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F U L L T E X T P R I M A L S O U R C E : Trends in Cell Biology
Highlights
- DNA damage accumulates with aging.
- Defects in DNA repair lead to premature aging.
- Emerging drugs that target DNA repair may alleviate age-associated phenotypes.
Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including reducing damaging molecules, repairing DNA damage, and inducing senescence or apoptosis in response to persistent DNA damage. Mutations in or failure of these pathways can lead to accelerated or premature aging and age-related decline in vital organs, supporting the hypothesis that maintaining a pristine genome is paramount for human health. Understanding how we cope with DNA damage could inform on the aging process and further on how deficient DNA maintenance manifests in age-related phenotypes. This knowledge may lead to the development of novel interventions promoting healthspan.
From Increased DNA Damage to Aging
Multiple endogenous and exogenous molecules can chemically modify our DNA. To deal with these stressors, cells have developed ways to reduce the production of, or eliminate, endogenous damaging molecules before damage occurs (Box 1), to repair damage once it occurs, or to eliminate cells that have accumulated too much damage (Figure 1). These three tiers of defense are the focus of this review. The most well-described mechanism to reduce toxic molecules is antioxidant removal of reactive oxygen species (ROS) before they can react with other molecules such as DNA, proteins, or lipids. In addition, oxidized lipids and proteins can react and form toxic adducts with DNA [1,2]. Nonenzymatic antioxidants such as glutathione and vitamin C and E as well as antioxidant enzymes such as superoxide dismutase, catalase, and peroxidases attempt to counter these reactive molecules and could protect the genome. If this first tier of defense fails, repair enzymes coordinate the processes that attempt to reverse the damage and return the DNA to its undamaged (functional) state. These highly conserved repair mechanisms can be classified into the following pathways: direct reversal, base excision repair, nucleotide excision repair, double-strand break repair, and interstrand crosslink repair (Box 2).
Box 1
Endogenous Sources of DNA Damage
Oxidative stress is not the only metabolic byproduct that can damage DNA. Complex lesions can occur by a multitude of other processes. For example, acetaldehyde, formed as a byproduct of acetyl metabolism or after alcohol consumption, readily reacts with DNA forming a variety of single-base adducts that can further react to form highly toxic interstrand DNA crosslinks [165]. An important way to deal with this stress is through enzymatic removal of acetaldehyde by the enzyme acetaldehyde dehydrogenase that converts this molecule into acetate. Accordingly, point mutations in the ALDH2 gene that encodes the acetaldehyde dehydrogenase lead to increased susceptibility to alcohol-induced cancers [166]. Interestingly, the dehydrogenation of alcohol to acetaldehyde is reversible with the equilibrium pointing heavily towards alcohol, and acetaldehyde levels, even in the case of intoxication, hover in the micromolar range while ethanol concentrations remain 100-fold higher. Conversely, acetaldehyde dehydrogenation to acetate is essentially irreversible and acetate levels reach millimolar levels during intoxication. Thus, cells may have developed biochemical processes that attempt to minimize the amount of acetaldehyde present in cells perhaps to limit the genotoxic effect of these metabolites.
Another source of endogenous DNA damage is single-base methylation facilitated by S-adenosylmethionine (SAM). SAM is an important molecule that acts as a physiological methylation donor in various enzymatic reactions such as CpG island methylation in our genome thereby regulating gene expression. However, SAM can also nonenzymatically react with DNA and thereby induce mutagenic DNA methyl adducts [167,168] that need to be repaired through the direct reversal pathway as indicated in Box 2. Interestingly, SAM is synthesized from methionine and adenosine and dietary methionine restriction has been shown to reduce SAM levels [169] as well as extend the lifespan of multiple organisms [170]. One speculative hypothesis is thus that methionine restriction could reduce spontaneous mutagenesis in our genome by lowering SAM levels, a phenomenon that has been observed in bacteria [167,168]. Accordingly, decreasing SAM levels increases Drosophila and Caenorhabditis elegans lifespans [171,172].
In sum, processes removing genotoxic molecules have evolved and their absence or dysfunction can lead to pathologies associated with aging.
Figure 1Three Tiers of Defense against DNA Damage.
(I) Regulation of toxic molecules such as free radicals, reactive acyls, and S-adenosyl methionine limit the amount of damage that occurs in DNA. (II) DNA repair attempts to correct damage that may occur as a result of either endogenous or exogenous DNA damage, but also as a result of normal cellular DNA metabolic processes such as DNA replication. (III) If repair fails and damage accumulates, the cell may activate programs leading to permanent cell cycle arrest, termed senescence, or the induction of programmed cell death through apoptosis.
Box 2
Mammalian DNA Repair Pathways
DNA repair in general is a three-step process: damage detection, damage removal, and resynthesis of new DNA (Figure I). Direct reversal repair deals with the removal of simple base modifications without altering the base or backbone of the DNA and is primarily used in repairing damage from DNA-alkylating agents. This process occurs with two major types of proteins: O6-methylguanine-DNA methyltransferases (MGMTs) using a single repair reaction where the methyl group is transferred to the MGMT protein thereby inactivating it; and repair via AlkB dioxygenases using an iron-catalyzed multistep repair reaction. Mutations in these enzymes have been associated with increased brain, lung, and bladder cancer risk [173,174] perhaps due to the mutagenic nature of the O6-methylguanine lesion.
Base excision repair deals with single-base modifications where the damaged base is recognized and removed and one, in short-patch repair, or several, in long-patch repair, new undamaged bases are added instead. Defects in this process have most commonly been linked with neurodegeneration and cancer [175], two central pathologies in aging.
Mismatch DNA repair deals with misincorporated bases during replication or after post-replicative DNA synthesis as part of other DNA repair pathways. The classic genetic mismatch repair disease is Lynch syndrome where DNA mutations accumulate in the rapidly proliferating cells in the gastrointestinal tract resulting in a high risk of colon cancer development [26].
Nucleotide excision repair corrects bulkier and/or helix-distorting lesions, often caused by UV irradiation, that require the removal of a piece of single-stranded DNA, an oligonucleotide, containing the DNA damage. Accordingly, patients with inherited defects in nucleotide excision repair suffer from sun sensitivity and increased risk of skin cancer development [111,176]. In addition, neurodegeneration and short stature are common features, although the pathogenesis for these particular traits is still debated [177].
Homologous recombination is one of two pathways that attempt to repair double-strand DNA breaks. The process relies on homologous chromosomes that occur during S or G2/M phase in the cell cycle. The enzymatic steps involve detection of the break, resection of the 5′ end of the DNA, and invasion of the single-stranded DNA in the sister chromatid after which elongation of the invaded DNA can occur to allow bridging of the area of DNA that was broken. Inherited deficiency in homologous recombination can lead to a long list of phenotypes including neurodegeneration, microcephaly, ionizing radiation sensitivity, short stature, cancer, anemia, immune deficiency, skeletal defects, pigmentation changes, and hypogonadism [125,178].
A second major pathway that attempts to correct double-strand DNA breaks is nonhomologous end joining. This process entails no, or very minor, resection of the 5′ DNA end followed by simple ligation of the DNA ends. Inherited deficiencies in nonhomologous end joining most prominently lead to immunodeficiency due to the role that nonhomologous end joining has in DNA recombination at antibody loci. In addition, patients can display microcephaly, short stature, anemia, ionizing radiation sensitivity, cardiovascular disease, skeletal defects, and immune deficiency [119].
One of the most complex lesions to occur in our cells is the interstrand crosslink, where the two complementary DNA strands are covalently connected. Here, the lesion is detected and a strand is incised on each side of the crosslink allowing the crosslinked base to be flipped out of the helix in what is called an unhooking step. Resynthesis by a translesion polymerase allows bridging of the gap. Subsequent removal of the unhooked crosslinked base is done by nucleotide excision repair. Inherited deficiency in the repair of interstrand crosslinks typically results in Fanconi anemia, which primarily affects rapidly proliferating cells in the bone marrow eventually leading to bone marrow failure and pancytopenia [27]. In addition, patients with Fanconi anemia can suffer from microcephaly, short stature, neurodegeneration, cancer, skeletal defects, and skin pigmentation changes [143,179].
Figure IDifferent Pathways Deal with Different Lesions.
Direct reversal repair attempts to correct single-base methylation events. Base excision repair corrects single-base lesions such as guanine oxidation. Nucleotide excision repair deals with bulky or helix-distorting lesions such as 6–4 photoproducts or cyclopyrimidine dimers. Interstrand crosslink repair is required to correct covalently linked DNA strands while double-strand break repair deals with breaks to both strands. A plethora of clinical phenotypes are associated with defects in the different pathways.
The association between DNA damage and aging is well established with extensive data from humans and animal models showing increased markers of genome instability with age [3,4]. One possible reason for an age-associated increase in DNA damage is that DNA repair capacity may decrease with age [5, 6, 7, 8]. Markers of DNA damage have been observed in age-associated diseases such as dementias, cardiovascular disease, and cancer, suggesting that genome instability could be a causal factor in these pathologies [9, 10, 11]. A compelling piece of evidence for a causal role of DNA damage is the observation that some patients with inherited defects in DNA repair proteins show features of premature or accelerated aging (Figure 2) [12,13]. Importantly, defects in different pathways lead to aging features in different tissues. For example, individuals with Cockayne syndrome and ataxia-telangiectasia display features of premature neurological aging [14,15], while Werner syndrome and Hutchinson–Gilford progeria patients display features of cardiovascular aging [16,17]. Due to the significant clinical heterogeneity between the diseases, the impact of some genes on processes outside DNA repair and the observation that none of the diseases perfectly phenocopies human aging, the diseases are often called segmental progerias. More than 50 DNA repair disorders have been described with various degrees of overlapping phenotypes with aging, such as neurodegeneration, cancer, and cardiovascular diseases (Table 1, Key Table) [12]. This could suggest that different types of DNA damage contribute to different pathologies in aging (Figure 3).
Figure 2An Overview of Clinical Features Associated with Mutations in Specific Proteins.
Abbreviations: AOA, ataxia oculomotor apraxia; ATLD, ataxia telangiectasia-like disorder; HIGM, immunodeficiency with hyper-IgM; KIN, karyomegalic interstitial nephritis; LIG IV, Ligase IV; MDPL, mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome; NBS, Nijmegen breakage syndrome; NHEJ1, nonhomologous end joining factor 1; RS-SCID, radiation-sensitive severe combined immunodeficiency; SCAN1, spinocerebellar ataxia with axonal neuropathy-1; SSMED, short stature, microcephaly, and endocrine dysfunction.
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