DNA damage theory of aging

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damages. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly (by increasing apoptosis or cellular senescence) or directly (by increasing cell dysfunction).[1][2][3]

In humans and other mammals, DNA damage occurs frequently and DNA repair processes have evolved to compensate. In estimates made for mice, on average approximately 1,500 to 7,000 DNA lesions occur per hour in each mouse cell, or about 36,000 to 160,000 per cell per day.[4] In any cell some DNA damage may remain 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.

DNA damage and mutation

To understand the DNA damage theory of aging it is important to distinguish between DNA damage and mutation, the two major types of errors that occur in DNA. Damage and mutation are fundamentally different. DNA damage is any physical abnormality in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damage can be recognized by enzymes, and thus can be correctly repaired using the complementary undamaged sequence in a homologous chromosome if it is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die. Descriptions of reduced function, characteristic of aging and associated with accumulation of DNA damage, are given later in this article.

In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.

Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell’s survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.

The first person to suggest that DNA damage, as distinct from mutation, is the primary cause of aging was Alexander in 1967.[5] By the early 1980s there was significant experimental support for this idea in the literature.[6] 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.[7][8][9][10][11]

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."[12][13][14][15][16]

Age-associated accumulation of DNA damage and decline in gene expression

In tissues composed of non- or infrequently replicating cells, DNA damage can accumulate with age and lead either to loss of cells, or, in surviving cells, loss of gene expression. Accumulated DNA damage is usually measured directly. Numerous studies of this type have indicated that oxidative damage to DNA is particularly important.[17] The loss of expression of specific genes can be detected at both the mRNA level and protein level.

Brain

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.[18] 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.[18]). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human.

Rutten et al.[19] 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.[20] Sen et al.[21] 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).[22] Wolf et al.[23] 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.[24]

Lu et al.[25] 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.[25] In cultured human neurons, these gene promoters are selectively damaged by oxidative stress. Thus Lu et al.[25] 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

Further information: 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.[18] We will mention here only two of the more recent studies in rodents plus one in humans. Hamilton et al.[26] 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.[27] 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%.[28][29] These findings suggest that mitochondria are a significant source of the oxidative damages contributing to aging.

Protein synthesis and protein degradation decline with age in skeletal and heart muscle, as would be expected, since DNA damage blocks gene transcription. In a recent study Piec et al.[30] 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

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.[18] For instance, Helbock et al.[31] estimated that the steady state level of oxidative DNA base alterations increased from 24,000 per cell in the liver of young rats to 66,000 per cell in the liver of old rats.

Kidney

Further information: 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).[18] For instance Hashimoto et al.[32] showed that 8-OHdG accumulates in rat kidney DNA with age.

Long-lived stem cells

Further information: Stem cell and Stem cell theory of aging

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.[33] Sharpless and Depinho reviewed evidence that hematopoietic stem cells, as well as stem cells in other tissues, undergo intrinsic aging.[34] 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.[35]

A key aspect of hair loss with age is the aging of the hair follicle.[36] 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.[37]

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.[38][39][40] 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.[41] On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation.[42]

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. Yet these mice showed no obvious features of rapidly accelerated aging.[43] The probable explanation for the apparent lack of effect of the additional mutations in mitochondrial DNA is that, within a typical cell, there are large numbers of mitochondria and each mitochondrion can have multiple copies of mitochondrial DNA. Since most mutations are recessive, any particular deleterious mutation would not be expected to have a pronounced effect when many copies of the correct DNA sequence are present in the same and in other mitochondria in the cell. Overall, the observations discussed in this section indicate that mutations are not the primary cause of aging.

Dietary restriction

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.[26] More recently, Wolf et al.[23] 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.[44]).

Hutchinson-Guilford Progeria is due to a defect in Lamin A protein which forms a scaffolding within the cell nucleus to organize chromatin and is needed for repair of double-strand breaks in DNA.[45] 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.[46] Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and are more sensitive to DNA damaging agents.[47]

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.[48]

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.

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.[49][50][51]) In particular, mutant mice defective in Ku70, or Ku80, or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging.[52] 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.

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,[53] 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.[54] 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.[55] 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.

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 PARP (poly ADP ribose polymerase) than cell lines from younger (20 to 70 years old) individuals.[56] 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.[57]

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 about 1 million oocytes are present at birth 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 a constantly increasing rate with age,[58] 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.[59] 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.[59] also showed that expression of four key DNA repair genes that are necessary for homologous recombinational repair (BRCA1, MRE11, Rad51 and ATM) decline in oocytes with age. This age-related decline in ability to repair double-strand damages can account for the accumulation of these damages, which then likely contributes to the decline in ovarian reserve.

Women with an inherited mutation in the DNA repair gene BRCA1 undergo menopause prematurely,[60] 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.[61] 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.

Conclusions

Numerous studies have shown that DNA damage accumulates in brain, muscle, liver, kidney, long-lived stem cells, and in oocytes. These accumulated DNA damages are the likely cause of the decline in gene expression and loss of functional capacity observed with increasing age. On the other hand, accumulation of mutations, as distinct from DNA damages, is not a plausible candidate as the primary cause of aging. A calorie-restricted diet in mammals improves lifespan, and this improvement is associated with a decrease in oxidative DNA damage. Several inherited genetic defects in ability to repair DNA damage give rise to premature aging suggesting a causal relationship between DNA damage and aging. In comparisons of different mammalian species that differ in lifespan, DNA repair capacity is found to correlate with lifespan. Also, centenarians tend to have elevated levels of DNA repair. Menopause appears to be a consequence of DNA damage accumulation in oocytes. The principal source of the DNA damages leading to normal aging appears to be reactive oxygen species, produced as byproducts of normal cellular metabolism.

See also

References

  1. Best,BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research. 12 (3): 199–208. doi:10.1089/rej.2009.0847. PMID 19594328.
  2. Freitas AA, de Magalhães JP (2011). "A review and appraisal of the DNA damage theory of ageing". Mutation Research (journal). 728 (1-2): 12–22. doi:10.1016/j.mrrev.2011.05.001. PMID 21600302.
  3. Burhans WC1, Weinberger M (2007). "DNA replication stress, genome instability and aging". Nucleic Acids Research. 35 (22): 7545–7556. doi:10.2217/imt.10.107. PMC 2190710Freely accessible. PMID 18055498.
  4. 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. doi:10.1073/pnas.090099497. PMID 10792040.
  5. "The role of DNA lesions in the processes leading to aging in mice.". Symp Soc Exp Biol. 21: 29–50. 1967. PMID 4860956.
  6. Gensler, HL; Bernstein, H (Sep 1981). "DNA damage as the primary cause of aging". Q Rev Biol. 56 (3): 279–303. doi:10.1086/412317. PMID 7031747.
  7. Bernstein C, Bernstein H. (1991) Aging, Sex, and DNA Repair. Academic Press, San Diego. ISBN 978-0120928606 partly available at https://books.google.com/books?id=BaXYYUXy71cC&pg=PA3&lpg=PA3&dq=Aging,+Sex,+and+DNA+Repair&source=bl&ots=9E6VrRl7fJ&sig=kqUROJfBM6EZZeIrkuEFygsVVpo&hl=en&sa=X&ei=z8BqUpi7D4KQiALC54Ew&ved=0CFUQ6AEwBg#v=onepage&q=Aging%2C%20Sex%2C%20and%20DNA%20Repair&f=false
  8. Ames, BN; Gold, LS (1991). "Endogenous mutagens and the causes of aging and cancer". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 250 (1-2): 3–16. doi:10.1016/0027-5107(91)90157-j. PMID 1944345.
  9. Holmes, GE; Bernstein, C; Bernstein, H (1992). "Oxidative and other DNA damages as the basis of aging: a review". Mutat Res. 275 (3-6): 305–315. doi:10.1016/0921-8734(92)90034-M. PMID 1383772.
  10. Rao, KS; Loeb, LA (September 1992). "DNA damage and repair in brain: relationship to aging". Mutation Research/DNAging. 275 (3-6): 317–29. doi:10.1016/0921-8734(92)90035-N. PMID 1383773.
  11. 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. doi:10.1073/pnas.90.17.7915. PMC 47258Freely accessible. PMID 8367443.
  12. 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.
  13. 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.
  14. Acharya, PVN. Isolation and Partial Characterization of Age-Correlated Oligo-nucleotides with Covalently Bound Peptides. 14th Nordic Congress, Umea, Sweden, June 19, 1971.
  15. Acharya, PVN. DNA-damage: The Cause of Aging. Ninth International Congress of Biochemistry: Stockholm. July 1–7, 1973 (Abs.3 m 12).
  16. 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.
  17. 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.
  18. 1 2 3 4 5 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
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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. doi:10.1038/nature02661. PMID 15190254.
  26. 1 2 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. doi:10.1073/pnas.171202698. PMC 56984Freely accessible. PMID 11517304.
  27. "Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscle.". Free Radic Biol Med. 26 (3-4): 303–8. Feb 1999. doi:10.1016/s0891-5849(98)00208-1. PMID 9895220.
  28. 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. doi:10.1126/science.1106653. PMID 15879174.
  29. Linford, NJ; Schriner, SE; Rabinovitch, PS (Mar 2006). "Oxidative damage and aging: spotlight on mitochondria". Cancer Res. 66 (5): 2497–9. doi:10.1158/0008-5472.CAN-05-3163. PMID 16510562.
  30. Piec, I; Listrat, A; Alliot, J; Chambon, C; Taylor, RG; Bechet, D (Jul 2005). "Differential proteome analysis of aging in rat skeletal muscle". FASEB J. 19 (9): 1143–5. doi:10.1096/fj.04-3084fje. PMID 15831715.
  31. 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. doi:10.1073/pnas.95.1.288. PMC 18204Freely accessible. PMID 9419368.
  32. "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. Aug 2007. doi:10.2131/jts.32.249. PMID 17785942.
  33. 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. doi:10.1038/nature05862. PMID 17554309.
  34. 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.
  35. 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
  36. Lei M, Chuong CM (2016). "STEM CELLS. Aging, alopecia, and stem cells". Science. 351 (6273): 559–60. doi:10.1126/science.aaf1635. PMID 26912687.
  37. 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.
  38. 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.
  39. 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 1460990Freely accessible. PMID 10757770.
  40. Hill, KA; Halangoda, A; Heinmoeller, PW; Gonzalez, K; Chitaphan, C; Longmate, J; Scaringe, WA; Wang, JC; Sommer, SS (Jun 2005). "Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice". Environ Mol Mutagen. 45 (5): 442–54. doi:10.1002/em.20119. PMID 15690342.
  41. 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. doi:10.1073/pnas.94.7.3122. PMC 20332Freely accessible. PMID 9096356.
  42. Dollé, ME; Busuttil, RA; Garcia, AM; Wijnhoven, S; van Drunen, E; Niedernhofer, LJ; van der Horst, G; Hoeijmakers, JH; van Steeg, H; Vijg, J (Apr 2006). "Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice". Mutat Res. 596 (1-2): 22–35. doi:10.1016/j.mrfmmm.2005.11.008. PMID 16472827.
  43. 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.
  44. 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. PMID 16449207.
  45. 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. PMID 17848622.
  46. 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 3180193Freely accessible. PMID 21701264.
  47. 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.
  48. 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.
  49. 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. doi:10.1073/pnas.96.19.10770. PMC 17958Freely accessible. PMID 10485901.
  50. 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. doi:10.1038/nature05456. PMID 17183314.
  51. 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.
  52. 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 2169178Freely accessible. PMID 17875923.
  53. "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. Jun 1974. doi:10.1073/pnas.71.6.2169. PMID 4526202.
  54. 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.
  55. 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 (Albany NY). 7 (12): 1171–84. doi:10.18632/aging.100866. PMC 4712340Freely accessible. PMID 26729707.
  56. 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.
  57. 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.
  58. 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.
  59. 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. PMID 23408054.
  60. 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.
  61. 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 4661791Freely accessible. PMID 26414677.
This article is issued from Wikipedia - version of the 11/29/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.