Damage or Error (Based) Theory of Aging
DNA Damage
The accumulation of DNA damage theory of aging was first proposed in 1959. In human cells, both normal metabolic activities (endogenous sources: ROS, methylation, replication errors, spontaneous random mutation) and environmental factors can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. Sources of exogenous DNA damage include UV light induced free radical, X-ray or other radiation, glycation, environmental toxins, cigarette smoke, hydrolysis or thermal disruption, virus and even some antibiotics and anti-inflammatory medications.
DNA damage is in the form of deletions, or deleted sections, mutations, or changes in the sequence of DNA bases and structural damage such as crosslinking. The vast majority of DNA structural damage affects the primary structure (instead of tertiary structure) of the double helix; that is, the bases themselves are chemically modified in a single or double strand breaks such as 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. There are four main types of damage to DNA base due to endogenous cellular processes:
- oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
- alkylation of bases (usually methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine
- hydrolysis of bases, such as deamination, depurination and depyrimidination.
- “bulky adduct formation” (i.e. benzo[a]pyrene diol epoxide-dG adduct)
- mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.
Although distinctly different from each other, DNA structural damages and mutations are related because DNA structural damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation. Damage caused by exogenous agents (e.g. UV and other radiation, industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar) comes in many forms (DNA adducts, oxidized bases, alkylated phosphotriesters and crosslinking) .Visit our “stress induced premature aging” section to find our how environmental stress can trigger DNA mutation and damage.
In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
1. an irreversible state of dormancy, known as senescence
2. cell suicide, also known as apoptosis or programmed cell death
3. unregulated cell division, which can lead to the formation of a tumor that is cancerous
It is theorized that this DNA damage, which gradually accumulates, leads to malfunctioning genes, proteins, cells, and, as the years go by, deteriorating tissues and organs. Consequences can include cell apoptosis, failure to reproduce, abnormal tissue replacement and renewal, and premature cell senescence. The list of age-related maladies resulting from genetic damage is long including immunodeficiency, rheumatoid arthritis, cancers of all kinds, arteriosclerosis, and chronic diseases such as chronic fatigue. DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. It appears that DNA damage is also the source of a number of neuro-degenerative diseases including Parkinson’s disease and Alzheimer’s disease. Failure to correct molecular lesions in cells that form gametes can introduce mutations into the genomes of the offspring.
As has been mentioned in “Introduction”, our body has an internal “maintenance, repair and defense mechanism/system” that would repair and protect us from the various damaging effects. Usually this repair and defense system functions well while we are young, however when we progressively become more and more aged, this system itself also deteriorates and declines together with other body functions. DNA damage is no exception. However, even though our cell can repair over 99 percent of DNA point mutations, thousands of errors go un-repaired each day, leading to a life-long accumulation of molecular rubbish that, in turn, leads to errors in the manufacture of related proteins and helps accelerate the aging process.
DNA repair system is comprised of numerous enzymes in the cell which functions to detect and repair damaged DNA. For repair, transcription, and replication to occur, the double-helical structure that makes up DNA must be partially unwound. Enzymes called helicases do the unwinding. Depending on the type of damage inflicted on the DNA’s double helical structure, a variety of repair strategies have evolved to restore lost information. The types of molecules involved and the mechanism of repair that is mobilized depend on the type of damage that has occurred and the phase of the cell cycle that the cell is in. There are 4 types of repair which will be discussed in order: direct reversal, repair for single strand damage, repair for double strand break, and translesion synthesis. The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment.
There are 3 types of damage which can be reversed chemically without a template, since the types of damage they counteract can only occur in one of the four bases and o not involve breakage of the phosphodiester backbone (see table below).
| Damage | Reverse Mechanism |
| thymine dimers (abnormal covalent bond between adjacent thymidine bases by UV irradiaton) | photoreactivation process directly reverses this damage by the action of the enzyme photolyase, |
| methylation of guanine bases | directly reversed by the protein methyl guanine methyl transferase (MGMT) |
| methylation of the bases cytosine and adenine. |
DNA structural damages can be recognized by enzymes, and thus they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. In other words, when only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. Base excision repair (BER), which repairs damage to a single base caused by oxidation, alkylation, hydrolysis, or deamination. The damaged base is removed by a DNA glycosylase, resynthesized by a DNA polymerase, and a DNA ligase performs the final nick-sealing step. Nucleotide excision repair (NER), which recognizes bulky, helix-distorting lesions such as pyrimidine dimers and 6,4 photoproducts. A specialized form of NER known as transcription-coupled repair deploys NER enzymes to genes that are being actively transcribed. Mismatch repair (MMR), which corrects errors of DNA replication and recombination that result in mispaired (but undamaged) nucleotides.
Double-strand breaks (DSBs), in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Three mechanisms exist to repair DSBs: non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ) and recombinational repair (also known as template-assisted repair or homologous recombination repair). In NHEJ, DNA Ligase IV, a specialized DNA Ligase that forms a complex with the cofactor XRCC4, directly joins the two ends. MMEJ is distinguished from the other repair mechanisms by its use of 5 – 25 base pair microhomologous sequences to align the broken strands before joining. MMEJ uses a Ku protein and DNA-PK independent repair mechanism and repair occurs during the S phase of the cell cycle as opposed to the G0/G1 and early S phases in NHEJ and late S to G2 phase in HR. Recombinational repair requires the presence of an identical or nearly identical sequence to be used for recombination. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome.
However, DNA mutation cannot be recognized by enzymes when the base change is present in both DNA strands. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort. Translesion synthesis is a DNA damage tolerance process that allows the DNA replication machinery to replicate past DNA lesions such as thymine dimers or AP sites.[19] It involves switching out regular DNA polymerases for specialized translesion polymerases (e.g. DNA polymerase V), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, Pol η mediates error-free bypass of lesions induced by UV irradiation, whereas Pol ζ introduces mutations at these sites. From a cellular perspective, risking the introduction of point mutations during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death.
If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die.
The repair process interests gerontologists for many reasons. The DNA repair ability of a cell is vital to the integrity of its genome and thus to its normal functioning of the organism. An animal’s ability to repair certain types of DNA damage is directly related to the lifespan of its species. Humans repair DNA, for example, more quickly and efficiently than mice or other animals with shorter life spans. This suggests that DNA damage and repair are in some way part of the aging puzzle. Many genes that were initially shown to influence lifespan have turned out to be involved in DNA damage repair and protection. Visit our “Programmed Theory of Aging” part “aging or longevity genes identified” for more information. In addition, researchers have found defects in DNA repair in people with a genetic or familial susceptibility to cancer. If DNA repair processes decline with age while damage accumulates as scientists hypothesize, it could help explain why cancer is more common among older people.
Mitochondria possess their own genome. Repair to mitochondrial DNA (mtDNA) that resides not in the cell’s nucleus but in its mitochondria is especially intriguing and is more important since ROS originate in the mitochondrion. How mitochondrial DNA damage/mutation is repaired and how accumulation of mtDNA damage influence aging will be discussed in “Mitochondria Damage” together with other mechanisms of mitochondrion damage including free radical, crosslinking.
Investigators have found that people who have Werner’s syndrome (WS), a rare disease with several features of premature aging, have a defect in one of their helicases. Scientists are exploring the mechanisms involved in DNA repair in WS and similar disorders, collectively known as progeroid syndromes. This research could help explain why DNA repair becomes less efficient during normal human aging.
