Genomic Instability and Aging


Genome instability is the propensity of genetic material to undergo spontaneous changes in their DNA; it is regarded as a cellular hallmark of aging.

Somatic cells are vulnerable to DNA damage. Physical and chemical mutating agents in the environment as well as radiation (e.g. ultraviolet light) may trigger modifications in the cells’ DNA sequences. Reactive oxygen species produced in the body as a result of an imbalance between antioxidants and free radicals can also serve as mutagens. Over millions of years of evolution, the body has developed a network of genome integrity and stability maintenance mechanisms to cope with DNA lesions; these mechanisms eliminate damaged DNA bases and replace them with the correct base pairs. Limitations in the DNA repair process lead to genome instability which is the proximate cause of untimely aging and rare aging disorders.

A high frequency of mutations that involves the change of nucleotide sequence - by transversion, transition, insertion, or deletion during DNA repair - may cause genome reorganization. Mutations can be spontaneous or induced. Spontaneous changes in the nucleotide sequence arise from biochemical cellular processes. Induced changes in DNA sequences are errors triggered by environmental agents. Genome instability as a result of the accumulation of mutations may cause complications such as transcription of mutated genes, giving rise to an increase of aberrant proteins; the build-up of abnormal protein interactions leads to aging and aging-related pathologies.

Genome instability is also caused by an impaired DNA damage restoration mechanism. Biochemical processes like oxidative stress cause DNA damage. Reactive oxygen species such as peroxide that arises from cellular metabolism may inflict lesions as well as break DNA strands. In normal operation, the DNA repair system reverses the chemical damage and restores aberrant nucleotides. Repair enzymes identify and correct DNA physical and chemical damage. Defective DNA response mechanisms can lead to a loss of genome stability. A buildup of DNA damage causes faster apparent aging. In vivo studies done on mice showed that mice that lacked DNA repairing genes exhibited similar phenotypic characteristics to mice that age naturally. Age-related disorders like arthritis are linked to the agglomeration of DNA damages.

Defective DNA replication machinery facilitates the loss of genome integrity. Enzymes such as DNA polymerases, DNA helicases, DNA primase, and DNA ligases are involved in the DNA replication process. DNA polymerases add nucleotides to the 3’ end of the leading strand, DNA helicases untwist the double DNA strand, DNA primase synthesizes RNA sequences used as primers and DNA ligases maintain genome integrity by joining the phosphodiester bonds that hold together polynucleotides the building blocks of DNA and RNA. Defects in DNA replication mechanism induces replication stress. Cell cycle control systems regulate DNA replication processes inhibiting cell cycle progression during stress or damage hence maintaining genome integrity. Failure of regulatory proteins ATR (Ataxia telangiectasia and Rad3)and ATM (Ataxia-telangiectasia-mutated) to control replication stress leads to genome instability, aging, and disorders related to loss of genome stability for instance cancer.

The breakdown of epigenetic mechanisms contributes to genome instability. When epigenetic processes like DNA methylation are inefficient, embryogenesis, genomic imprinting, and chromosomal stability can be affected. Epigenetic errors can give rise to the expression of abnormal genes hence resulting in the synthesize of abnormal proteins. Accumulation of abnormal proteins impairs protein homeostasis, accelerating aging and the pathogenesis of neurodegenerative disorders as well as cancer.

Loss of genome integrity is a hallmark of age-related pathologies, cancer, neurodegenerative maladies, arthritis, cardiac disease, gastrointestinal disorder, and multiple sclerosis. Epigenetic dysregulation causes lupus, diabetes, and other neurological diseases. Studies have shown that Huntington’s disease is caused by post-translational modification of histone. Alzheimer’s and Parkinson’s pathogenesis is also linked to loss of genome stability.

Breakdown of genome integrity is a hallmark of cancer. Disruption of pathways that sustain genome stability may lead to the accumulation of a high frequency of mutations that may affect genes involved in cell division, cell cycle control, and tumor suppression. Upregulation of these defective genes and mutation of tumor suppressor genes may induce an uncontrolled proliferation of cells resulting in tumorigenesis. Further mutation of metastasis suppressor genes generates malignancy.

The impairment of the DNA repair mechanism is associated with the pathogenesis of arthritis. Accumulation of DNA damage is a result of the increase of free radicals and reactive oxygen species. Uncontrolled chromatin remodeling correlates with a dysregulated DNA repair network. Studies have shown that Rheumatoid arthritis patients exhibit defective DNA damage and repair mechanisms. DNA damage and repair systems deteriorate with age hence the susceptibility of the elderly to arthritis.

DNA damage and repair network dysregulation corresponds to the pathogenesis of cardiovascular disorders. An imbalance between reactive oxygen species, free radicals, and antioxidants generates oxidative stress that damages DNA strands. Clinical and experimental studies have shown that mitochondrial DNA damage is connected with heart failure. Reactive oxygen species triggers muscle cell hypertrophy, interstitial fibrosis, and apoptosis by inducing enzymes such as matrix metalloproteinase. MMPs (metalloproteinase) expression is linked to inflammation and cardiovascular diseases such as atherosclerosis, platelet aggregation, plaque formation, restenosis, acute coronary syndrome, peripheral vascular disease, and aortic aneurysms. Loss of genome maintenance among the elderly makes them vulnerable to such cardiovascular disorders.

In vivo studies in mice have shown that the DNA damage response network declines with age. The senescence of intestinal cells as a result of the loss of genome integrity causes gastrointestinal disorders such as ulcerative colitis and Crohn's disease. DNA damage accumulates as a consequence of oxidative stress, inflammation, irradiation, mitotic stress, telomere shortening, and chemical exposure. Dysregulation of DNA damage response mechanism enhances cellular senescence and pathogenesis of inflammatory bowel diseases.

Dysfunctional DNA damage response networks have been linked with metabolic diseases such as diabetes. DNA damage aggregation as a consequence of telomere erosion and oxidative stress triggers cellular senescence. Agglomeration of senescent cells could inhibit homeostasis and tissue regeneration giving rise to metabolic dysfunction pathologies such as diabetes. Uncontrolled DNA damage response mechanisms make older people susceptible to conditions such as metabolic syndrome.

genomic changes Genome instability is also linked with loss of proteostasis and pathologies related to toxic protein aggregation. Mitochondrial DNA damage affects the normal functioning of chaperones hence impairing the molecular folding mechanism of proteins, the defects in the DNA replication network may result in the expression of aberrant genes giving rise to abnormal proteins. Accumulation of atypical proteins leads to the pathogenesis of age-related disorders such as Parkinson’s disease, Gaucher's disease, Creutzfeldt–Jakob disease, Alzheimer’s disease, and Huntington's disorder.

Defects in the DNA damage and repair network have been linked to the pathogenesis of systemic lupus erythematosus (SLE). Studies have shown that cells obtained from systemic lupus erythematosus patients are less capable of repairing DNA lesions effectively when compared to control cells. DNA repair mechanism is essential in antibody production hence the correlation of atypical DNA and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, SLE, psoriasis, and type 1 diabetes mellitus. All these pathologies are related to loss of genome integrity, and they are common among the elderly.

Loss of genome integrity is a medical challenge; if we could stop it we could avoid deaths and complications that arise from genome instability related pathologies. Stem cell therapy has been effective in animal studies however clinical trials are still ongoing. Some scientists feel DNA repair targeted treatment is the future of genome stability management and therapy.

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