Introduction:
In mammals, aging is a complex process that is accompanied by a progressive degeneration of tissues and organs which results in the loss of the ability to retain normal homeostasis. Aging is caused by accumulated damage to DNA, RNA, proteins, and lipids which in turn inhibits the ability of the cell to function normally and express appropriate genes, thereby, leading to increased risk of morbidity and mortality.
Biomolecules such as protein, lipids, and nucleic acid are frequently damaged by both exogenous and endogenous sources that can be physical, chemical, biological sources.
Sunlight, diet, and chemicals are included in exogenous sources while endogenous sources of DNA damage include chemical instability, such as depurination, alkylation, errors during DNA replication and repair, and reactive oxygen species (ROS).
There are several theories which explain the mechanism of DNA damage are:
- DNA Damage/Repair Theory
- Free Radical /Oxidation theory
- Mitochondrial DNA theory
- Â Radiation Theory
Mechanism of DNA Damage:
DNA Damage/Repair Theory
Free radicals are any molecules with one or more unpaired electrons in its valence shell that are string oxidizing agents. In the discussion of aging, the free radicals of importance are oxygen-based molecules such as superoxide, hydroxyl radical, singlet oxygen, hydrogen peroxide and hydrochlorous acid. Free radicals are damaging to the body because they are extremely reactive; they tend to rip electrons off from other molecules in order to pair off their lone electrons.
Unfortunately, free radicals cannot be avoided since they are by-products of essential reactions in the body, such as the process of metabolizing oxygen. Free radicals can also be found in abundance in the environments due to air pollution, tobacco smoke, radiation, toxic waste, and certain chemicals.
Free radicals at cellular level impose deleterious effects on the cell. e.g.:
- They break off cell membrane proteins, thereby destroying cellular identity.
- Fuse membrane lipids and proteins, harden the cell membrane and lead to brittle and non-functional cells.
- It may disrupt the nuclear membrane that may expose genetic material in the nucleus, leaving the DNA open for mutation or destruction.
- Burden the immune system by damaging immune cells.
- Cause chronic diseases
These effects are known as oxidative stress, and may lead to DNA mutations, cell death and diseases, all of which contribute to the overall effects of aging.
Antioxidants
Antioxidants are the body’s solution to oxidative stress. These molecules neutralize free radicals by supplying them with extra electrons. This exchange results in lowering the reactivity of the free radicals and leaving the antioxidant itself with an unpaired electron. The structure of an antioxidant, however, is not damaging to the body since it is stabilized through chain reactions with other antioxidants. The common antioxidants are:
- Enzymes include catalases, glutathione peroxidases, and superoxide dismutase.
- Nutrients including vitamins C and E, beta-carotene, selenium, cysteine, uric acid.
The free Radical/Oxidation Theory
This is one of the most accepted and well-studied theories which rests on the fact that oxidants induce a variety of distinct biochemical changes in target cells. Hydrogen peroxide is considered to be one of the more troublesome oxidants, as it diffuses into target cells where site-directed hydroxyl radical formation injures specific targets. DNA is particularly sensitive to hydroxyl radical induced damage; both DNA strands activate a DNA binding protein (poly ADP ribose) polymerase, which forms polymers of ADP-ribose bound to various nuclear proteins using NAD as its substrate. NAD turnover under these circumstances increases so dramatically that it affects ATP synthesis, to the point where high enough concentrations inactivate mitochondrial ATP synthesis.
If the concentration of the hydrogen peroxide is high enough, these pathways will lead to cell death, and, therefore, hydrogen peroxide-induced alterations will not be passed on to future generations. If, however, cells are exposed to sub-lethal concentrations of hydrogen peroxide, the ensuing injury could cause permanent and transmissible cellular alterations which could be biologically detrimental. For example, if hydroxyl anion-induced DNA damage is not repaired or is repaired poorly, it may result in genetic changes such as mutations, deletions, and rearrangements. Moreover, if these genetic alterations occur in critical genes that are involved in cell growth and differentiation, they could lead to deregulated cell growth and differentiation and ultimately contribute to the malignant transformation of cells. Hence, the growing number of free radical diseases includes the two major causes of death, cancer, and arteriosclerosis.
Since hydrogen peroxide easily diffuses through cell membranes, hydroxyl anion formation may occur extra-or intracellularly, depending on the availability of transition metals. Because of its high reactivity, the hydroxyl radical will always cause site directed damage at the site of its formation. However, the body does have some natural antioxidants in the form of enzymes that help to prevent the hazardous buildup of these free radicals, without which cellular death rates would rise dramatically and life expectancies would decline.
Mitochondrial DNA Theory
This theory suggests that the loss of effectiveness of mitochondrial leads to age-related degenerative diseases. The mitochondria, which are the energy producing bodies within a cell, have their own genome (mt-DNA).
This mt-DNA is synthesised at the inner mitochondrial membrane near the sites of formation of highly reactive oxygen species. Mitochondrial DNA seems unable to counteract the damage inflicted by these by-products of respiration because, unlike the nuclear genome, it lacks advanced repair mechanism. Gradually, the cell loses its ability to produce energy and subsequently dies. This theory is supported by observation confirming the genomic instability of mitochondria, as well as widespread mtDNA deletions and other types of injury to the mitochondrial genome.
 DNA Damage/Repair theory
DNA damage occurs on a continuous basis in live cells. While most of these damages are corrected, some accumulate because DNA polymerases and other repair processes cannot remove errors as quickly as they appear. There is evidence that DNA damage accumulates in non-dividing mammalian cells.
Thus, these accumulated DNA damage will probably interfere RNA transcription. It has been suggested that the decline in the ability of DNA to serve as a template for gene expression is the primary cause of aging. Most damage comes in the form of oxidation damage, and hence is likely to be a prominent cause of aging.
Radiation Theory
This theory focuses particularly on the aging of skin cells, which are the most immediately affected by external sources of radiation. Radiation can create free radicals in cells, as the radiation strikes surrounding water molecules and other proximal targets. Thus, the aging process goes back to the free radical theory on aging mentioned above, with radiation servicing to increase its rate.
In the recent experimental it has been shown that the shorter, more energetic spectrum of the ultraviolet range (UVB) is responsible for the dermal connective tissue destruction observed in photoaged skin. Also, it has been shown that UVA and infrared radiation contribute significantly to photoaging, producing, among other changes, severe elastosis. Thus, small amounts of radiation are enough to accelerate the aging process.