DNA damage theory of aging

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The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. 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] [4]

Contents

Several review articles have shown that deficient DNA repair, allowing greater accumulation of DNA damage, causes premature aging; and that increased DNA repair facilitates greater longevity, e.g. [5] [6] 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. [7] Human population studies show that single-nucleotide polymorphisms in DNA repair genes, causing up-regulation of their expression, correlate with increases in longevity. [8] Lombard et al. compiled a lengthy list of mouse mutational models with pathologic features of premature aging, all caused by different DNA repair defects. [9] 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. [10] [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. [11] 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. [12] 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. [13]

DNA damage and mutation

8-Hydroxydeoxyguanosine 8-Oxo-2'-deoxyguanosine.svg
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 strand in DNA as a template or an 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 described in the next section.

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. [14] By the early 1980s there was significant experimental support for this idea in the literature. [15] 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. [16] [17] [13] [18] [19]

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." [20] [21] [22] [23] [24]

Age-associated accumulation of DNA damage and changes 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. [25] The loss of expression of specific genes can be detected at both the mRNA level and protein level.

Other form of age-associated changes in gene expression is increased transcriptional variability, that was found first in a selected panel of genes in heart cells [26] and, more recently, in the whole transcriptomes of immune cells, [27] and human pancreas cells. [28]

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. [29] 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. [29] ). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human. [13]

Rutten et al. [30] 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. [31] Sen et al. [32] 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). [33] Wolf et al. [34] 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 to 97 years, 8-OHdG accumulates in the brain. [35]

Lu et al. [36] 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. [36] In cultured human neurons, these gene promoters are selectively damaged by oxidative stress. Thus Lu et al. [36] 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. [29] Hamilton et al. [37] 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. [38] 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%. [39] [40] 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 2005, Piec et al. [41] 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. [29] For instance, Helbock et al. [42] 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.

One or two months after inducing DNA double-strand breaks in the livers of young mice, the mice showed multiple symptoms of aging similar to those seen in untreated livers of normally aged control mice. [43]

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). [29] For instance Hashimoto et al. [44] 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. [45] Sharpless and Depinho reviewed evidence that hematopoietic stem cells, as well as stem cells in other tissues, undergo intrinsic aging. [46] 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. [2]

A key aspect of hair loss with age is the aging of the hair follicle. [47] 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. [48]

Mutation theories of aging

A related theory is that mutation, as distinct from DNA damage, is the primary cause of aging. A comparison of somatic mutation rate across several mammal species found that the total number of accumulated mutations at the end of lifespan was roughly equal across a broad range of lifespans. [49] The authors state that this strong relationship between somatic mutation rate and lifespan across different mammalian species suggests that evolution may constrain somatic mutation rates, perhaps by selection acting on different DNA repair pathways.[ citation needed ]

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. [50] [51] [52] 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. [53] On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation. [54]

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. [55] 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. [37] More recently, Wolf et al. [34] 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. [56] ).

Huchinson–Gilford 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. [57] 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. [58] Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and are more sensitive to DNA damaging agents. [59]

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. [60]

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 Ku bound to DNA.png
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. [61] [62] [63] ) In particular, mutant mice defective in Ku70, or Ku80, or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging. [64] 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. [65] [66] [67] [68] ). If a DNA repair protein is deficient, unrepaired DNA damages tend to accumulate. [69] 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.

Table 1. DNA repair proteins that, when deficient, cause features of accelerated aging (segmental progeria).
ProteinPathwayDescription
ATR Nucleotide excision repair [70] 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 [66]
DNA-PKcs Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; [71] [72] higher level of DNA damage persistence [73]
ERCC1 Nucleotide excision repair, Interstrand cross link repair [74] deficient transcription coupled NER with time-dependent accumulation of transcription-blocking damages; [75] mouse life span reduced from 2.5 years to 5 months; [68] Ercc1−/− mice are leukopenic and thrombocytopenic, and there is extensive adipose transformation of the bone marrow, hallmark features of normal aging in mice [74]
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 [76]
ERCC4 (XPF) Nucleotide excision repair, Interstrand cross link repair, Single-strand annealing, Microhomology-mediated end joining [74] 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 [74]
ERCC5 (XPG) Nucleotide excision repair, [77] Homologous recombinational repair, [78] Base excision repair [79] [80] 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, [81] deficient transcription coupled NER with accumulation of unrepaired DNA damages, [82] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines [82]
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, [81] deficient transcription coupled NER with accumulation of unrepaired DNA damages, [82] also defective repair of oxidatively generated DNA damages including 8-oxoguanine, 5-hydroxycytosine and cyclopurines [82]
GTF2H5 (TTDA) Nucleotide excision repair deficiency causes trichothiodystrophy (TTD) a premature-ageing and neuroectodermal disease; humans with GTF2H5 mutations have a partially inactivated protein [83] with retarded repair of 6-4-photoproducts [84]
Ku70 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; [67] persistent foci of DNA double-strand break repair proteins [85]
Ku80 Non-homologous end joining shorter lifespan, earlier onset of aging related pathologies; [64] defective repair of spontaneous DNA damage [67]
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 [86]
NRMT1 Nucleotide excision repair [87] mutation in NRMT1 causes decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration [65]
RECQL4 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining [88] mutations in RECQL4 cause Rothmund–Thomson syndrome, with alopecia, sparse eyebrows and lashes, cataracts and osteoporosis [88]
SIRT6 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining [89] SIRT6-deficient mice develop profound lymphopenia, loss of subcutaneous fat and lordokyphosis, and these defects overlap with aging-associated degenerative processes [63]
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 [90]
Werner syndrome helicase Homologous recombination, [91] [92] Non-homologous end joining, [93] Base excision repair, [94] [95] Replication arrest recovery [96] shorter lifespan, earlier onset of aging related pathologies, genome instability [97] [98]
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 [59]

Increased DNA repair and extended longevity

Table 2 lists DNA repair proteins whose increased expression is connected to extended longevity.

Table 2. DNA repair proteins that, when highly- or over-expressed, cause (or are associated with) extended longevity.
ProteinPathwayDescription
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 [99] [100]
NUDT1 (MTH1)Oxidized nucleotide removaldegrades 8-oxodGTP; prevents the age-dependent accumulation of DNA 8-oxoguanine [101] A transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed, [102] giving over-expression of hMTH1, increases the median lifespan of mice to 914 days vs. 790 days for wild-type mice. [101] Mice with over-expressed hMTH1 have behavioral changes of reduced anxiety and enhanced investigation of environmental and social cues
PARP1 Base excision repair, [103] Nucleotide excision repair, [104] Microhomology-mediated end joining, [105] Single-strand break repair [106] 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. [107]
SIRT1 Nucleotide excision repair, Homologous recombination, Non-homologous end joining [108] 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 [109] [110]
SIRT6 Base excision repair, Nucleotide excision repair, Homologous recombination, Non-homologous end joining [89] male, but not female, transgenic mice overexpressing Sirt6 have a significantly longer lifespan than wild-type mice [111]

Lifespan in different mammalian species

DNA repair capacity

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, [112] 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. [113] 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. [114] 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. [115] [116] [117] [118] The mitochondrial DNA base composition is thought 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).

DNA damage accumulation and repair decline

The rate of accumulation of DNA damage (double-strand breaks) in the leukocytes of dolphins, goats, reindeer, American flamingos, and griffon vultures was compared to the longevity of individuals of these different species. [119] The species with longer lifespans were found to have slower accumulation of DNA damage, a finding consistent with the DNA damage theory of aging. [119] In healthy humans after age 50, endogenous DNA single- and double-strand breaks increase linearly, and other forms of DNA damage also increase with age in blood mononuclear cells. [120] Also, after age 50 DNA repair capability decreases with age. [120]

In mice, the DNA repair process of non-homologous end-joining that repairs DNA double strand breaks, declines in efficiency from 1.8-3.8-fold, depending on the specific tissue, when 5 month old animals are compared to 24 month old animals. [121] A study of fibroblast cells from humans varying in age from 16-75 years showed that the efficiency and fidelity of non-homologous end joining, and the efficiency of homologous recombinational DNA repair decline with age leading to increased sensitivity to ionizing radiation in older individuals. [122] In middle aged human adults, oxidative DNA damage was found to be greater among individuals who were both frail and living in poverty. [123]

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). [124] [ 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. [10] [125]

Among centenarians, those with the most severe cognitive impairment have the lowest activity of the central DNA repair enzyme apurinic/apyrimidinc (AP) endonuclease 1. [126] AP endonuclease I is employed in the DNA base excision repair pathway and its main role is the repair of damaged or mismatched nucleotides in DNA.

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, [127] 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, [128] [127] 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.

BRCA1 and BRCA2 are homologous recombination repair genes. The role of declining ATM-Mediated DNA double strand DNA break (DSB) repair in oocyte aging was first proposed by Kutluk Oktay, MD, PhD based on his observations that women with BRCA mutations produced fewer oocytes in response to ovarian stimulation repair. [129] [130] [131] His laboratory has further studied this hypothesis and provided an explanation for the decline in ovarian reserve with age. [132] 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. [132] from Oktay Laboratory 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 as further explained by Turan and Oktay. [133]

Women with an inherited mutation in the DNA repair gene BRCA1 undergo menopause prematurely, [134] 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. [135] 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. [136] [137] [138]

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. [139] DNA strand breaks also increased in atherosclerotic plaques, thus linking DNA damage to plaque formation. [139]

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. [137] 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 [140] [141] [142] 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 [140] 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. [143] 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. [144] 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

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<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

<span class="mw-page-title-main">Nucleotide excision repair</span> DNA repair mechanism

Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals, radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucleotide excision repair (NER), base excision repair (BER), and DNA mismatch repair (MMR). While the BER pathway can recognize specific non-bulky lesions in DNA, it can correct only damaged bases that are removed by specific glycosylases. Similarly, the MMR pathway only targets mismatched Watson-Crick base pairs.

<span class="mw-page-title-main">Base excision repair</span> DNA repair process

Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.

<span class="mw-page-title-main">MUTYH</span> Protein-coding gene in the species Homo sapiens

MUTYH is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.

DNA oxidation is the process of oxidative damage of deoxyribonucleic acid. As described in detail by Burrows et al., 8-oxo-2'-deoxyguanosine (8-oxo-dG) is the most common oxidative lesion observed in duplex DNA because guanine has a lower one-electron reduction potential than the other nucleosides in DNA. The one electron reduction potentials of the nucleosides are guanine 1.29, adenine 1.42, cytosine 1.6 and thymine 1.7. About 1 in 40,000 guanines in the genome are present as 8-oxo-dG under normal conditions. This means that >30,000 8-oxo-dGs may exist at any given time in the genome of a human cell. Another product of DNA oxidation is 8-oxo-dA. 8-oxo-dA occurs at about 1/10 the frequency of 8-oxo-dG. The reduction potential of guanine may be reduced by as much as 50%, depending on the particular neighboring nucleosides stacked next to it within DNA.

Cell damage is a variety of changes of stress that a cell suffers due to external as well as internal environmental changes. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Cell damage can be reversible or irreversible. Depending on the extent of injury, the cellular response may be adaptive and where possible, homeostasis is restored. Cell death occurs when the severity of the injury exceeds the cell's ability to repair itself. Cell death is relative to both the length of exposure to a harmful stimulus and the severity of the damage caused. Cell death may occur by necrosis or apoptosis.

A DNA repair-deficiency disorder is a medical condition due to reduced functionality of DNA repair.

<span class="mw-page-title-main">ERCC2</span> Mammalian protein found in humans

TFIIH subunit XPD is a protein that in humans is encoded by the ERCC2 gene. It is a component of the general transcription and DNA repair factor IIH (TFIIH) core complex involved in transcription-coupled nucleotide excision repair.

<span class="mw-page-title-main">XRCC1</span> Protein

DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the XRCC1 gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III.

<span class="mw-page-title-main">Oxoguanine glycosylase</span> DNA glycosylase enzyme

8-Oxoguanine glycosylase, also known as OGG1, is a DNA glycosylase enzyme that, in humans, is encoded by the OGG1 gene. It is involved in base excision repair. It is found in bacterial, archaeal and eukaryotic species.

<span class="mw-page-title-main">ERCC1</span> Protein-coding gene in the species Homo sapiens

DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ERCC1 gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.

<span class="mw-page-title-main">DNA polymerase beta</span> Protein-coding gene in the species Homo sapiens

DNA polymerase beta, also known as POLB, is an enzyme present in eukaryotes. In humans, it is encoded by the POLB gene.

<span class="mw-page-title-main">ERCC6</span> Gene of the species Homo sapiens

DNA excision repair protein ERCC-6 is a protein that in humans is encoded by the ERCC6 gene. The ERCC6 gene is located on the long arm of chromosome 10 at position 11.23.

<span class="mw-page-title-main">ERCC5</span> Protein-coding gene in the species Homo sapiens

DNA repair protein complementing XP-G cells is a protein that in humans is encoded by the ERCC5 gene.

<span class="mw-page-title-main">8-Oxo-2'-deoxyguanosine</span> Chemical compound

8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.

<span class="mw-page-title-main">Thymine glycol</span> Chemical compound

Thymine glycol (5,6-dihydroxy-5,6-dihydrothymine) is one of the principal DNA lesions that can be induced by oxidation and ionizing radiation.

References

  1. ↑ Best, BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research. 12 (3): 199–208. CiteSeerX   10.1.1.318.738 . doi:10.1089/rej.2009.0847. PMID   19594328. Archived from the original (PDF) on 2017-11-15. Retrieved 2009-08-04.
  2. 1 2 3 4 5 Freitas AA, de Magalhães JP (2011). "A review and appraisal of the DNA damage theory of ageing". Mutation Research . 728 (1–2): 12–22. Bibcode:2011MRRMR.728...12F. doi:10.1016/j.mrrev.2011.05.001. PMID   21600302.
  3. ↑ Burhans WC, Weinberger M (2007). "DNA replication stress, genome instability and aging". Nucleic Acids Research . 35 (22): 7545–56. doi:10.1093/nar/gkm1059. PMC   2190710 . PMID   18055498.
  4. ↑ Ou HL, Schumacher B (2018). "DNA damage responses and p53 in the aging process". Blood . 131 (5): 488–495. doi:10.1182/blood-2017-07-746396. PMC   6839964 . PMID   29141944.
  5. ↑ Vijg, J. (2021). "From DNA damage to mutations: All roads lead to aging". Ageing Research Reviews. 68: 101316. doi:10.1016/j.arr.2021.101316. PMC   10018438 . PMID   33711511.
  6. ↑ Niedernhofer, L. J.; Gurkar, A. U.; Wang, Y.; Vijg, J.; Hoeijmakers JHJ; Robbins, P. D. (2018). "Nuclear Genomic Instability and Aging". Annual Review of Biochemistry. 87: 295–322. doi: 10.1146/annurev-biochem-062917-012239 . PMID   29925262. S2CID   49343005.
  7. ↑ Hoeijmakers JH (2009). "DNA damage, aging, and cancer". N. Engl. J. Med. 361 (15): 1475–85. doi:10.1056/NEJMra0804615. PMID   19812404.
  8. ↑ 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.
  9. ↑ 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. S2CID   18469405.
  10. 1 2 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". Rejuvenation Res. 10 (2): 191–204. doi:10.1089/rej.2006.0514. PMID   17518695.
  11. ↑ Karanjawala ZE, Lieber MR (June 2004). "DNA damage and aging". Mech Ageing Dev. 125 (6): 405–16. doi:10.1016/j.mad.2004.04.003. PMID   15272504.
  12. ↑ 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.
  13. 1 2 3 Holmes GE, Bernstein C, Bernstein H (September 1992). "Oxidative and other DNA damages as the basis of aging: a review". Mutat Res. 275 (3–6): 305–15. doi:10.1016/0921-8734(92)90034-m. PMID   1383772.
  14. ↑ Alexander, P. (1967). The role of DNA lesions in the processes leading to aging in mice. Symp Soc Exp Biol. Vol. 21. pp. 29–50. PMID   4860956.
  15. ↑ Gensler, H. L.; Bernstein, H. (September 1981). "DNA damage as the primary cause of aging". Q Rev Biol. 56 (3): 279–303. doi:10.1086/412317. PMID   7031747. S2CID   20822805.
  16. ↑ Bernstein, C.; Bernstein, H. (1991). Aging, Sex, and DNA Repair. San Diego: Academic Press. ISBN   978-0-12-092860-6.
  17. ↑ Ames, B. N.; Gold, L. S. (1991). "Endogenous mutagens and the causes of aging and cancer". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 250 (1–2): 3–16. Bibcode:1991MRFMM.250....3A. doi:10.1016/0027-5107(91)90157-j. PMID   1944345.
  18. ↑ Rao, K. S.; Loeb, L. A. (September 1992). "DNA damage and repair in brain: relationship to aging". Mutation Research/DNAging. 275 (3–6): 317–329. doi:10.1016/0921-8734(92)90035-N. PMID   1383773.
  19. ↑ Ames, B. N.; Shigenaga, M. K.; Hagen, T. M. (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.
  20. ↑ Acharya, P. V. (1972). "The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides". Johns Hopkins Med. J. Suppl. (1): 254–260. PMID   5055816.
  21. ↑ Acharya, P. V.; Ashman, S. M.; Bjorksten, J (1972). "The isolation and partial characterization of age-correlated oligo-deoxyribo-ribo nucleo peptides". Finska Kemists Medd. 81 (3).
  22. ↑ Acharya, P. V. N. (June 19, 1971). Isolation and Partial Characterization of Age-Correlated Oligo-nucleotides with Covalently Bound Peptides. 14th Nordic Congress. Umeå, Sweden.
  23. ↑ Acharya, P. V. N. (July 1–7, 1973). DNA-damage: The Cause of Aging. Ninth International Congress of Biochemistry. Stockholm.
  24. ↑ Acharya, P. V. N. (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.
  25. ↑ 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. S2CID   9934178.
  26. ↑ Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dollé ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J (June 2006). "Increased cell-to-cell variation in gene expression in ageing mouse heart". Nature. 441 (7096): 1011–4. doi:10.1038/nature04844. PMID   16791200.
  27. ↑ Martinez-Jimenez CP, Eling N, Chen HC, Vallejos CA, Kolodziejczyk AA, Connor F, Stojic L, Rayner TF, Stubbington MJ, Teichmann SA, de la Roche M, Marioni JC, Odom DT (March 2017). "Aging increases cell-to-cell transcriptional variability upon immune stimulation". Science. 355 (6332): 1433–6. doi:10.1126/science.aah4115. PMC   5405862 . PMID   28360329.
  28. ↑ Enge M, Arda HE, Mignardi M, Beausang J, Bottino R, Kim SK, Quake SR (October 2017). "Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Aging and Somatic Mutation Patterns". Cell. 171 (2): 321–330.e14. doi:10.1016/j.cell.2017.09.004. PMC   6047899 . PMID   28965763.
  29. 1 2 3 4 5 Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). "1. Cancer and aging as consequences of un-repaired DNA damage". In Kimura H, Suzuki A (eds.). New Research on DNA Damages. Nova Science. pp. 1–47. ISBN   978-1-60456-581-2. OCLC   213848806.
  30. ↑ 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. S2CID   14620944.
  31. ↑ 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. S2CID   42442582.
  32. ↑ 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. S2CID   23610941.
  33. ↑ 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. S2CID   22466782.
  34. 1 2 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. S2CID   23752647.
  35. ↑ 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. S2CID   25479410.
  36. 1 2 3 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. S2CID   1867993.
  37. 1 2 Hamilton, M. L.; Van Remmen, H.; Drake, J. A.; Yang, H.; Guo, Z. M.; Kewitt, K.; Walter, C. A.; Richardson, A. (August 2001). "Does oxidative damage to DNA increase with age?". Proceedings of the National Academy of Sciences of the United States of America. 98 (18): 10469–74. Bibcode:2001PNAS...9810469H. doi: 10.1073/pnas.171202698 . PMC   56984 . PMID   11517304.
  38. ↑ Mecocci, P.; Fanó, G.; Fulle, S.; MacGarvey, U.; Shinobu, L.; Polidori, M. C.; Cherubini, A; Vecchiet, J.; Senin, U.; Beal, M. F. (February 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.
  39. ↑ Schriner, S. E.; Linford, NJ; Martin, G. M.; Treuting, P.; Ogburn, C. E.; Emond, M.; Coskun, P. E.; Ladiges, W.; Wolf, N.; Van Remmen, H.; Wallace, D. C.; Rabinovitch, P. S. (June 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. S2CID   38568666.
  40. ↑ Linford, N. J.; Schriner, S. E.; Rabinovitch, P. S. (March 2006). "Oxidative damage and aging: spotlight on mitochondria". Cancer Res. 66 (5): 2497–9. doi: 10.1158/0008-5472.CAN-05-3163 . PMID   16510562.
  41. ↑ Piec, I.; Listrat, A.; Alliot, J.; Chambon, C.; Taylor, R. G.; Bechet, D. (July 2005). "Differential proteome analysis of aging in rat skeletal muscle". FASEB J. 19 (9): 1143–5. doi: 10.1096/fj.04-3084fje . PMID   15831715. S2CID   33187815.
  42. ↑ Helbock, HJ; Beckman, KB; Shigenaga, MK (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.
  43. ↑ White RR, Milholland B, de Bruin A, Curran S, Laberge RM, van Steeg H, Campisi J, Maslov AY, Vijg J (April 2015). "Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing". Nat Commun. 6: 6790. doi:10.1038/ncomms7790. PMC   4394211 . PMID   25858675.
  44. ↑ 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.
  45. ↑ 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. S2CID   4416445.
  46. ↑ 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. S2CID   36305591.
  47. ↑ 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.
  48. ↑ 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. S2CID   5078019.
  49. ↑ Cagan, Alex; Baez-Ortega, Adrian; Brzozowska, Natalia; Abascal, Federico; Coorens, Tim H. H.; Sanders, Mathijs A.; Lawson, Andrew R. J.; Harvey, Luke M. R.; Bhosle, Shriram; Jones, David; Alcantara, Raul E. (April 2022). "Somatic mutation rates scale with lifespan across mammals". Nature. 604 (7906): 517–524. Bibcode:2022Natur.604..517C. doi:10.1038/s41586-022-04618-z. ISSN   1476-4687. PMC   9021023 . PMID   35418684.
  50. ↑ 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. S2CID   20773771.
  51. ↑ 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. doi:10.1093/genetics/154.3.1291. PMC   1460990 . PMID   10757770.
  52. ↑ 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. Bibcode:2005EnvMM..45..442H. doi:10.1002/em.20119. PMID   15690342. S2CID   32204458.
  53. ↑ 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.
  54. ↑ 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. Bibcode:2006MRFMM.596...22D. doi:10.1016/j.mrfmmm.2005.11.008. PMID   16472827.
  55. ↑ 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. S2CID   291780.
  56. ↑ 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.
  57. ↑ 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.
  58. ↑ 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.
  59. 1 2 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. S2CID   11798376.
  60. ↑ 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.
  61. ↑ 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.
  62. ↑ 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. S2CID   4358515.
  63. 1 2 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. S2CID   18517518.
  64. 1 2 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.
  65. 1 2 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.
  66. 1 2 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.
  67. 1 2 3 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.
  68. 1 2 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.
  69. ↑ 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.
  70. ↑ 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.
  71. ↑ 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.
  72. ↑ 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.
  73. ↑ 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.
  74. 1 2 3 4 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.
  75. ↑ 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.
  76. ↑ 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.
  77. ↑ 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. doi:10.1128/MCB.24.6.2237-2242.2004. PMC   355871 . PMID   14993263.
  78. ↑ 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.
  79. ↑ 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.
  80. ↑ Weinfeld M, Xing JZ, Lee J, Leadon SA, Cooper PK, Le XC (2001). "Factors influencing the removal of thymine glycol from DNA in γ-irradiated human cells". Base Excision Repair. Progress in Nucleic Acid Research and Molecular Biology. Vol. 68. pp. 139–49. doi:10.1016/S0079-6603(01)68096-6. ISBN   978-0-12-540068-8. PMID   11554293.
  81. 1 2 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.
  82. 1 2 3 4 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. S2CID   25146054.
  83. ↑ 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.
  84. ↑ 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.
  85. ↑ 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.
  86. ↑ Gonzalo S, Kreienkamp R (2016). "Methods to Monitor DNA Repair Defects and Genomic Instability in the Context of a Disrupted Nuclear Lamina". The Nuclear Envelope. Methods in Molecular Biology. Vol. 1411. pp. 419–37. doi:10.1007/978-1-4939-3530-7_26. ISBN   978-1-4939-3528-4. PMC   5044759 . PMID   27147057.
  87. ↑ 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.
  88. 1 2 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. S2CID   28321025.
  89. 1 2 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. S2CID   3195442.
  90. ↑ 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.
  91. ↑ 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.
  92. ↑ 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.
  93. ↑ 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.
  94. ↑ 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.
  95. ↑ 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.
  96. ↑ 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.
  97. ↑ 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.
  98. ↑ 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. S2CID   29498397.
  99. ↑ 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.
  100. ↑ 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.
  101. 1 2 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. S2CID   43503856.
  102. ↑ 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.
  103. ↑ 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.
  104. ↑ 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.
  105. ↑ 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.
  106. ↑ 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.
  107. ↑ 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.
  108. ↑ 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.
  109. ↑ 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.
  110. ↑ 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.
  111. ↑ 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. S2CID   4417564.
  112. ↑ 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.
  113. ↑ 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.
  114. ↑ 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.
  115. ↑ Lehmann, Gilad; Budovsky, Arie; Muradian, K. Muradian; Fraifeld, Vadim E. (2006). "Mitochondrial genome anatomy and species-specific lifespan". Rejuvenation Res. 9 (2): 223–6. doi:10.1089/rej.2006.9.223. PMID   16706648.
  116. ↑ 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.
  117. ↑ Lehmann, Gilad; Muradian, K. Muradian; Fraifeld, Vadim E. (2013). "Telomere length and body temperature-independent determinants of mammalian longevity?". Front Genet. 4 (111): 111. doi: 10.3389/fgene.2013.00111 . PMC   3680702 . PMID   23781235.
  118. ↑ 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.
  119. 1 2 Whittemore K, Martínez-Nevado E, Blasco MA (November 2019). "Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals". Aging (Albany NY). 11 (21): 9829–45. doi:10.18632/aging.102430. PMC   6874430 . PMID   31730540.
  120. 1 2 Vlachogiannis NI, Ntouros PA, Pappa M, Kravvariti E, Kostaki EG, Fragoulis GE, Papanikolaou C, Mavroeidi D, Bournia VK, Panopoulos S, Laskari K, Arida A, Gorgoulis VG, Tektonidou MG, Paraskevis D, Sfikakis PP, Souliotis VL (April 2023). "Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age". Int J Mol Sci. 24 (8): 7148. doi: 10.3390/ijms24087148 . PMC   10138488 . PMID   37108309.
  121. ↑ Vaidya A, Mao Z, Tian X, Spencer B, Seluanov A, Gorbunova V (July 2014). "Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age". PLOS Genet. 10 (7): e1004511. doi: 10.1371/journal.pgen.1004511 . PMC   4102425 . PMID   25033455.
  122. ↑ Li Z, Zhang W, Chen Y, Guo W, Zhang J, Tang H, Xu Z, Zhang H, Tao Y, Wang F, Jiang Y, Sun FL, Mao Z (November 2016). "Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans". Cell Death Differ. 23 (11): 1765–77. doi:10.1038/cdd.2016.65. PMC   5071568 . PMID   27391797.
  123. ↑ Smith JT, Noren Hooten N, Mode NA, Zonderman AB, Ezike N, Kaushal S, Evans MK (September 2023). "Frailty, sex, and poverty are associated with DNA damage and repair in frail, middle-aged urban adults". DNA Repair (Amst). 129: 103530. doi:10.1016/j.dnarep.2023.103530. PMC   10807508 . PMID   37437502.
  124. ↑ 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. S2CID   24616650.
  125. ↑ 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.
  126. ↑ Sanchez-Roman I, Ferrando B, Holst CM, Mengel-From J, Rasmussen SH, Thinggaard M, Bohr VA, Christensen K, Stevnsner T (February 2022). "Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians". Geroscience. 44 (1): 103–125. doi:10.1007/s11357-021-00502-2. PMC   8810979 . PMID   34966960.
  127. 1 2 Jirge PR (Apr–Jun 2016). "Poor ovarian reserve". Journal of Human Reproductive Sciences. 9 (2): 63–9. doi: 10.4103/0974-1208.183514 . PMC   4915288 . PMID   27382229.
  128. ↑ 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.
  129. ↑ Oktay, Kutluk; Kim, Ja Yeon; Barad, David; Babayev, Samir N. (2010-01-10). "Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks". Journal of Clinical Oncology. 28 (2): 240–4. doi:10.1200/JCO.2009.24.2057. ISSN   1527-7755. PMC   3040011 . PMID   19996028.
  130. ↑ Oktay, Kutluk; Turan, Volkan; Titus, Shiny; Stobezki, Robert; Liu, Lin (September 2015). "BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging". Biology of Reproduction. 93 (3): 67. doi:10.1095/biolreprod.115.132290. ISSN   0006-3363. PMC   4710189 . PMID   26224004.
  131. ↑ Lin, Wayne; Titus, Shiny; Moy, Fred; Ginsburg, Elizabeth S.; Oktay, Kutluk (October 1, 2017). "Ovarian Aging in Women With BRCA Germline Mutations". The Journal of Clinical Endocrinology and Metabolism. 102 (10): 3839–47. doi:10.1210/jc.2017-00765. ISSN   1945-7197. PMC   5630253 . PMID   28938488.
  132. 1 2 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.
  133. ↑ Turan, Volkan; Oktay, Kutluk (2020-01-01). "BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging". Human Reproduction Update. 26 (1): 43–57. doi:10.1093/humupd/dmz043. ISSN   1355-4786. PMC   6935693 . PMID   31822904.
  134. ↑ 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. S2CID   19572648.
  135. ↑ 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.
  136. ↑ 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.
  137. 1 2 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.
  138. ↑ Shah AV, Bennett MR (2017). "DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature". Eur. J. Pharmacol. 816: 116–128. doi:10.1016/j.ejphar.2017.03.050. PMID   28347738. S2CID   1034518.
  139. 1 2 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.
  140. 1 2 Ding, Ning; Maiuri, Ashley R.; o'Hagan, Heather M. (2019). "The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases". Mutation Research/Reviews in Mutation Research. 780: 69–81. Bibcode:2019MRRMR.780...69D. doi:10.1016/j.mrrev.2017.09.005. PMC   6690501 . PMID   31395351.
  141. ↑ 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. hdl: 2433/160134 . PMID   22796521. S2CID   206226588.
  142. ↑ 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.
  143. ↑ 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.
  144. ↑ 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.
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