DNA damage theory of aging
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damages. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly (by increasing apoptosis or cellular senescence) or directly (by increasing cell dysfunction).[1][2][3]
Several review articles have shown that deficient DNA repair, allowing greater accumulation of DNA damages, causes premature aging; and that increased DNA repair facilitates greater longevity. Mouse models of nucleotide-excision–repair syndromes reveal a striking correlation between the degree to which specific DNA repair pathways are compromised and the severity of accelerated aging, strongly suggesting a causal relationship.[4] Human populations studies show that single-nucleotide polymorphisms in DNA repair genes, causing up-regulation of their expression, correlate with increases in longevity.[5] Lombard et al. compiled a lengthy list of mouse mutational models with pathologic features of premature aging, all caused by different DNA repair defects.[6] Freitas and de Magalhães presented a comprehensive review and appraisal of the DNA damage theory of aging, including a detailed analysis of many forms of evidence linking DNA damage to aging.[2] As an example, they described a study showing that centenarians of 100 to 107 years of age had higher levels of two DNA repair enzymes, PARP1 and Ku70, than general-population old individuals of 69 to 75 years of age.[7][2] Their analysis supported the hypothesis that improved DNA repair leads to longer life span. Overall, they concluded that while the complexity of responses to DNA damage remains only partly understood, the idea that DNA damage accumulation with age is the primary cause of aging remains an intuitive and powerful one.[2]
In humans and other mammals, DNA damage occurs frequently and DNA repair processes have evolved to compensate.[citation needed] In estimates made for mice, DNA lesions occur on average 25 to 115 times per minute in each cell, or about 36,000 to 160,000 per cell per day.[8] Some DNA damage may remain in any cell despite the action of repair processes. The accumulation of unrepaired DNA damage is more prevalent in certain types of cells, particularly in non-replicating or slowly replicating cells, such as cells in the brain, skeletal and cardiac muscle.[citation needed]
Contents
1 DNA damage and mutation
2 Age-associated accumulation of DNA damage and decline in gene expression
2.1 Brain
2.2 Muscle
2.3 Liver
2.4 Kidney
2.5 Long-lived stem cells
3 Mutation theories of aging
4 Dietary restriction
5 Inherited defects that cause premature aging
5.1 Defects in DNA repair cause features of premature aging
5.2 Increased DNA repair and extended longevity
6 Lifespan in different mammalian species
7 Centenarians
8 Menopause
9 Atherosclerosis
10 DNA damage and the epigenetic clock
11 See also
12 References
DNA damage and mutation
8-Hydroxydeoxyguanosine
To understand the DNA damage theory of aging it is important to distinguish between DNA damage and mutation, the two major types of errors that occur in DNA. Damage and mutation are fundamentally different. DNA damage is any physical abnormality in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damage can be recognized by enzymes, and thus can be correctly repaired using the complementary undamaged sequence in a homologous chromosome if it is available for copying. 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. Descriptions of reduced function, characteristic of aging and associated with accumulation of DNA damage, are given later in this article.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. 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. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell’s survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.
The first person to suggest that DNA damage, as distinct from mutation, is the primary cause of aging was Alexander in 1967.[9] By the early 1980s there was significant experimental support for this idea in the literature.[10] By the early 1990s experimental support for this idea was substantial, and furthermore it had become increasingly evident that oxidative DNA damage, in particular, is a major cause of aging.[11][12][13][14][15]
In a series of articles from 1970 to 1977, PV Narasimh Acharya, Phd. (1924–1993) theorized and presented evidence that cells undergo "irreparable DNA damage," whereby DNA crosslinks occur when both normal cellular repair processes fail and cellular apoptosis does not occur. Specifically, Acharya noted that double-strand breaks and a "cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate."[16][17][18][19][20]
Age-associated accumulation of DNA damage and decline in gene expression
In tissues composed of non- or infrequently replicating cells, DNA damage can accumulate with age and lead either to loss of cells, or, in surviving cells, loss of gene expression. Accumulated DNA damage is usually measured directly. Numerous studies of this type have indicated that oxidative damage to DNA is particularly important.[21] The loss of expression of specific genes can be detected at both the mRNA level and protein level.
Brain
The adult brain is composed in large part of terminally differentiated non-dividing neurons. Many of the conspicuous features of aging reflect a decline in neuronal function. Accumulation of DNA damage with age in the mammalian brain has been reported during the period 1971 to 2008 in at least 29 studies.[22] This DNA damage includes the oxidized nucleoside 8-oxo-2'-deoxyguanosine (8-oxo-dG), single- and double-strand breaks, DNA-protein crosslinks and malondialdehyde adducts (reviewed in Bernstein et al.[22]). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human.
Rutten et al.[23] showed that single-strand breaks accumulate in the mouse brain with age. Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.[24] Sen et al.[25] showed that DNA damages which block the polymerase chain reaction in rat brain accumulate with age. Swain and Rao observed marked increases in several types of DNA damages in aging rat brain, including single-strand breaks, double-strand breaks and modified bases (8-OHdG and uracil).[26] Wolf et al.[27] also showed that the oxidative DNA damage 8-OHdG accumulates in rat brain with age. Similarly, it was shown that as humans age from 48–97 years, 8-OHdG accumulates in the brain.[28]
Lu et al.[29] studied the transcriptional profiles of the human frontal cortex of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose expression was altered after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. In the brain, promoters of genes with reduced expression have markedly increased DNA damage.[29] In cultured human neurons, these gene promoters are selectively damaged by oxidative stress. Thus Lu et al.[29] concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a program of brain aging that starts early in adult life.
Muscle
Muscle strength, and stamina for sustained physical effort, decline in function with age in humans and other species. Skeletal muscle is a tissue composed largely of multinucleated myofibers, elements that arise from the fusion of mononucleated myoblasts. Accumulation of DNA damage with age in mammalian muscle has been reported in at least 18 studies since 1971.[22] We will mention here only two of the more recent studies in rodents plus one in humans. Hamilton et al.[30] reported that the oxidative DNA damage 8-OHdG accumulates in heart and skeletal muscle (as well as in brain, kidney and liver) of both mouse and rat with age. In humans, increases in 8-OHdG with age were reported for skeletal muscle.[31] Catalase is an enzyme that removes hydrogen peroxide, a reactive oxygen species, and thus limits oxidative DNA damage. In mice, when catalase expression is increased specifically in mitochondria, oxidative DNA damage (8-OHdG) in skeletal muscle is decreased and lifespan is increased by about 20%.[32][33] These findings suggest that mitochondria are a significant source of the oxidative damages contributing to aging.
Protein synthesis and protein degradation decline with age in skeletal and heart muscle, as would be expected, since DNA damage blocks gene transcription. In a recent study Piec et al.[34] found numerous changes in protein expression in rat skeletal muscle with age, including lower levels of several proteins related to myosin and actin. Force is generated in striated muscle by the interactions between myosin thick filaments and actin thin filaments.
Liver
Liver hepatocytes do not ordinarily divide and appear to be terminally differentiated, but they retain the ability to proliferate when injured. With age, the mass of the liver decreases, blood flow is reduced, metabolism is impaired, and alterations in microcirculation occur. At least 21 studies have reported an increase in DNA damage with age in liver.[22] For instance, Helbock et al.[35] estimated that the steady state level of oxidative DNA base alterations increased from 24,000 per cell in the liver of young rats to 66,000 per cell in the liver of old rats.
Kidney
In kidney, changes with age include reduction in both renal blood flow and glomerular filtration rate, and impairment in the ability to concentrate urine and to conserve sodium and water. DNA damages, particularly oxidative DNA damages, increase with age (at least 8 studies).[22] For instance Hashimoto et al.[36] showed that 8-OHdG accumulates in rat kidney DNA with age.
Long-lived stem cells
Tissue-specific stem cells produce differentiated cells through a series of increasingly more committed progenitor intermediates. In hematopoiesis (blood cell formation), the process begins with long-term hematopoietic stem cells that self-renew and also produce progeny cells that upon further replication go through a series of stages leading to differentiated cells without self-renewal capacity. In mice, deficiencies in DNA repair appear to limit the capacity of hematopoietic stem cells to proliferate and self-renew with age.[37] Sharpless and Depinho reviewed evidence that hematopoietic stem cells, as well as stem cells in other tissues, undergo intrinsic aging.[38] They speculated that stem cells grow old, in part, as a result of DNA damage. DNA damage may trigger signalling pathways, such as apoptosis, that contribute to depletion of stem cell stocks. This has been observed in several cases of accelerated aging and may occur in normal aging too.[39]
A key aspect of hair loss with age is the aging of the hair follicle.[40] Ordinarily, hair follicle renewal is maintained by the stem cells associated with each follicle. Aging of the hair follicle appears to be due to the DNA damage that accumulates in renewing stem cells during aging.[41]
Mutation theories of aging
A popular idea, that has failed to gain significant experimental support, is the idea that mutation, as distinct from DNA damage, is the primary cause of aging. As discussed above, mutations tend to arise in frequently replicating cells as a result of errors of DNA synthesis when template DNA is damaged, and can give rise to cancer. However, in mice there is no increase in mutation in the brain with aging.[42][43][44] Mice defective in a gene (Pms2) that ordinarily corrects base mispairs in DNA have about a 100-fold elevated mutation frequency in all tissues, but do not appear to age more rapidly.[45] On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation.[46]
One variation of the idea that mutation is the basis of aging, that has received much attention, is that mutations specifically in mitochondrial DNA are the cause of aging. Several studies have shown that mutations accumulate in mitochondrial DNA in infrequently replicating cells with age. DNA polymerase gamma is the enzyme that replicates mitochondrial DNA. A mouse mutant with a defect in this DNA polymerase is only able to replicate its mitochondrial DNA inaccurately, so that it sustains a 500-fold higher mutation burden than normal mice. These mice showed no clear features of rapidly accelerated aging.[47] Overall, the observations discussed in this section indicate that mutations are not the primary cause of aging.
Dietary restriction
In rodents, caloric restriction slows aging and extends lifespan. At least 4 studies have shown that caloric restriction reduces 8-OHdG damages in various organs of rodents. One of these studies showed that caloric restriction reduced accumulation of 8-OHdG with age in rat brain, heart and skeletal muscle, and in mouse brain, heart, kidney and liver.[30] More recently, Wolf et al.[27] showed that dietary restriction reduced accumulation of 8-OHdG with age in rat brain, heart, skeletal muscle, and liver. Thus reduction of oxidative DNA damage is associated with a slower rate of aging and increased lifespan.
Inherited defects that cause premature aging
If DNA damage is the underlying cause of aging, it would be expected that humans with inherited defects in the ability to repair DNA damages should age at a faster pace than persons without such a defect. Numerous examples of rare inherited conditions with DNA repair defects are known. Several of these show multiple striking features of premature aging, and others have fewer such features. Perhaps the most striking premature aging conditions are Werner syndrome (mean lifespan 47 years), Huchinson-Gilford Progeria (mean lifespan 13 years), and Cockayne syndrome (mean lifespan 13 years).
Werner syndrome is due to an inherited defect in an enzyme (a helicase and exonuclease) that acts in base excision repair of DNA (e.g. see Harrigan et al.[48]).
Hutchinson-Guilford Progeria is due to a defect in Lamin A protein which forms a scaffolding within the cell nucleus to organize chromatin and is needed for repair of double-strand breaks in DNA.[49] A-type lamins promote genetic stability by maintaining levels of proteins that have key roles in the DNA repair processes of non-homologous end joining and homologous recombination.[50] Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and are more sensitive to DNA damaging agents.[51]
Cockayne Syndrome is due to a defect in a protein necessary for the repair process, transcription coupled nucleotide excision repair, which can remove damages, particularly oxidative DNA damages, that block transcription.[52]
In addition to these three conditions, several other human syndromes, that also have defective DNA repair, show several features of premature aging. These include ataxia telangiectasia, Nijmegen breakage syndrome, some subgroups of xeroderma pigmentosum, trichothiodystrophy, Fanconi anemia, Bloom syndrome and Rothmund-Thomson syndrome.
Ku bound to DNA
In addition to human inherited syndromes, experimental mouse models with genetic defects in DNA repair show features of premature aging and reduced lifespan.(e.g. refs.[53][54][55]) In particular, mutant mice defective in Ku70, or Ku80, or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging.[56] The mean lifespans of the three mutant mouse strains were similar to each other, at about 37 weeks, compared to 108 weeks for the wild-type control. Six specific signs of aging were examined, and the three mutant mice were found to display the same aging signs as the control mice, but at a much earlier age. Cancer incidence was not increased in the mutant mice. Ku70 and Ku80 form the heterodimer Ku protein essential for the non-homologous end joining (NHEJ) pathway of DNA repair, active in repairing DNA double-strand breaks. This suggests an important role of NHEJ in longevity assurance.
Defects in DNA repair cause features of premature aging
Many authors have noted an association between defects in the DNA damage response and premature aging (see e.g.[57][58][59][60]). If a DNA repair protein is deficient, unrepaired DNA damages tend to accumulate.[61] Such accumulated DNA damages appear to cause features of premature aging (segmental progeria). Table 1 lists 18 DNA repair proteins which, when deficient, cause numerous features of premature aging.
| Protein | Pathway | Description |
|---|---|---|
ATR | Nucleotide excision repair[62] | deletion of ATR in adult mice leads to a number of disorders including hair loss and graying, kyphosis, osteoporosis, premature involution of the thymus, fibrosis of the heart and kidney and decreased spermatogenesis[58] |
DNA-PKcs | Non-homologous end joining | shorter lifespan, earlier onset of aging related pathologies;[63][64] higher level of DNA damage persistence[65] |
ERCC1 | Nucleotide excision repair, Interstrand cross link repair[66] | deficient transcription coupled NER with time-dependent accumulation of transcription-blocking damages;[67] mouse life span reduced from 2.5 years to 5 months;[60]Ercc1−/− mice are leukopenic and thrombocytopenic, and there is extensive adipose transformation of the bone marrow, hallmark features of normal aging in mice[66] |
ERCC2 (XPD) | Nucleotide excision repair (also transcription as part of TFIIH) | some mutations in ERCC2 cause Cockayne syndrome in which patients have segmental progeria with reduced stature, mental retardation, cachexia (loss of subcutaneous fat tissue), sensorineural deafness, retinal degeneration, and calcification of the central nervous system; other mutations in ERCC2 cause trichothiodystrophy in which patients have segmental progeria with brittle hair, short stature, progressive cognitive impairment and abnormal face shape; still other mutations in ERCC2 cause xeroderma pigmentosum (without a progeroid syndrome) and with extreme sun-mediated skin cancer predisposition[68] |
ERCC4 (XPF) | Nucleotide excision repair, Interstrand cross link repair, Single-strand annealing, Microhomology-mediated end joining[66] | mutations in ERCC4 cause symptoms of accelerated aging that affect the neurologic, hepatobiliary, musculoskeletal, and hematopoietic systems, and cause an old, wizened appearance, loss of subcutaneous fat, liver dysfunction, vision and hearing loss, renal insufficiency, muscle wasting, osteopenia, kyphosis and cerebral atrophy[66] |
ERCC5 (XPG) | Nucleotide excision repair,[69]Homologous recombinational repair,[70]Base excision repair[71][72] | mice with deficient ERCC5 show loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months |
ERCC6 (Cockayne syndrome B or CS-B) | Nucleotide excision repair [especially transcription coupled repair (TC-NER) and interstrand crosslink repair] | premature aging features with shorter life span and photosensitivity,[73] deficient transcription coupled NER with accumulation of unrepaired DNA damages,[74] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines[74] |
ERCC8 (Cockayne syndrome A or CS-A) | Nucleotide excision repair [especially transcription coupled repair (TC-NER) and interstrand crosslink repair] | premature aging features with shorter life span and photosensitivity,[73] deficient transcription coupled NER with accumulation of unrepaired DNA damages,[74] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines[74] |
GTF2H5 (TTDA) | Nucleotide excision repair | deficiency causes trichothiodystrophy (TTD) a premature-ageing and neuroectodermal disease; humans with GTF2H5 mutations have a partially inactivated protein[75] with retarded repair of 6-4-photoproducts[76] |
Ku70 | Non-homologous end joining | shorter lifespan, earlier onset of aging related pathologies;[59] persistent foci of DNA double-strand break repair proteins[77] |
Ku80 | Non-homologous end joining | shorter lifespan, earlier onset of aging related pathologies;[56] defective repair of spontaneous DNA damage[59] |
Lamin A | Non-homologous end joining, Homologous recombination | increased DNA damage and chromosome aberrations; progeria; aspects of premature aging; altered expression of numerous DNA repair factors[78] |
| NRMT1 | Nucleotide excision repair[79] | mutation in NRMT1 causes decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration[57] |
RECQL4 | Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining[80] | mutations in RECQL4 cause Rothmund-Thomson syndrome, with alopecia, sparse eyebrows and lashes, cataracts and osteoporosis[80] |
SIRT6 | Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining[81] | SIRT6-deficient mice develop profound lymphopenia, loss of subcutaneous fat and lordokyphosis, and these defects overlap with aging-associated degenerative processes[55] |
SIRT7 | Non-homologous end joining | mice defective in SIRT7 show phenotypic and molecular signs of accelerated aging such as premature pronounced curvature of the spine, reduced life span, and reduced non-homologous end joining[82] |
Werner syndrome helicase | Homologous recombination,[83][84]Non-homologous end joining,[85]Base excision repair,[86][87] Replication arrest recovery[88] | shorter lifespan, earlier onset of aging related pathologies, genome instability[89][90] |
ZMPSTE24 | Homologous recombination | lack of Zmpste24 prevents lamin A formation and causes progeroid phenotypes in mice and humans, increased DNA damage and chromosome aberrations, sensitivity to DNA-damaging agents and deficiency in homologous recombination[51] |
Increased DNA repair and extended longevity
Table 2 lists DNA repair proteins whose increased expression is connected to extended longevity.
| Protein | Pathway | Description |
|---|---|---|
NDRG1 | Direct reversal | long-lived Snell dwarf, GHRKO, and PAPPA-KO mice have increased expression of NDRG1; higher expression of NDRG1 can promote MGMT protein stability and enhanced DNA repair[91][92] |
NUDT1 (MTH1) | Oxidized nucleotide removal | degrades 8-oxodGTP; prevents the age-dependent accumulation of DNA 8-oxoguanine[93] A transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed,[94] giving over-expression of hMTH1, increases the median lifespan of mice to 914 days vs. 790 days for wild-type mice.[93] Mice with over-expressed hMTH1 have behavioral changes of reduced anxiety and enhanced investigation of environmental and social cues |
PARP1 | Base excision repair,[95]Nucleotide excision repair,[96]Microhomology-mediated end joining,[97] Single-strand break repair[98] | PARP1 activity in blood cells of thirteen mammalian species (rat, guinea pig, rabbit, marmoset, sheep, pig, cattle, pigmy chimpanzee, horse, donkey, gorilla, elephant and man) correlates with maximum lifespan of the species.[99] |
SIRT1 | Nucleotide excision repair, Homologous recombination, Non-homologous end joining[100] | Increased expression of SIRT1 in male mice extends the lifespan of mice fed a standard diet, accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity[101][102] |
SIRT6 | Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining[81] | male, but not female, transgenic mice overexpressing Sirt6 have a significantly longer lifespan than wild-type mice[103] |
Lifespan in different mammalian species
Studies comparing DNA repair capacity in different mammalian species have shown that repair capacity correlates with lifespan. The initial study of this type, by Hart and Setlow,[104] showed that the ability of skin fibroblasts of seven mammalian species to perform DNA repair after exposure to a DNA damaging agent correlated with lifespan of the species. The species studied were shrew, mouse, rat, hamster, cow, elephant and human. This initial study stimulated many additional studies involving a wide variety of mammalian species, and the correlation between repair capacity and lifespan generally held up. In one of the more recent studies, Burkle et al.[105] studied the level of a particular enzyme, Poly ADP ribose polymerase, which is involved in repair of single-strand breaks in DNA. They found that the lifespan of 13 mammalian species correlated with the activity of this enzyme.
The DNA repair transcriptomes of the liver of humans, naked mole-rats and mice were compared.[106] The maximum lifespans of humans, naked mole-rat, and mouse are respectively ~120, 30 and 3 years. The longer-lived species, humans and naked mole rats expressed DNA repair genes, including core genes in several DNA repair pathways, at a higher level than did mice. In addition, several DNA repair pathways in humans and naked mole-rats were up-regulated compared with mouse. These findings suggest that increased DNA repair facilitates greater longevity.
Over the past decade, a series of papers have shown that the mitochondrial DNA (mtDNA) base composition correlates with animal species maximum life span.[107][108][109][110] The mitochondrial DNA base composition is though to reflect its nucleotide-specific (guanine, cytosine, thymidine and adenine) different mutation rates (i.e., accumulation of guanine in the mitochondrial DNA of an animal species is due to low guanine mutation rate in the mitochondria of that species).
Centenarians
Lymphoblastoid cell lines established from blood samples of humans who lived past 100 years (centenarians) have significantly higher activity of the DNA repair protein Poly (ADP-ribose) polymerase (PARP) than cell lines from younger individuals (20 to 70 years old).[111][unreliable medical source?] The lymphocytic cells of centenarians have characteristics typical of cells from young people, both in their capability of priming the mechanism of repair after H2O2 sublethal oxidative DNA damage and in their PARP capacity.[7][112]
Menopause
As women age, they experience a decline in reproductive performance leading to menopause. This decline is tied to a decline in the number of ovarian follicles. Although 6 to 7 million oocytes are present at mid-gestation in the human ovary,[113] only about 500 (about 0.05%) of these ovulate, and the rest are lost. The decline in ovarian reserve appears to occur at an increasing rate with age,[114][113] and leads to nearly complete exhaustion of the reserve by about age 51. As ovarian reserve and fertility decline with age, there is also a parallel increase in pregnancy failure and meiotic errors resulting in chromosomally abnormal conceptions.
Titus et al.[115] have proposed an explanation for the decline in ovarian reserve with age. They showed that as women age, double-strand breaks accumulate in the DNA of their primordial follicles. Primordial follicles are immature primary oocytes surrounded by a single layer of granulosa cells. An enzyme system is present in oocytes that normally accurately repairs DNA double-strand breaks. This repair system is referred to as homologous recombinational repair, and it is especially active during meiosis. Titus et al.[115] also showed that expression of four key DNA repair genes that are necessary for homologous recombinational repair (BRCA1, MRE11, Rad51 and ATM) decline in oocytes with age. This age-related decline in ability to repair double-strand damages can account for the accumulation of these damages, which then likely contributes to the decline in ovarian reserve.
Women with an inherited mutation in the DNA repair gene BRCA1 undergo menopause prematurely,[116] suggesting that naturally occurring DNA damages in oocytes are repaired less efficiently in these women, and this inefficiency leads to early reproductive failure. Genomic data from about 70,000 women were analyzed to identify protein-coding variation associated with age at natural menopause.[117] Pathway analyses identified a major association with DNA damage response genes, particularly those expressed during meiosis and including a common coding variant in the BRCA1 gene.
Atherosclerosis
The most important risk factor for cardiovascular problems is chronological aging. Several research groups have reviewed evidence for a key role of DNA damage in vascular aging.[118][119][120]
Atherosclerotic plaque contains vascular smooth muscle cells, macrophages and endothelial cells and these have been found to accumulate 8-oxoG, a common type of oxidative DNA damage.[121] DNA strand breaks also increased in atherosclerotic plaques, thus linking DNA damage to plaque formation.[121]
Werner syndrome (WS), a premature aging condition in humans, is caused by a genetic defect in a RecQ helicase that is employed in several DNA repair processes. WS patients develop a substantial burden of atherosclerotic plaques in their coronary arteries and aorta.[119] These findings link excessive unrepaired DNA damage to premature aging and early atherosclerotic plaque development.
DNA damage and the epigenetic clock
Endogenous, naturally occurring DNA damages are frequent, and in humans include an average of about 10,000 oxidative damages per day and 50 double-strand DNA breaks per cell cycle [see DNA damage (naturally occurring)].
Several reviews[122][123][124] summarize evidence that the methylation enzyme DNMT1 is recruited to sites of oxidative DNA damage. Recruitment of DNMT1 leads to DNA methylation at the promoters of genes to inhibit transcription during repair. In addition, the 2018 review[122] describes recruitment of DNMT1 during repair of DNA double-strand breaks. DNMT1 localization results in increased DNA methylation near the site of recombinational repair, associated with altered expression of the repaired gene. In general, repair-associated hyper-methylated promoters are restored to their former methylation level after DNA repair is complete. However, these reviews also indicate that transient recruitment of epigenetic modifiers can occasionally result in subsequent stable epigenetic alterations and gene silencing after DNA repair has been completed.
In human and mouse DNA, cytosine followed by guanine (CpG) is the least frequent dinucleotide, making up less than 1% of all dinucleotides (see CG suppression). At most CpG sites cytosine is methylated to form 5-methylcytosine. As indicated in the article CpG site, in mammals, 70% to 80% of CpG cytosines are methylated. However, in vertebrates there are CpG islands, about 300 to 3,000 base pairs long, with interspersed DNA sequences that deviate significantly from the average genomic pattern by being CpG-rich. These CpG islands are predominantly nonmethylated.[125] In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island (see CpG islands in promoters). If the initially nonmethylated CpG sites in a CpG island become largely methylated, this causes stable silencing of the associated gene.
For humans, after adulthood is reached and during subsequent aging, the majority of CpG sequences slowly lose methylation (called epigenetic drift). However, the CpG islands that control promoters tend to gain methylation with age.[126] The gain of methylation at CpG islands in promoter regions is correlated with age, and has been used to create an epigenetic clock (see article Epigenetic clock).
There may be some relationship between the epigenetic clock and epigenetic alterations accumulating after DNA repair. Both unrepaired DNA damage accumulated with age and accumulated methylation of CpG islands would silence genes in which they occur, interfere with protein expression, and contribute to the aging phenotype.
See also
- Aging brain
- Biological immortality
- DNA damage (naturally occurring)
- DNA repair
- Life expectancy
- Longevity
- Maximum life span
- Rejuvenation (aging)
- Senescence
- Telomere
References
^ Best, BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research. 12 (3): 199–208. doi:10.1089/rej.2009.0847. PMID 19594328..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"""""""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("//upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
^ abcd Freitas AA, de Magalhães JP (2011). "A review and appraisal of the DNA damage theory of ageing". Mutation Research. 728 (1–2): 12–22. doi:10.1016/j.mrrev.2011.05.001. PMID 21600302.
^ Burhans WC1, Weinberger M (2007). "DNA replication stress, genome instability and aging". Nucleic Acids Research. 35 (22): 7545–7556. doi:10.1093/nar/gkm1059. PMC 2190710. PMID 18055498.
^ Hoeijmakers JH (2009). "DNA damage, aging, and cancer". N. Engl. J. Med. 361 (15): 1475–85. doi:10.1056/NEJMra0804615. PMID 19812404.
^ Cho M, Suh Y (2014). "Genome maintenance and human longevity". Curr. Opin. Genet. Dev. 26: 105–15. doi:10.1016/j.gde.2014.07.002. PMC 4254320. PMID 25151201.
^ Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW (2005). "DNA repair, genome stability, and aging". Cell. 120 (4): 497–512. doi:10.1016/j.cell.2005.01.028. PMID 15734682.
^ ab Chevanne M, Calia C, Zampieri M, Cecchinelli B, Caldini R, Monti D, Bucci L, Franceschi C, Caiafa P (2007). "Oxidative DNA damage repair and parp 1 and parp 2 expression in Epstein-Barr virus-immortalized B lymphocyte cells from young subjects, old subjects, and centenarians" (PDF). Rejuvenation Res. 10 (2): 191–204. doi:10.1089/rej.2006.0514. PMID 17518695.
^ Vilenchik, MM; Knudson, AG (May 2000). "Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates". Proc Natl Acad Sci U S A. 97 (10): 5381–6. Bibcode:2000PNAS...97.5381V. doi:10.1073/pnas.090099497. PMC 25837. PMID 10792040.
^ Alexander, P (1967). "The role of DNA lesions in the processes leading to aging in mice". Symp Soc Exp Biol. 21: 29–50. PMID 4860956.
^ Gensler, HL; Bernstein, H (Sep 1981). "DNA damage as the primary cause of aging". Q Rev Biol. 56 (3): 279–303. doi:10.1086/412317. PMID 7031747.
^ Bernstein C, Bernstein H. (1991) Aging, Sex, and DNA Repair. Academic Press, San Diego.
ISBN 978-0120928606 partly available at https://books.google.com/books?id=BaXYYUXy71cC&pg=PA3&lpg=PA3&dq=Aging,+Sex,+and+DNA+Repair&source=bl&ots=9E6VrRl7fJ&sig=kqUROJfBM6EZZeIrkuEFygsVVpo&hl=en&sa=X&ei=z8BqUpi7D4KQiALC54Ew&ved=0CFUQ6AEwBg#v=onepage&q=Aging%2C%20Sex%2C%20and%20DNA%20Repair&f=false
^ Ames, BN; Gold, LS (1991). "Endogenous mutagens and the causes of aging and cancer". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 250 (1–2): 3–16. doi:10.1016/0027-5107(91)90157-j. PMID 1944345.
^ Holmes, GE; Bernstein, C; Bernstein, H (1992). "Oxidative and other DNA damages as the basis of aging: a review". Mutat Res. 275 (3–6): 305–315. doi:10.1016/0921-8734(92)90034-M. PMID 1383772.
^ Rao, KS; Loeb, LA (September 1992). "DNA damage and repair in brain: relationship to aging". Mutation Research/DNAging. 275 (3–6): 317–29. doi:10.1016/0921-8734(92)90035-N. PMID 1383773.
^ Ames, BN; Shigenaga, MK; Hagen, TM (September 1993). "Oxidants, antioxidants, and the degenerative diseases of aging". Proceedings of the National Academy of Sciences. 90 (17): 7915–22. Bibcode:1993PNAS...90.7915A. doi:10.1073/pnas.90.17.7915. PMC 47258. PMID 8367443.
^ Acharya PV (1972). "The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides". Johns Hopkins Med. J. Suppl. (1): 254–60. PMID 5055816.
^ Acharya, PV; Ashman, SM; Bjorksten, J; The isolation and partial characterization of age-correlated oligo-deoxyribo-ribo nucleo peptides. Finska Kemists Medd. 81 No. 3 (1972) Suomen Kemists. Tied. Chemical Abstacts, Vol 78, No. 19. May 14, 1973. Abs. N. 122001 g.
^ Acharya, PVN. Isolation and Partial Characterization of Age-Correlated Oligo-nucleotides with Covalently Bound Peptides. 14th Nordic Congress, Umea, Sweden, June 19, 1971.
^ Acharya, PVN. DNA-damage: The Cause of Aging. Ninth International Congress of Biochemistry: Stockholm. July 1–7, 1973 (Abs.3 m 12).
^ Acharya, PVN (1977). "Irreparable DNA-damage by Industrial Pollutants in Pre-mature Aging, Chemical Carcinogenesis and Cardiac Hypertrophy: Experiments and Theory". Israel Journal of Medical Sciences. 13: 441.
^ Sinha, Jitendra Kumar; Ghosh, Shampa; Swain, Umakanta; Giridharan, Nappan Veethil; Raghunath, Manchala (2014). "Increased macromolecular damage due to oxidative stress in the neocortex and hippocampus of WNIN/Ob, a novel rat model of premature aging". Neuroscience. 269: 256–64. doi:10.1016/j.neuroscience.2014.03.040. PMID 24709042.
^ abcde Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1–47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247
ISBN 1604565810
ISBN 978-1604565812
^ Rutten, BP; Schmitz, C; Gerlach, OH; Oyen, HM; de Mesquita, EB; Steinbusch, HW; Korr, H (Jan 2007). "The aging brain: accumulation of DNA damage or neuron loss?". Neurobiol Aging. 28 (1): 91–8. doi:10.1016/j.neurobiolaging.2005.10.019. PMID 16338029.
^ Mandavilli BS, Rao KS (1996). "Accumulation of DNA damage in aging neurons occurs through a mechanism other than apoptosis". J. Neurochem. 67 (4): 1559–65. doi:10.1046/j.1471-4159.1996.67041559.x. PMID 8858940.
^ Sen, T; Jana, S; Sreetama, S; Chatterjee, U; Chakrabarti, S (Mar 2007). "Gene-specific oxidative lesions in aged rat brain detected by polymerase chain reaction inhibition assay". Free Radic Res. 41 (3): 288–94. doi:10.1080/10715760601083722. PMID 17364957.
^ Swain, U; Subba Rao, K (Aug 2011). "Study of DNA damage via the comet assay and base excision repair activities in rat brain neurons and astrocytes during aging". Mech Ageing Dev. 132 (8–9): 374–81. doi:10.1016/j.mad.2011.04.012. PMID 21600238.
^ ab Wolf, FI; Fasanella, S; Tedesco, B; Cavallini, G; Donati, A; Bergamini, E; Cittadini, A (Mar 2005). "Peripheral lymphocyte 8-OHdG levels correlate with age-associated increase of tissue oxidative DNA damage in Sprague-Dawley rats. Protective effects of caloric restriction". Exp Gerontol. 40 (3): 181–8. doi:10.1016/j.exger.2004.11.002. PMID 15763395.
^ Mecocci, P; MacGarvey, U; Kaufman, AE; Koontz, D; Shoffner, JM; Wallace, DC; Beal, MF (Oct 1993). "Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain". Ann Neurol. 34 (4): 609–16. doi:10.1002/ana.410340416. PMID 8215249.
^ abc Lu, T; Pan, Y; Kao, SY; Li, C; Kohane, I; Chan, J; Yankner, BA (Jun 2004). "Gene regulation and DNA damage in the ageing human brain". Nature. 429 (6994): 883–91. Bibcode:2004Natur.429..883L. doi:10.1038/nature02661. PMID 15190254.
^ ab Hamilton, ML; Van Remmen, H; Drake, JA; Yang, H; Guo, ZM; Kewitt, K; Walter, CA; Richardson, A (Aug 2001). "Does oxidative damage to DNA increase with age?". Proc Natl Acad Sci U S A. 98 (18): 10469–74. Bibcode:2001PNAS...9810469H. doi:10.1073/pnas.171202698. PMC 56984. PMID 11517304.
^ Mecocci, P; Fanó, G; Fulle, S; MacGarvey, U; Shinobu, L; Polidori, MC; Cherubini, A; Vecchiet, J; Senin, U; Beal, MF (Feb 1999). "Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscle". Free Radic Biol Med. 26 (3–4): 303–8. doi:10.1016/s0891-5849(98)00208-1. PMID 9895220.
^ Schriner, SE; Linford, NJ; Martin, GM; Treuting, P; Ogburn, CE; Emond, M; Coskun, PE; Ladiges, W; Wolf, N; Van Remmen, H; Wallace, DC; Rabinovitch, PS (Jun 2005). "Extension of murine life span by overexpression of catalase targeted to mitochondria". Science. 308 (5730): 1909–11. Bibcode:2005Sci...308.1909S. doi:10.1126/science.1106653. PMID 15879174.
^ Linford, NJ; Schriner, SE; Rabinovitch, PS (Mar 2006). "Oxidative damage and aging: spotlight on mitochondria". Cancer Res. 66 (5): 2497–9. doi:10.1158/0008-5472.CAN-05-3163. PMID 16510562.
^ Piec, I; Listrat, A; Alliot, J; Chambon, C; Taylor, RG; Bechet, D (Jul 2005). "Differential proteome analysis of aging in rat skeletal muscle". FASEB J. 19 (9): 1143–5. doi:10.1096/fj.04-3084fje. PMID 15831715.
^ Helbock, HJ; Beckman, KB; Shigenaga, MK; et al. (January 1998). "DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine". Proc. Natl. Acad. Sci. U.S.A. 95 (1): 288–93. Bibcode:1998PNAS...95..288H. doi:10.1073/pnas.95.1.288. PMC 18204. PMID 9419368.CS1 maint: Explicit use of et al. (link)
^ Hashimoto, K; Takasaki, W; Sato, I; Tsuda, S (Aug 2007). "DNA damage measured by comet assay and 8-OH-dG formation related to blood chemical analyses in aged rats". J Toxicol Sci. 32 (3): 249–59. doi:10.2131/jts.32.249. PMID 17785942.
^ Rossi, DJ; Bryder, D; Seita, J; Nussenzweig, A; Hoeijmakers, J; Weissman, IL (Jun 2007). "Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age". Nature. 447 (7145): 725–9. Bibcode:2007Natur.447..725R. doi:10.1038/nature05862. PMID 17554309.
^ Sharpless, NE; DePinho, RA (Sep 2007). "How stem cells age and why this makes us grow old". Nat Rev Mol Cell Biol. 8 (9): 703–13. doi:10.1038/nrm2241. PMID 17717515.
^ Freitas AA1, de Magalhães JP. A review and appraisal of the DNA damage theory of ageing. Mutat Res. 2011 Jul-Oct;728(1-2):12-22. doi: 10.1016/j.mrrev.2011.05.001.
PMID 21600302
^ Lei M, Chuong CM (2016). "STEM CELLS. Aging, alopecia, and stem cells". Science. 351 (6273): 559–60. Bibcode:2016Sci...351..559L. doi:10.1126/science.aaf1635. PMID 26912687.
^ Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, Nishimura EK (2016). "Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis". Science. 351 (6273): aad4395. doi:10.1126/science.aad4395. PMID 26912707.
^ Dollé, ME; Giese, H; Hopkins, CL; Martus, HJ; Hausdorff, JM; Vijg, J (Dec 1997). "Rapid accumulation of genome rearrangements in liver but not in brain of old mice". Nat Genet. 17 (4): 431–4. doi:10.1038/ng1297-431. PMID 9398844.
^ Stuart, GR; Oda, Y; de Boer, JG; Glickman, BW (March 2000). "Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice". Genetics. 154 (3): 1291–300. PMC 1460990. PMID 10757770.
^ Hill, KA; Halangoda, A; Heinmoeller, PW; Gonzalez, K; Chitaphan, C; Longmate, J; Scaringe, WA; Wang, JC; Sommer, SS (Jun 2005). "Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice". Environ Mol Mutagen. 45 (5): 442–54. doi:10.1002/em.20119. PMID 15690342.
^ Narayanan, L; Fritzell, JA; Baker, SM; Liskay, RM; Glazer, PM (Apr 1997). "Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2". Proceedings of the National Academy of Sciences. 94 (7): 3122–7. Bibcode:1997PNAS...94.3122N. doi:10.1073/pnas.94.7.3122. PMC 20332. PMID 9096356.
^ Dollé, ME; Busuttil, RA; Garcia, AM; Wijnhoven, S; van Drunen, E; Niedernhofer, LJ; van der Horst, G; Hoeijmakers, JH; van Steeg, H; Vijg, J (Apr 2006). "Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice". Mutat. Res. 596 (1–2): 22–35. doi:10.1016/j.mrfmmm.2005.11.008. PMID 16472827.
^ Vermulst, M; Bielas, JH; Kujoth, GC; Ladiges, WC; Rabinovitch, PS; Prolla, TA; Loeb, LA (Apr 2007). "Mitochondrial point mutations do not limit the natural lifespan of mice". Nat Genet. 39 (4): 540–3. doi:10.1038/ng1988. PMID 17334366.
^ Harrigan, JA; Wilson, DM; Prasad, R; Opresko, PL; Beck, G; May, A; Wilson, SH; Bohr, VA (Jan 2006). "The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta". Nucleic Acids Res. 34 (2): 745–54. doi:10.1093/nar/gkj475. PMC 1356534. PMID 16449207.
^ Liu, Y; Wang, Y; Rusinol, AE; Sinensky, MS; Liu, J; Shell, SM; Zou, Y (Feb 2008). "Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A". FASEB J. 22 (2): 603–11. doi:10.1096/fj.07-8598com. PMC 3116236. PMID 17848622.
^ Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S (2011). "A dual role for A-type lamins in DNA double-strand break repair". Cell Cycle. 10 (15): 2549–60. doi:10.4161/cc.10.15.16531. PMC 3180193. PMID 21701264.
^ ab Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadiñanos J, López-Otín C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z (2005). "Genomic instability in laminopathy-based premature aging". Nat. Med. 11 (7): 780–5. doi:10.1038/nm1266. PMID 15980864.
^ D'Errico, M; Parlanti, E; Teson, M; Degan, P; Lemma, T; Calcagnile, A; Iavarone, I; Jaruga, P; Ropolo, M; Pedrini, AM; Orioli, D; Frosina, G; Zambruno, G; Dizdaroglu, M; Stefanini, M; Dogliotti, E (Jun 2007). "The role of CSA in the response to oxidative DNA damage in human cells". Oncogene. 26 (30): 4336–43. doi:10.1038/sj.onc.1210232. PMID 17297471.
^ Vogel H, Lim DS, Karsenty G, Finegold M, Hasty P (1999). "Deletion of Ku86 causes early onset of senescence in mice". Proc. Natl. Acad. Sci. U.S.A. 96 (19): 10770–5. Bibcode:1999PNAS...9610770V. doi:10.1073/pnas.96.19.10770. PMC 17958. PMID 10485901.
^ Niedernhofer, LJ; Garinis, GA; Raams, A; Lalai, AS; Robinson, AR; Appeldoorn, E; Odijk, H; Oostendorp, R; Ahmad, A; van Leeuwen, W; Theil, AF; Vermeulen, W; van der Horst, GT; Meinecke, P; Kleijer, WJ; Vijg, J; Jaspers, NG; Hoeijmakers, JH (Dec 2006). "A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis". Nature. 444 (7122): 1038–43. Bibcode:2006Natur.444.1038N. doi:10.1038/nature05456. PMID 17183314.
^ ab Mostoslavsky, R; Chua, KF; Lombard, DB; Pang, WW; Fischer, MR; Gellon, L; Liu, P; Mostoslavsky, G; Franco, S; Murphy, MM; Mills, KD; Patel, P; Hsu, JT; Hong, AL; Ford, E; Cheng, HL; Kennedy, C; Nunez, N; Bronson, R; Frendewey, D; Auerbach, W; Valenzuela, D; Karow, M; Hottiger, MO; Hursting, S; Barrett, JC; Guarente, L; Mulligan, R; Demple, B; Yancopoulos, GD; Alt, FW (Jan 2006). "Genomic instability and aging-like phenotype in the absence of mammalian SIRT6". Cell. 124 (2): 315–29. doi:10.1016/j.cell.2005.11.044. PMID 16439206.
^ ab Li H, Vogel H, Holcomb VB, Gu Y, Hasty P (2007). "Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer". Mol. Cell. Biol. 27 (23): 8205–14. doi:10.1128/MCB.00785-07. PMC 2169178. PMID 17875923.
^ ab Bonsignore LA, Tooley JG, Van Hoose PM, Wang E, Cheng A, Cole MP, Schaner Tooley CE (2015). "NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging". Mech. Ageing Dev. 146–148: 42–52. doi:10.1016/j.mad.2015.03.012. PMC 4457563. PMID 25843235.
^ ab Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, Brown EJ (2007). "Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss". Cell Stem Cell. 1 (1): 113–26. doi:10.1016/j.stem.2007.03.002. PMC 2920603. PMID 18371340.
^ abc Holcomb VB, Vogel H, Hasty P (2007). "Deletion of Ku80 causes early aging independent of chronic inflammation and Rag-1-induced DSBs". Mech. Ageing Dev. 128 (11–12): 601–8. doi:10.1016/j.mad.2007.08.006. PMC 2692937. PMID 17928034.
^ ab Dollé ME, Kuiper RV, Roodbergen M, Robinson J, de Vlugt S, Wijnhoven SW, Beems RB, de la Fonteyne L, de With P, van der Pluijm I, Niedernhofer LJ, Hasty P, Vijg J, Hoeijmakers JH, van Steeg H (2011). "Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice". Pathobiol Aging Age Relat Dis. 1: 7219. doi:10.3402/pba.v1i0.7219. PMC 3417667. PMID 22953029.
^ Musich PR, Zou Y (2011). "DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome". Biochem. Soc. Trans. 39 (6): 1764–9. doi:10.1042/BST20110687. PMC 4271832. PMID 22103522.
^ Park JM, Kang TH (2016). "Transcriptional and Posttranslational Regulation of Nucleotide Excision Repair: The Guardian of the Genome against Ultraviolet Radiation". Int J Mol Sci. 17 (11): 1840. doi:10.3390/ijms17111840. PMC 5133840. PMID 27827925.
^ Espejel S, Martín M, Klatt P, Martín-Caballero J, Flores JM, Blasco MA (2004). "Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice". EMBO Rep. 5 (5): 503–9. doi:10.1038/sj.embor.7400127. PMC 1299048. PMID 15105825.
^ Reiling E, Dollé ME, Youssef SA, Lee M, Nagarajah B, Roodbergen M, de With P, de Bruin A, Hoeijmakers JH, Vijg J, van Steeg H, Hasty P (2014). "The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency". PLoS ONE. 9 (4): e93568. Bibcode:2014PLoSO...993568R. doi:10.1371/journal.pone.0093568. PMC 3989187. PMID 24740260.
^ Peddi P, Loftin CW, Dickey JS, Hair JM, Burns KJ, Aziz K, Francisco DC, Panayiotidis MI, Sedelnikova OA, Bonner WM, Winters TA, Georgakilas AG (2010). "DNA-PKcs deficiency leads to persistence of oxidatively induced clustered DNA lesions in human tumor cells". Free Radic. Biol. Med. 48 (10): 1435–43. doi:10.1016/j.freeradbiomed.2010.02.033. PMC 2901171. PMID 20193758.
^ abcd Gregg SQ, Robinson AR, Niedernhofer LJ (2011). "Physiological consequences of defects in ERCC1-XPF DNA repair endonuclease". DNA Repair (Amst.). 10 (7): 781–91. doi:10.1016/j.dnarep.2011.04.026. PMC 3139823. PMID 21612988.
^ Vermeij WP, Dollé ME, Reiling E, Jaarsma D, Payan-Gomez C, Bombardieri CR, Wu H, Roks AJ, Botter SM, van der Eerden BC, Youssef SA, Kuiper RV, Nagarajah B, van Oostrom CT, Brandt RM, Barnhoorn S, Imholz S, Pennings JL, de Bruin A, Gyenis Á, Pothof J, Vijg J, van Steeg H, Hoeijmakers JH (2016). "Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice". Nature. 537 (7620): 427–431. Bibcode:2016Natur.537..427V. doi:10.1038/nature19329. PMC 5161687. PMID 27556946.
^ Fuss JO, Tainer JA (2011). "XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase". DNA Repair (Amst.). 10 (7): 697–713. doi:10.1016/j.dnarep.2011.04.028. PMC 3234290. PMID 21571596.
^ Tian M, Jones DA, Smith M, Shinkura R, Alt FW (2004). "Deficiency in the nuclease activity of xeroderma pigmentosum G in mice leads to hypersensitivity to UV irradiation". Mol. Cell. Biol. 24 (6): 2237–42. PMC 355871. PMID 14993263.
^ Trego KS, Groesser T, Davalos AR, Parplys AC, Zhao W, Nelson MR, Hlaing A, Shih B, Rydberg B, Pluth JM, Tsai MS, Hoeijmakers JH, Sung P, Wiese C, Campisi J, Cooper PK (2016). "Non-catalytic Roles for XPG with BRCA1 and BRCA2 in Homologous Recombination and Genome Stability". Mol. Cell. 61 (4): 535–46. doi:10.1016/j.molcel.2015.12.026. PMC 4761302. PMID 26833090.
^ Bessho T (1999). "Nucleotide excision repair 3' endonuclease XPG stimulates the activity of base excision repair enzyme thymine glycol DNA glycosylase". Nucleic Acids Res. 27 (4): 979–83. doi:10.1093/nar/27.4.979. PMC 148276. PMID 9927729.
^ Weinfeld M, Xing JZ, Lee J, Leadon SA, Cooper PK, Le XC (2001). "Factors influencing the removal of thymine glycol from DNA in gamma-irradiated human cells". Prog. Nucleic Acid Res. Mol. Biol. 68: 139–49. PMID 11554293.
^ ab Iyama T, Wilson DM (2016). "Elements That Regulate the DNA Damage Response of Proteins Defective in Cockayne Syndrome". J. Mol. Biol. 428 (1): 62–78. doi:10.1016/j.jmb.2015.11.020. PMC 4738086. PMID 26616585.
^ abcd D'Errico M, Pascucci B, Iorio E, Van Houten B, Dogliotti E (2013). "The role of CSA and CSB protein in the oxidative stress response". Mech. Ageing Dev. 134 (5–6): 261–9. doi:10.1016/j.mad.2013.03.006. PMID 23562424.
^ Theil AF, Nonnekens J, Steurer B, Mari PO, de Wit J, Lemaitre C, Marteijn JA, Raams A, Maas A, Vermeij M, Essers J, Hoeijmakers JH, Giglia-Mari G, Vermeulen W (2013). "Disruption of TTDA results in complete nucleotide excision repair deficiency and embryonic lethality". PLoS Genet. 9 (4): e1003431. doi:10.1371/journal.pgen.1003431. PMC 3630102. PMID 23637614.
^ Theil AF, Nonnekens J, Wijgers N, Vermeulen W, Giglia-Mari G (2011). "Slowly progressing nucleotide excision repair in trichothiodystrophy group A patient fibroblasts". Mol. Cell. Biol. 31 (17): 3630–8. doi:10.1128/MCB.01462-10. PMC 3165551. PMID 21730288.
^ Ahmed EA, Vélaz E, Rosemann M, Gilbertz KP, Scherthan H (2017). "DNA repair kinetics in SCID mice Sertoli cells and DNA-PKcs-deficient mouse embryonic fibroblasts". Chromosoma. 126 (2): 287–298. doi:10.1007/s00412-016-0590-9. PMC 5371645. PMID 27136939.
^ Gonzalo S, Kreienkamp R (2016). "Methods to Monitor DNA Repair Defects and Genomic Instability in the Context of a Disrupted Nuclear Lamina". Methods Mol. Biol. 1411: 419–37. doi:10.1007/978-1-4939-3530-7_26. PMC 5044759. PMID 27147057.
^ Cai Q, Fu L, Wang Z, Gan N, Dai X, Wang Y (2014). "α-N-methylation of damaged DNA-binding protein 2 (DDB2) and its function in nucleotide excision repair". J. Biol. Chem. 289 (23): 16046–56. doi:10.1074/jbc.M114.558510. PMC 4047379. PMID 24753253.
^ ab Lu L, Jin W, Wang LL (2017). "Aging in Rothmund-Thomson syndrome and related RECQL4 genetic disorders". Ageing Res. Rev. 33: 30–35. doi:10.1016/j.arr.2016.06.002. PMID 27287744.
^ ab Chalkiadaki A, Guarente L (2015). "The multifaceted functions of sirtuins in cancer". Nat. Rev. Cancer. 15 (10): 608–24. doi:10.1038/nrc3985. PMID 26383140.
^ Vazquez BN, Thackray JK, Simonet NG, Kane-Goldsmith N, Martinez-Redondo P, Nguyen T, Bunting S, Vaquero A, Tischfield JA, Serrano L (2016). "SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair". EMBO J. 35 (14): 1488–503. doi:10.15252/embj.201593499. PMC 4884211. PMID 27225932.
^ Saintigny Y, Makienko K, Swanson C, Emond MJ, Monnat RJ (2002). "Homologous recombination resolution defect in werner syndrome". Mol. Cell. Biol. 22 (20): 6971–8. doi:10.1128/mcb.22.20.6971-6978.2002. PMC 139822. PMID 12242278.
^ Sturzenegger A, Burdova K, Kanagaraj R, Levikova M, Pinto C, Cejka P, Janscak P (2014). "DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells". J. Biol. Chem. 289 (39): 27314–26. doi:10.1074/jbc.M114.578823. PMC 4175362. PMID 25122754.
^ Shamanna RA, Lu H, de Freitas JK, Tian J, Croteau DL, Bohr VA (2016). "WRN regulates pathway choice between classical and alternative non-homologous end joining". Nat Commun. 7: 13785. Bibcode:2016NatCo...713785S. doi:10.1038/ncomms13785. PMC 5150655. PMID 27922005.
^ Das A, Boldogh I, Lee JW, Harrigan JA, Hegde ML, Piotrowski J, de Souza Pinto N, Ramos W, Greenberg MM, Hazra TK, Mitra S, Bohr VA (2007). "The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1". J. Biol. Chem. 282 (36): 26591–602. doi:10.1074/jbc.M703343200. PMID 17611195.
^ Kanagaraj R, Parasuraman P, Mihaljevic B, van Loon B, Burdova K, König C, Furrer A, Bohr VA, Hübscher U, Janscak P (2012). "Involvement of Werner syndrome protein in MUTYH-mediated repair of oxidative DNA damage". Nucleic Acids Res. 40 (17): 8449–59. doi:10.1093/nar/gks648. PMC 3458577. PMID 22753033.
^ Pichierri P, Ammazzalorso F, Bignami M, Franchitto A (2011). "The Werner syndrome protein: linking the replication checkpoint response to genome stability". Aging. 3 (3): 311–8. doi:10.18632/aging.100293. PMC 3091524. PMID 21389352.
^ Rossi ML, Ghosh AK, Bohr VA (2010). "Roles of Werner syndrome protein in protection of genome integrity". DNA Repair (Amst.). 9 (3): 331–44. doi:10.1016/j.dnarep.2009.12.011. PMC 2827637. PMID 20075015.
^ Veith S, Mangerich A (2015). "RecQ helicases and PARP1 team up in maintaining genome integrity". Ageing Res. Rev. 23 (Pt A): 12–28. doi:10.1016/j.arr.2014.12.006. PMID 25555679.
^ Dominick G, Bowman J, Li X, Miller RA, Garcia GG (2017). "mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice". Aging Cell. 16 (1): 52–60. doi:10.1111/acel.12525. PMC 5242303. PMID 27618784.
^ Weiler M, Blaes J, Pusch S, Sahm F, Czabanka M, Luger S, Bunse L, Solecki G, Eichwald V, Jugold M, Hodecker S, Osswald M, Meisner C, Hielscher T, Rübmann P, Pfenning PN, Ronellenfitsch M, Kempf T, Schnölzer M, Abdollahi A, Lang F, Bendszus M, von Deimling A, Winkler F, Weller M, Vajkoczy P, Platten M, Wick W (2014). "mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy". Proc. Natl. Acad. Sci. U.S.A. 111 (1): 409–14. Bibcode:2014PNAS..111..409W. doi:10.1073/pnas.1314469111. PMC 3890826. PMID 24367102.
^ ab De Luca G, Ventura I, Sanghez V, Russo MT, Ajmone-Cat MA, Cacci E, Martire A, Popoli P, Falcone G, Michelini F, Crescenzi M, Degan P, Minghetti L, Bignami M, Calamandrei G (2013). "Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1". Aging Cell. 12 (4): 695–705. doi:10.1111/acel.12094. PMID 23648059.
^ De Luca G, Russo MT, Degan P, Tiveron C, Zijno A, Meccia E, Ventura I, Mattei E, Nakabeppu Y, Crescenzi M, Pepponi R, Pèzzola A, Popoli P, Bignami M (2008). "A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration". PLoS Genet. 4 (11): e1000266. doi:10.1371/journal.pgen.1000266. PMC 2580033. PMID 19023407.
^ Almeida KH, Sobol RW (2007). "A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification". DNA Repair (Amst.). 6 (6): 695–711. doi:10.1016/j.dnarep.2007.01.009. PMC 1995033. PMID 17337257.
^ Pines A, Vrouwe MG, Marteijn JA, Typas D, Luijsterburg MS, Cansoy M, Hensbergen P, Deelder A, de Groot A, Matsumoto S, Sugasawa K, Thoma N, Vermeulen W, Vrieling H, Mullenders L (2012). "PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1". J. Cell Biol. 199 (2): 235–49. doi:10.1083/jcb.201112132. PMC 3471223. PMID 23045548.
^ Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, Iliakis G (2006). "PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways". Nucleic Acids Res. 34 (21): 6170–82. doi:10.1093/nar/gkl840. PMC 1693894. PMID 17088286.
^ Okano S, Lan L, Caldecott KW, Mori T, Yasui A (2003). "Spatial and temporal cellular responses to single-strand breaks in human cells". Mol. Cell. Biol. 23 (11): 3974–81. doi:10.1128/mcb.23.11.3974-3981.2003. PMC 155230. PMID 12748298.
^ Grube K, Bürkle A (Dec 1992). "Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span". Proceedings of the National Academy of Sciences of the United States of America. 89 (24): 11759–63. Bibcode:1992PNAS...8911759G. doi:10.1073/pnas.89.24.11759. PMC 50636. PMID 1465394.
^ Mei Z, Zhang X, Yi J, Huang J, He J, Tao Y (2016). "Sirtuins in metabolism, DNA repair and cancer". J. Exp. Clin. Cancer Res. 35 (1): 182. doi:10.1186/s13046-016-0461-5. PMC 5137222. PMID 27916001.
^ Mercken EM, Mitchell SJ, Martin-Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye-Knudsen M, Palacios HH, Licata JJ, Zhang Y, Becker KG, Khraiwesh H, González-Reyes JA, Villalba JM, Baur JA, Elliott P, Westphal C, Vlasuk GP, Ellis JL, Sinclair DA, Bernier M, de Cabo R (2014). "SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass". Aging Cell. 13 (5): 787–96. doi:10.1111/acel.12220. PMC 4172519. PMID 24931715.
^ Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH, Ward TM, Abulwerdi G, Minor RK, Vlasuk GP, Ellis JL, Sinclair DA, Dawson J, Allison DB, Zhang Y, Becker KG, Bernier M, de Cabo R (2014). "The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet". Cell Rep. 6 (5): 836–43. doi:10.1016/j.celrep.2014.01.031. PMC 4010117. PMID 24582957.
^ Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar-Joseph Z, Cohen HY (2012). "The sirtuin SIRT6 regulates lifespan in male mice". Nature. 483 (7388): 218–21. Bibcode:2012Natur.483..218K. doi:10.1038/nature10815. PMID 22367546.
^ Hart, RW; Setlow, RB (Jun 1974). "Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species". Proceedings of the National Academy of Sciences. 71 (6): 2169–73. Bibcode:1974PNAS...71.2169H. doi:10.1073/pnas.71.6.2169. PMC 388412. PMID 4526202.
^ Bürkle, A; Brabeck, C; Diefenbach, J; Beneke, S (May 2005). "The emerging role of poly(ADP-ribose) polymerase-1 in longevity". Int J Biochem Cell Biol. 37 (5): 1043–53. doi:10.1016/j.biocel.2004.10.006. PMID 15743677.
^ MacRae SL, Croken MM, Calder RB, Aliper A, Milholland B, White RR, Zhavoronkov A, Gladyshev VN, Seluanov A, Gorbunova V, Zhang ZD, Vijg J (2015). "DNA repair in species with extreme lifespan differences". Aging. 7 (12): 1171–84. doi:10.18632/aging.100866. PMC 4712340. PMID 26729707.
^ Lehmann, Gilad; Budovsky, Arie; Muradian, K. Muradian; Fraifeld, Vadim E. (2006). "Mitochondrial genome anatomy and species-specific lifespan". Rejuvenation Res. 9 (2): 223–226. doi:10.1089/rej.2006.9.223. PMID 16706648.
^ Lehmann, Gilad; Segal, Elena; Muradian, K. Muradian; Fraifeld, Vadim E. (2008). "Do mitochondrial DNA and metabolic rate complement each other in determination of the mammalian maximum longevity?". Rejuvenation Res. 11 (2): 409–417. doi:10.1089/rej.2008.0676. PMID 18442324.
^ Lehmann, Gilad; Muradian, K. Muradian; Fraifeld, Vadim E. (2013). "Telomere length and body temperature-independent determinants of mammalian longevity?". Front Genet. 4 (111). doi:10.3389/fgene.2013.00111. PMC 3680702. PMID 23781235.
^ Toren, Dmitri; Barzilay, Thomer; Tacutu, Robi; Lehmann, Gilad; Muradian, Khachik K.; Fraifeld, Vadim E. (2016). "MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity". Nucleic Acids Res. 44 (D1): D1262–5. doi:10.1093/nar/gkv1187. PMC 4702847. PMID 26590258.
^ Muiras ML, Müller M, Schächter F, Bürkle A (1998). "Increased poly(ADP-ribose) polymerase activity in lymphoblastoid cell lines from centenarians". J. Mol. Med. 76 (5): 346–54. doi:10.1007/s001090050226. PMID 9587069.
^ Wagner KH, Cameron-Smith D, Wessner B, Franzke B (2 June 2016). "Biomarkers of aging: from function to molecular biology". Nutrients. 8 (6): 338. doi:10.3390/nu8060338. PMC 4924179. PMID 27271660.
^ ab Jirge PR (Apr–Jun 2016). "Poor ovarian reserve". J Hum Reprod Sci. 9 (2): 63–9. doi:10.4103/0974-1208.183514. PMC 4915288. PMID 27382229.
^ Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA (2008). "A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause". Hum. Reprod. 23 (3): 699–708. doi:10.1093/humrep/dem408. PMID 18192670.
^ ab Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K (2013). "Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans". Sci Transl Med. 5 (172): 172ra21. doi:10.1126/scitranslmed.3004925. PMC 5130338. PMID 23408054.
^ Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A (2006). "Premature menopause in patients with BRCA1 gene mutation". Breast Cancer Res. Treat. 100 (1): 59–63. doi:10.1007/s10549-006-9220-1. PMID 16773440.
^ Day FR, Ruth KS, Thompson DJ, et al. (2015). "Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair". Nat. Genet. 47 (11): 1294–303. doi:10.1038/ng.3412. PMC 4661791. PMID 26414677.
^ Wu H, Roks AJ (2014). "Genomic instability and vascular aging: a focus on nucleotide excision repair". Trends Cardiovasc. Med. 24 (2): 61–8. doi:10.1016/j.tcm.2013.06.005. PMID 23953979.
^ ab Bautista-Niño PK, Portilla-Fernandez E, Vaughan DE, Danser AH, Roks AJ (2016). "DNA damage: a main determinant of vascular aging". Int J Mol Sci. 17 (5): 748. doi:10.3390/ijms17050748. PMC 4881569. PMID 27213333.
^ Shah AV, Bennett MR (2017). "DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature". Eur. J. Pharmacol. doi:10.1016/j.ejphar.2017.03.050. PMID 28347738.
^ ab Uryga AK, Bennett MR (15 April 2016). "Ageing induced vascular smooth muscle cell senescence in atherosclerosis". J Physiol. 594 (8): 2115–24. doi:10.1113/JP270923. PMC 4933105. PMID 26174609.
^ ab https://dx.doi.org/10.1016/j.mrrev.2017.09.005
^ Chiba T, Marusawa H, Ushijima T (2012). "Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation". Gastroenterology. 143 (3): 550–563. doi:10.1053/j.gastro.2012.07.009. PMID 22796521.
^ Nishida N, Kudo M (2014). "Alteration of Epigenetic Profile in Human Hepatocellular Carcinoma and Its Clinical Implications". Liver Cancer. 3 (3–4): 417–27. doi:10.1159/000343860. PMC 4531427. PMID 26280003.
^ Deaton AM, Bird A (May 2011). "CpG islands and the regulation of transcription". Genes Dev. 25 (10): 1010–22. doi:10.1101/gad.2037511. PMC 3093116. PMID 21576262.
^ Jones MJ, Goodman SJ, Kobor MS (December 2015). "DNA methylation and healthy human aging". Aging Cell. 14 (6): 924–32. doi:10.1111/acel.12349. PMC 4693469. PMID 25913071.
