which distinguishes it from the process of passive death - necrosis.

In the first quarter of the 20th century. a tiny ciliate Tetrahymena pyriformis was caught from a reservoir, which, like all its fellows, reproduced by ordinary divisions in half, but due to some deviations from the norm could not engage in sexual intercourse with its own kind*. So, the descendants of that cell still feel great in many laboratories around the world, although, according to the most conservative estimates, more than two hundred thousand divisions-generations separate them from the progenitor cell. In other words, the clone (strain) of these ciliates is practically immortal.

No one has ever seen an elderly bacterium. Given its pace and methods of reproduction of its own kind, talking about aging is completely pointless. Death in old age becomes a truly relevant and discussed phenomenon only in sexually reproducing multicellular organisms. In fact: if the life program is completed - the reproductive period is over, the offspring are left and thereby the set of genes inherited from the ancestors is tested and preserved, why should the parents continue to live? Just enjoy life? But they interfere with the new generation... It is more rational to stop the senseless waste of resources by elderly ancestors, sending them to waste. In other words, at a certain stage of evolution, the programmed death of multicellular organisms in the post-reproductive period became a phenomenon beneficial for the prosperity of the species as a whole. If so, then clear mechanisms would inevitably arise to ensure this death.

An excellent example in this regard is demonstrated by a very simply structured multicellular creature - a tiny worm, a self-fertilizing hermaphrodite, the nematode Caenorabditis elegans. Its dimensions barely reach 1 mm, and the total number of cells is absolutely constant in all adult individuals (about 3 thousand), and more than half of them are in the reproductive organs (for comparison: a newborn rat consists of approximately 3 billion cells). The amount of DNA in each cell of Coenorhabditis is only twenty times greater than the amount of DNA in the average bacterium. The life of this nematode is amazingly short-lived and lasts only three and a half days, which is only two hundred and fifty times longer than the life of E. coli, which favorable conditions divided every 20 minutes. But the rod is dividing, that is, its molecular factory continues to work successfully, regularly doubling its cellular economy, but the nematode that has laid eggs inevitably dies. It is clear that in this case there is no talk of any aging due to the accumulation of possible defects and damage in cells. What kind of decrepitude is there when you are no more than three days old! The little worm is brought to its fatal point by the inevitable, clear and deadly, like the gaze of Abadonna, work of genes, a family of which biologists have named CED (Caenorabditis elegans death). The product of one gene triggers the expression of the second, which activates the third, the seventh... and as a result, the lysis of all cells and the death of the organism as a whole. Biologists and doctors call this programmed cell death apoptosis.

If such a clear mechanism of death worked in higher vertebrates, our pension program would be completely unnecessary. Indeed, why save for old age if, for example, after forty-seven and a half years a quick and painless decay inevitably follows. Thank God, this is not happening, and perhaps those gerontologists who talk about the phenomenon of old age as a result of the accumulation of all kinds of errors in the work of the cells of which we are composed are right. Are there any programs for limiting the lifespan of human cells? The hypothesis of their programmed death was confirmed in the early 60s. L. Hayflick. He showed that human connective tissue cells—fibroblasts—are capable of only undergoing a certain number of divisions when cultivated outside the body. Moreover, this number depends on the age of the donor. Fetal fibroblasts undergo about 50 divisions. Such cells from a newborn are capable of dividing only 20–30 times, but taken from older people, they barely survive several cell cycles. In “multi-age” mixtures, younger cells always live longer than their “elderly” neighbors. Consequently, it is impossible to attribute all differences to differences in cultivation conditions. In experiments on mice, it was shown that “old” cells transplanted into the body of a young individual are not able to rejuvenate and die after some time.

It seems that in the cells of humans and higher vertebrates a kind of chronometer measures the course of life. Until the plant runs out, the cell is capable of dividing. As soon as divisions stop, so-called replicative aging occurs. The very number of divisions of our cells, in principle, can be almost as infinite as that of single-celled amoebas. This is confirmed by constantly multiplying cancer cells, in which such a chronometer may be broken or absent altogether. They have been regularly and vigorously divided in laboratories for decades, and the phenomenon of aging is simply ignored. An indicative case in this regard is HeLa cancer cells, which were obtained from a black woman, Henrietta Lambert, who died in the 30s. XX century in the USA from cervical carcinoma. To this day, they continue to be successfully shared in dozens of biological and medical institutes around the world.

Another striking example of the enormous capabilities of cells to resist the passage of time is demonstrated by generative cells. In fact: we all come from one egg, which was formed in the mother’s body. Our parents, in turn, were also once one cell. In this way, it is possible to extend a kind of “generative vector” back into the past by 2.5 billion years – almost to the Proterozoic. After all, our fish-like ancestors were born from someone’s eggs.

Sometimes the operating time of the “life chronometer” can be sharply shortened. This happens with congenital diseases of rapid aging - progeria (gr. pro - earlier, gerontos - old man). The most tragic is progeria in children, which is also called Hutchinson-Gilford syndrome. Children with this terrible diagnosis are rapidly aging. On average, they barely reach the age of 12 and most often die at this seemingly young age from banal senile heart attacks. By this time, they look like very old people - they go bald, suffer from atherosclerosis and myocardial fibrosis, almost completely lose the subcutaneous fat layer, lose teeth... Fortunately, such children are born extremely rarely, with a frequency of one in a million (which, by the way, complicates genetic analysis of the causes of the disease). The main diagnostic feature of cells from patients with Hutchinson–Gilford syndrome is a sharply reduced Hayflick number compared to the norm, that is, the number of doublings that cells can make in culture. At the same time, the duration of the cell cycle itself in the culture of their fibroblasts does not differ significantly from the control. In other words, their “chronometer of life” runs at normal speed, but it is only wound up “half a turn of the spring” and quickly stops.

Another typical example– adult progeria, or Werner’s syndrome, first described back in 1904. People suffering from it develop at a normal rate until the age of 17–18, and then begin to age rapidly. Only a few reach fifty, dying very old. They quickly develop a wide range of various pathologies, usually associated with age-related changes - atherosclerosis, diabetes, cataracts, Various types benign and malignant tumors. In Japan, the incidence of this disease is significantly higher than in other countries, reaching one case in forty thousand. As a result of genetic analysis, it was found that adult progeria is an autosomal recessive disease. This means that it will manifest itself in adulthood only in those newborns who simultaneously received from each parent a specific mutant gene located on the eighth chromosome. Cells from patients with Werner syndrome usually stop dividing in culture after 10–20 doublings, which also indicates some kind of disruption in their normal “life chronometer”. However, how does a cell manage to measure the number of divisions it has already completed?

For the first time on possible mechanism the work of such a “chronometer” was indicated in 1971 in a purely theoretical article by our compatriot, an employee of the Institute of Epidemiology and Microbiology of the USSR Academy of Sciences A.M. Olovnikov. The idea boiled down to the following. Even before a cell divides, all its chromosomes are doubled. Each chromosome is a tightly wound long strand of DNA. DNA is copied even before it is “coiled” into a chromosome using a special enzyme – DNA polymerase. If we compare DNA somewhat loosely with a rail track, then this enzyme resembles a rail laying machine that rides on rails, laying a parallel track next to it. As long as the DNA polymerase works along the main part of the path, everything is fine. But as soon as it “reaches” a kind of “dead end”, that is, one of the two ends of the DNA molecule, then a failure occurs. DNA polymerase is simply not able to build a copy of them. And the “parallel path” turns out to be a little shorter. And the next one - built from it - is even shorter. That is, with each cell division, its DNA strands should shorten slightly.

Later, this beautiful discovery, made, as they say, “at the tip of a pen,” was brilliantly confirmed. Now predicted by A.M. Olovnikov biologists call the phenomenon terminal underreplication of chromosomes. In the process of forming a sausage-like chromosome, the shortened ends of the DNA end up located at its edges - the telomeres. Telomere shortening is precisely the molecular clock that counts the number of cell divisions. It turned out that with each division, cells lose from 50 to 200 nitrogenous bases - the kind of “letters” that make up this macromolecule. Fortunately, proteins important for the cell are not encoded at the ends of the DNA strands. Telomeres are made up of identical, boringly repeating sequences of nucleotides (in mammals, TTAGGG), the length of which indicates the number of divisions the cell can still undergo. As soon as telomeres, as a result of completed cycles of chromosome copying, reach a certain critical length, the cell stops dividing - replicative aging occurs. Cells from children with Hutchinson-Gilford progeria have shortened telomeres. This is what explains the early onset of old age. But their parents' telomeres are of normal length. This means that Hutchinson-Gilford syndrome is the result of some rare mutation that occurs in one of the very first cells of the embryo. Chromosome telomeres in patients with Werner syndrome are normal, but, apparently, the “cell division stop point” in them is, on average, closer to the edge of the chromosome than in healthy people.

What happens to telomeres in potentially immortal single-celled organisms, in germ cells and cancer cells? In 1985, an enzyme was discovered in the Tetrahymena ciliates that actively completed the ends of telomeres that DNA polymerase could not cope with. Thus, these cells were provided with the opportunity to reproduce endlessly. The enzyme was called telomerase and was soon discovered in most of the cells that biologists usually experiment with—yeast, some insects, worms, and plants. It turned out that telomerase works perfectly in human germ and germ cells. They also work in so-called stem cells - that is, those whose constant division underlies the renewal of blood and some tissues (for example, skin and the inner lining of the intestines). Up to 90% of human tumors have telomerase activity, but in normal cells of the body (so-called somatic), on the contrary, these enzymes cannot be found. Thus, it is possible to directly link telomerase activity and the proliferative potential of cells (that is, their ability to divide). Cells in which telomerase does not complete the ends of chromosomes stop dividing after some time.

A number of intriguing conclusions and assumptions follow from these remarkable observations. First, it is possible that suppressing telomerase activity in tumor cells will help fight cancer.

A biological cell is a complex and extremely interesting object; in essence, it is a whole organism that is born, breathes, feeds, reproduces and dies. But this is not surprising, because a huge part of living beings on our planet consist of only one cell. After a post about antioxidants and reactive oxygen species, I wanted to write about such a gloomy, but required process as programmed cell death - scientifically called apoptosis. It is worth distinguishing apoptosis from necrosis, which is cell death as a result of injury and damage. The main difference is that during apoptosis, which does not occur by chance, apoptotic bodies are formed from the remains of cells, which are eaten by phagocytes called for this, which prevents inflammation and poisoning of neighboring cells, and with necrosis, the death of cells and entire tissues occurs, accompanied by severe inflammation.

An interesting fact is that the term “apoptosis” meant the falling off of petals and leaves in plants, which, in my opinion, is not entirely true, since during apoptosis, the remains of the cell are utilized by one’s own body, and when the leaves fall off, they simply fall off and are already processed by other organisms. Although both processes are programmed. But these are just philosophical and linguistic arguments.

Our cells are peculiar hypochondriacs and can commit suicide for any reason: overheating, radiation exposure, hypoxia and much more. In general, cells are so prone to suicide that they constantly receive a signal from other cells: “Live-live-live” and interruption of this signal immediately leads to severe depression with subsequent lathering of the rope to apoptosis. It’s funny that such cells make up an organism with a very tangible instinct of self-preservation... . In truth, nature is full of paradoxes.

Conventionally, three stages of apoptosis can be distinguished: initiation or receipt of a signal, the effector stage, in which degradation processes are launched and, in fact, the process of destruction and degradation - the formation of apoptotic bodies followed by consumption by macrophages.

There are 2 initiation pathways: mitochondrial and external signal.

Mitochondria are the energy stations of our body, where the process of cellular respiration actually occurs with the conversion of oxygen into water. In school textbooks, mitochondria were depicted as elongated ovals scattered throughout the cell. But it is not so. If you look at a section of a cell, you will indeed see such a picture, but when three-dimensionally reconstructing cells from these thin sections, scientists discovered that there is only one mitochondria in the cell, but it has a complex curved structure, so in the sections we see its various outgrowths.

Mitochondria are surrounded by two cell membranes and between them are apoptosis proteins, or apoptotic proteins, which are released when the outer membrane ruptures or forms pores in it. In fact, this is the key phase in the onset of apoptosis. The released proteins, through a series of biochemical reactions, activate caspases - enzymes that destroy other proteins. Caspases begin to destroy everything around them, destroying all the main cellular structures. In the process of destruction of the mitochondrial membrane, not only proteins are released, but also water begins to actively enter the mitochondria, causing it to swell.

The second pathway for the onset of apoptosis is signaling. On the surface of cells there are cell death receptors, special ligands produced by other cells (often these are activated macrophages, which later eat up the remains), bind to these ligands and activate them. Receptors are large molecules that sit in the cell membrane and protrude from both sides: into the cell and out. A ligand sits on the outside and a signal is transmitted throughout the receptor to inner side. Next, a chain of biochemical reactions is launched, as a result of which, as in the mitochondrial pathway, caspases are activated.

At the second stage of apoptosis - the effector stage, it is no longer so important how the cell received the signal. At this stage, the real apocalypse begins inside and main role caspases play in it. Second important element At this stage - the flavoprotein AIF, which leaves the mitochondria and activates endonucleases - proteins that destroy the cell's DNA. In fact, after this station, the cell represents a city after a nuclear bomb.

During the destruction of the mitochondrial membrane, the entire energy complex is also released, which provokes the formation of reactive oxygen species inside the cell. Free radicals trigger chain reactions that contribute to the destruction of cell contents. At this point, they can no longer be contained by antioxidants.

After this the third and last stage- degradation. The cell loses its shape and shrinks due to the destruction of the cellular skeleton. Next, the fragmentation of the cell begins into small parts, which represent cell membrane with residues inside - these formations are called apoptotic bodies. Macrophages are already on duty around the dying cell, ready to attack the remains. During the cell process, signaling proteins appear on the surface of the membrane, which attract hungry macrophages and now, they are already absorbing the remains of a dead relative.

As I write this, I think that this all reminds me of some scene from the now popular zombie apocalypse. It became downright scary. One bruise and they will attack you and eat you. Br-r.

But cells also have antidepressants that keep these processes under control, preventing them from reacting to the slightest stress - these are inhibitors of apoptotic proteins. But as soon as the mitochondrial membrane begins to release the precursors of the apocalypse, the SMAC protein is released, which is deactivated by these inhibitors and they become useless. After this stage, apoptosis is difficult to stop.

You should not think that apoptosis is an exclusively gloomy negative phenomenon in our body. Supported by apoptosis correct amount and the ratio of different cells in the body. Apoptosis plays an important role in our development: for example, the separation of fingers and toes is a consequence of programmed cell death. When teething in children, even before the tooth appears, the process of death of gum cells begins so that the tooth can easily come out. The tail of tadpoles also does not fall off with the appearance of legs, but degrades through the same phenomenon.

Apoptosis is indispensable in preventing the development cancerous tumors. During our ordinary life a huge number of cells in the body undergo pathological changes and degenerate into potentially cancerous cells. Neighboring cells, like the grandmothers on the benches near the entrance, closely monitor their neighbors and, if they behave inappropriately, send an apoptosis signal to the cell even before it multiplies and becomes dangerous. Actually, for this reason, over the past 20 years, interest in apoptosis has increased greatly as a means for preventing and combating malignant tumors.