Aging and Cell Death: Cellular Aging, Apoptosis, and Genetic Theories
Aging and Cell Death
1. Cellular Aging
Cellular aging is defined as “any progressive and irreversible change of the organism from conception until death” and also “the sum of all the alterations that occur in a body over time and that lead to functional loss and death.” At present, the period of human life is quantified in a maximum of 120 years.
During infancy, congenital diseases, infections, and allergies dominate the pathological spectrum. Adolescence is a stage of full development of the organs, and diseases are limited to mental illnesses, allergies, infections, and endocrine problems.
From the 40 listed major diseases that cause mortality, including cardiovascular, gastrointestinal, liver, kidney, and malignancy. In the elderly, the most frequent causes of death are the result of arteriosclerosis and hypertension and malignancy.
Life expectancy at birth is an index showing the number of years a statistically average individual from a population that was born at a time is likely to live, depending on the welfare conditions in society.
Evolution of the Cells in Aging
With age, the cells decrease their duties and suffer a set of processes, which “prepares” them for their final event, the death of the body. In cells, aging results in:
- Increased nuclear DNA content in the form of heterochromatin
- Appearance of binucleated cells and trinuclear
- Enlargement of the cytoplasm
- Accumulation of autophagosomes
- Many organelles lose their ability to protein synthesis
Genetic Theory of Aging
From the theories described above, those that include the alteration of the structure or the expression of genes are essential. The accumulation of errors that damage the genetic machinery that controls cell division would be the common cause of all the external signs associated with aging.
Cellular aging by depletion of mitosis would take place by one of the following mechanisms:
Alteration in DNA Replication
With age, DNA repair capacity deteriorates. During DNA replication prior to the division, the cell is unable to copy the entire sequence of telomeres, and telomeres as a result become shorter in each replication, losing about 50 to 200 nucleotides in each cycle of cell division.
When telomeres reach a certain minimum length, the cell enters the terminal crisis, stops dividing, and dies. There is an enzyme called telomerase that is able to restore the initial length of telomeres. The problem is that in most cells, the gene encoding it is idle. It is assumed that the gene is inactivated when cells specialize.
It was then thought that if we could genetically modify the cells that do not synthesize telomerase to do so, they could achieve immortality.
Formation of Free Radicals
Free radicals are formed by oxidation-reduction reactions during cellular metabolism, especially during oxidative phosphorylation. The most common free radicals are derived from the oxygen molecule, from which superoxide radicals are formed. About 1% of oxygen used in the mitochondria is converted into superoxide radicals.
Although this is normally removed by an enzyme, the mitochondrial mechanism is imperfect because it produces in turn H2O2, a strong oxidizing agent. Superoxide free radicals or hydroxyl type are capable of binding to macromolecules such as DNA, altering them. The primary lesion on DNA is the alteration of modified bases by the action of free radicals, which is over 100 per cell per day. This amount can escape the mechanisms of cell repair and contribute to the losses related to physiological age.
Cell Differentiation
Differentiated cells are expected to allocate a limited quantity of energy, which they get through mitochondrial respiration, including the repair and function of the cells themselves. Mitochondria of differentiated cells, which have very high levels of consumption of O2, would be the initial target of free radicals, which cause the inactivation of the genome and the gradual diminution of its bioenergetics capacity.
2. Apoptosis (Programmed Cell Death)
Apoptosis is an active process of cell death, genetically controlled, which affects isolated cells and is not accompanied by an inflammatory reaction. This cell death is necessary for the proper functioning of the body because it eliminates unnecessary or damaged cells.
From apoptosis, necrosis occurs only in pathological situations, when the cell is subjected to an injury that causes severe damage to its membranes. This impairs the ability to maintain homeostasis; extracellular water and ions enter inside the cell, the cytoplasmic organelles increase in volume and eventually rupture, with release in the middle of intra- and extracellular lysosomal enzymes and other substances. These in turn damage surrounding cells, resulting in an inflammatory response and subsequent healing.
Morphological Aspects
Three stages:
- Early stage: Reduction of cell volume and increased density of cytoplasm by intracellular fluid loss. Condensation and fragmentation of chromatin.
- Intermediate stage: Deformation of the plasma membrane, appearance of apoptotic bodies.
- Final stage: Phagocytosis of apoptotic bodies for complete degradation.
Biochemical Aspects
The biochemical mechanism of apoptosis involves a family of proteases called caspases, which are produced as inactive proenzymes called procaspases. They are activated by proteolytic cleavage in response to signals that induce programmed cell death. Activated caspases break down several key proteins of the cell. Caspases are efficient because they kill the cell quickly and cleanly.
Gene Control
- Bcl-2 gene: Results in the integral membrane protein mitochondrial Bcl-2 that prevents apoptosis. Leading to uncontrolled division, the accumulation of abnormal cells, and thus tumor growth. Certain normal cells produce high levels of Bcl-2.
- p53 gene: Encodes a p53 protein that triggers apoptosis. Mutant cells without the gene did not undergo apoptosis, which causes more mutations to accumulate and multiply uncontrollably, causing tumors.
From the above, it follows that the activity of certain genes is essential in death by apoptosis.