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).
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. Human populations studies show that single-nucleotide polymorphisms in DNA repair genes, causing up-regulation of their expression, correlate with increases in longevity. Lombard et al. compiled a lengthy list of mouse mutational models with pathologic features of premature aging, all caused by different DNA repair defects. 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. 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. 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.
In humans and other mammals, DNA damage occurs frequently and DNA repair processes have evolved to compensate. 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. 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.
* 1 DNA damage and mutation
* 2 Age-associated accumulation of DNA damage and decline in gene expression
* 3 Mutation theories of aging * 4 Dietary restriction
* 5 Inherited defects that cause premature aging
* 6 Lifespan in different mammalian species * 7 Centenarians * 8 Menopause * 9 Atherosclerosis * 10 See also * 11 References
DNA DAMAGE AND MUTATION
To understand the
DNA damage theory of aging
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. By the early 1980s there was significant experimental support for this idea in the literature. 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.
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."
AGE-ASSOCIATED ACCUMULATION OF DNA DAMAGE AND DECLINE IN GENE EXPRESSION
Further information: DNA damage (naturally occurring)
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. The loss of expression of specific genes can be detected at both the mRNA level and protein level.
Further information: Aging 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. 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. ). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human.
Rutten et al. 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. Sen et al. 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). Wolf et al. 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.
Lu et al. 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. In cultured human neurons, these gene promoters are selectively damaged by oxidative stress . Thus Lu et al. 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.
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. 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.
Further information: 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. For instance, Helbock et al. 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.
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). For instance Hashimoto et al. 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. Sharpless and Depinho reviewed evidence that hematopoietic stem cells, as well as stem cells in other tissues, undergo intrinsic aging. 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.
A key aspect of hair loss with age is the aging of the hair follicle. 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.
MUTATION THEORIES OF AGING
Further information: Evolution of ageing
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. 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. On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation.
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 the mutation rate is 500-fold higher than in normal mice. These mice showed clear features of rapidly accelerated aging (Kujoth et al., 2005, Trifunovic et al., 2004. ). Importantly, these accelerated aged mice did not have elevated levels of ROS, suggesting that the cause of their ageing is not associated with oxidative damage, but with compromised mitochondrial function. Overall, the observations discussed in this section indicate that mutations are not the primary cause of aging.
Further information: Calorie 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. More recently, Wolf et al. 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
Further information: DNA repair-deficiency disorder
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. ).
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.
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 .
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.
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. ) In particular, mutant mice defective in Ku70 , or Ku80 , or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging. 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. ). If a DNA repair protein is deficient, unrepaired DNA damages tend to accumulate. 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 ). PROTEIN PATHWAY DESCRIPTION
ATR Nucleotide excision repair 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
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
ERCC4 (XPF) Nucleotide excision repair , Interstrand cross link repair , Single-strand annealing , Microhomology-mediated end joining 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
ERCC5 (XPG) Nucleotide excision repair , Homologous recombinational repair , Base excision repair 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 premature aging features with shorter life span and photosensitivity, deficient transcription coupled NER with accumulation of unrepaired DNA damages, also defective repair of oxidatively generated DNA damages including 8-oxoguanine , 5-hydroxycytosine and cyclopurines
ERCC8 ( Cockayne syndrome A or CS-A) Nucleotide excision repair premature aging features with shorter life span and photosensitivity, deficient transcription coupled NER with accumulation of unrepaired DNA damages, also defective repair of oxidatively generated DNA damages including 8-oxoguanine , 5-hydroxycytosine and cyclopurines
GTF2H5 (TTDA) Nucleotide excision repair deficiency causes trichothiodystrophy (TTD) a premature-ageing and neuroectodermal disease; humans with GTF2H5 mutations have a partially inactivated protein with retarded repair of 6-4-photoproducts
NRMT1 Nucleotide excision repair mutation in NRMT1 causes decreased body size, female-specific infertility, kyphosis, decreased mitochondrial function, and early-onset liver degeneration
RECQL4 Base excision repair , Nucleotide excision repair , Homologous recombination , Non-homologous end joining mutations in RECQL4 cause Rothmund-Thomson syndrome, with alopecia, sparse eye brows and lashes, cataracts and osteoporosis
SIRT6 Base excision repair , Nucleotide excision repair , Homologous recombination , Non-homologous end joining SIRT6-deficient mice develop profound lymphopenia, loss of subcutaneous fat and lordokyphosis, and these defects overlap with aging-associated degenerative processes
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
Werner syndrome helicase Homologous recombination , Non-homologous end joining , Base excision repair , Replication arrest recovery shorter lifespan, earlier onset of aging related pathologies, genome instability
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
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. PROTEIN PATHWAY DESCRIPTION
NUDT1 (MTH1) Oxidized nucleotide removal degrades 8-oxodGTP; prevents the age-dependent accumulation of DNA 8-oxoguanine A transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed, giving over-expression of hMTH1, increases the median lifespan of mice to 914 days vs. 790 days for wild-type mice. Mice with over-expressed hMTH1 have behavioral changes of reduced anxiety and enhanced investigation of environmental and social cues
PARP1 Base excision repair , Nucleotide excision repair , Microhomology-mediated end joining , Single-strand break repair 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.
SIRT1 Nucleotide excision repair , Homologous recombination , Non-homologous end joining 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
SIRT6 Base excision repair , Nucleotide excision repair , Homologous recombination , Non-homologous end joining male, but not female, transgenic mice overexpressing Sirt6 have a significantly longer lifespan than wild-type mice
LIFESPAN IN DIFFERENT MAMMALIAN SPECIES
Further information: Maximum life span
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, 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. 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. 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. 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).
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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). 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.
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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 , 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, 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. 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. also showed that expression of
DNA repair genes that are necessary for homologous
recombinational repair (
Women with an inherited mutation in the
DNA repair gene
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.
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. DNA strand breaks also increased in atherosclerotic plaques, thus linking DNA damage to plaque formation.
Werner syndrome (WS), a premature aging condition in humans, is
caused by a genetic defect in a
* ^ Best, BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research. 12 (3): 199–208. PMID 19594328 . doi :10.1089/rej.2009.0847 . * ^ A B C D Freitas AA, de Magalhães JP (2011). "A review and appraisal of the DNA damage theory of ageing". Mutation Research . 728 (1–2): 12–22. PMID 21600302 . doi :10.1016/j.mrrev.2011.05.001 . * ^ Burhans WC1, Weinberger M (2007). "DNA replication stress, genome instability and aging". Nucleic Acids Research . 35 (22): 7545–7556. PMC 2190710 . PMID 18055498 . doi :10.1093/nar/gkm1059 . * ^ Hoeijmakers JH (2009). "DNA damage, aging, and cancer". N. Engl. J. Med. 361 (15): 1475–85. PMID 19812404 . doi :10.1056/NEJMra0804615 . * ^ Cho M, Suh Y (2014). "Genome maintenance and human longevity" . Curr. Opin. Genet. Dev. 26: 105–15. PMC 4254320 . PMID 25151201 . doi :10.1016/j.gde.2014.07.002 . * ^ Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW (2005). "DNA repair, genome stability, and aging". Cell. 120 (4): 497–512. PMID 15734682 . doi :10.1016/j.cell.2005.01.028 . * ^ A B 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. PMID 17518695 . doi :10.1089/rej.2006.0514 . * ^ 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. PMC 25837 . PMID 10792040 . doi :10.1073/pnas.090099497 . * ^ 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. PMID 7031747 . doi :10.1086/412317 . * ^ 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 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. PMID 1944345 . doi :10.1016/0027-5107(91)90157-j . * ^ 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. PMID 1383772 . doi :10.1016/0921-8734(92)90034-M .
* ^ Rao, KS; Loeb, LA (September 1992). "DNA damage and repair in brain: relationship to aging". Mutation Research/DNAging. 275 (3–6): 317–29. PMID 1383773 . doi :10.1016/0921-8734(92)90035-N . * ^ 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. PMC 47258 . PMID 8367443 . doi :10.1073/pnas.90.17.7915 . * ^ 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. PMID 24709042 . doi :10.1016/j.neuroscience.2014.03.040 . * ^ A B C D E 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. PMID 16338029 . doi :10.1016/j.neurobiolaging.2005.10.019 . * ^ 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. PMID 8858940 . doi :10.1046/j.1471-4159.1996.67041559.x . * ^ 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. PMID 17364957 . doi :10.1080/10715760601083722 . * ^ 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. PMID 21600238 . doi :10.1016/j.mad.2011.04.012 . * ^ A B 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. PMID 15763395 . doi :10.1016/j.exger.2004.11.002 . * ^ 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. PMID 8215249 . doi :10.1002/ana.410340416 . * ^ A B C 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. PMID 15190254 . doi :10.1038/nature02661 . * ^ A B 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. PMC 56984 . PMID 11517304 . doi :10.1073/pnas.171202698 . * ^ 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. PMID 9895220 . doi :10.1016/s0891-5849(98)00208-1 . * ^ 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. PMID 15879174 . doi :10.1126/science.1106653 . * ^ Linford, NJ; Schriner, SE; Rabinovitch, PS (Mar 2006). "Oxidative damage and aging: spotlight on mitochondria". Cancer Res. 66 (5): 2497–9. PMID 16510562 . doi :10.1158/0008-5472.CAN-05-3163 .
* ^ 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. PMID 15831715 . doi
* ^ 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. PMC 18204 . PMID 9419368 . doi
:10.1073/pnas.95.1.288 . 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.
PMID 17785942 . doi :10.2131/jts.32.249 .
* ^ 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. PMID 17554309 . doi :10.1038/nature05862 .
* ^ 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.
PMID 17717515 . doi :10.1038/nrm2241 .
* ^ 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. PMID 26912687 . doi
* ^ 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. PMID 26912707 . doi
* ^ 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. PMID
9398844 . doi :10.1038/ng1297-431 .
* ^ 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.
PMID 15690342 . doi :10.1002/em.20119 .
* ^ 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. PMC 20332 . PMID
9096356 . doi :10.1073/pnas.94.7.3122 .
* ^ 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. PMID 16472827 . doi
* ^ 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.
PMID 17334366 . doi :10.1038/ng1988 .
* ^ 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. PMC 1356534 . PMID
16449207 . doi :10.1093/nar/gkj475 .
* ^ 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. PMC 3116236 . PMID 17848622 . doi
* ^ 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.
PMC 3180193 . PMID 21701264 . doi :10.4161/cc.10.15.16531 .
* ^ A B 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. PMID 15980864 . doi :10.1038/nm1266 .
* ^ 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. PMID 17297471 . doi
* ^ 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. PMC 17958 . PMID
10485901 . doi :10.1073/pnas.96.19.10770 .
* ^ 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. PMID 17183314 . doi
* ^ A B 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. PMID 16439206 . doi :10.1016/j.cell.2005.11.044 .
* ^ A B 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. PMC 2169178
. PMID 17875923 . doi :10.1128/MCB.00785-07 .
* ^ A B 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" .
Ageing Dev. 146-148: 42–52. PMC 4457563 . PMID 25843235 .
doi :10.1016/j.mad.2015.03.012 .
* ^ A B 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. PMC 2920603 . PMID 18371340 . doi
* ^ A B C 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. PMC
2692937 . PMID 17928034 . doi :10.1016/j.mad.2007.08.006 .
* ^ A B 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" .
Aging Age Relat Dis. 1. PMC 3417667 . PMID 22953029 . doi
* ^ Musich PR, Zou Y (2011). "DNA-damage accumulation and
replicative arrest in Hutchinson-Gilford progeria syndrome" . Biochem.
Soc. Trans. 39 (6): 1764–9. PMC 4271832 . PMID 22103522 . doi
* ^ 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). PMC 5133840
. PMID 27827925 . doi :10.3390/ijms17111840 .
* ^ 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. PMC
1299048 . PMID 15105825 . doi :10.1038/sj.embor.7400127 .
* ^ 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. PMC
3989187 . PMID 24740260 . doi :10.1371/journal.pone.0093568 .
* ^ 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. PMC 2901171 . PMID 20193758 .
doi :10.1016/j.freeradbiomed.2010.02.033 .
* ^ A B C D Gregg SQ, Robinson AR, Niedernhofer LJ (2011).
"Physiological consequences of defects in ERCC1-XPF DNA repair
endonuclease" . DNA Repair (Amst.). 10 (7): 781–91. PMC 3139823 .
PMID 21612988 . doi :10.1016/j.dnarep.2011.04.026 .
* ^ 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. PMC 5161687 . PMID 27556946 . doi
* ^ 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. PMC 3234290 . PMID 21571596 . doi
* ^ 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
* ^ 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. PMC 4172519 . PMID 24931715 . doi :10.1111/acel.12220 .
* ^ 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. PMC 4010117 .
PMID 24582957 . doi :10.1016/j.celrep.2014.01.031 .
* ^ 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. PMID 22367546 . doi
* ^ 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. PMC 388412 . PMID 4526202 . doi
* ^ 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. PMID 15743677 . doi
* ^ 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. PMC 4712340 . PMID
26729707 . doi :10.18632/aging.100866 .
* ^ Lehmann, Gilad; Budovsky, Arie; Muradian, K. Muradian;
Fraifeld, Vadim E. (2006). "Mitochondrial genome anatomy and
species-specific lifespan". Rejuvenation Res. 9 (2): 223–226. PMID
16706648 . doi :10.1089/rej.2006.9.223 .
* ^ 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. PMID 18442324 . doi
* ^ Lehmann, Gilad; Muradian, K. Muradian; Fraifeld, Vadim E.
Telomere length and body temperature-independent determinants
of mammalian longevity?". Front Genet. 4 (111). PMID 23781235 . doi
* ^ 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). PMID 26590258 . doi
* ^ 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. PMID 9587069
. doi :10.1007/s001090050226 .
* ^ Wagner KH, Cameron-Smith D, Wessner B, Franzke B (2 June 2016).
"Biomarkers of aging: from function to molecular biology" . Nutrients.
8 (6). PMC 4924179 . PMID 27271660 . doi :10.3390/nu8060338 .
* ^ A B Jirge PR (Apr–Jun 2016). "Poor ovarian reserve". J Hum
Reprod Sci. 9 (2): 63–9. PMID 27382229 . doi
:10.4103/0974-1208.183514 . CS1 maint: Date format (link )
* ^ 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. PMID 18192670 . doi :10.1093/humrep/dem408
* ^ A B 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. PMC 5130338 .
PMID 23408054 . doi :10.1126/scitranslmed.3004925 .
* ^ Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B,
Zielińska D, Tołoczko-Grabarek A (2006). "Premature menopause in
* v * t * e
Antagonistic pleiotropy hypothesis
* DNA damage theory of aging
Evolution of ageing
Free-radical theory of aging
Negligibly senescent organism
Network theory of aging
Programmed cell death