The mitochondrial production of reactive oxygen species is inversely proportional to longevity in animals. A key question now is, which molecules, among those that are oxidized, affect the lifespan of the organism most significantly?
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Finch, C. E. Longevity, Senescence, and the Genome 922 (University of Chicago, Chicago, 1990).
Barja, G. Rate of generation of oxidative stress-related damage and animal longevity. Free Radic. Biol. Med. 33, 1167–1172 (2002).
Beckman, K. B. & Ames, B. N. The free radical theory of aging matures. Physiol. Rev. 78, 547–581 (1998).
Hasty, P., Campisi, J., Hoeijmakers, J., van Steeg, H. & Vijg, J. Aging and genome maintenance: lessons from the mouse? Science 299, 1355–1359 (2003).
Hekimi, S. & Guarente, L. Genetics and the specificity of the aging process. Science 299, 1351–1354 (2003).
Longo, V. & Finch, C. E. Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 299, 1342–1346 (2003).
Tartar, M., Bartke, A. & Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 299, 1346–1351 (2003).
Speakman, J. R., Selman, C., McLaren, J. S. & Harper, E. J. Living fast, dying when? The link between aging and energetics. J. Nutr. 132, 1583S–1597S (2002).
Sohal, R. S., Mockett, R. J. & Orr, W. C. Mechanisms of aging: an appraisal of the oxidative stress hypothesis. Free Radic. Biol. & Med. 33, 575–586 (2002).
Tower, J. Aging mechanisms in fruit flies. BioEssays 18, 799–807 (1996).
De Sandre-Giovannoli, A. et al. Lamin A truncation in Hutchinson–Gilford progeria. Science 300, 2055 (2003).
Eriksson, M. et al. Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome. Nature 423, 293–298 (2003).
Ku, H. H., Brunk, U. T. & Sohal, R. Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic. Biol. Med. 15, 621–627 (1993).
Sohal, R. S., Ku, H. H., Agarwal, S., Forster, M. & Lal, H. Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction. Mech. Ageing Dev. 74, 121–133 (1994).
Gredilla, R., Sanz, A., Lopez-Torres, M. & Barja, G. Caloric restriction decreases mitochondrial free radical generation at complex I and lowers oxidative damage to mitochondrial DNA in the rat heart. FASEB J. 15, 1589–1591 (2001).
Holmes, D. J., Fluckiger, R. & Austad, S. N. Comparative biology of aging in birds: an update. Exp. Gerontol. 36, 869–884 (2001).
Austad, S. N. & Fischer, K. E. Mammalian aging, metabolism, and ecology: evidence from bats and marsupials. J. Gerontol. 46, B47–B53 (1991).
Imlay, J. A. & Linn, S. DNA damage and oxygen radical toxicity. Science 240, 1302–1309 (1988).
Imlay, J. A. How oxygen damages microbes: oxygen tolerance and obligate anaerobiosis. Adv. Microb. Physiol. 46, 111–153 (2002).
Friedberg, E. C., Walker, G. C. & Siede, W. DNA Repair and Mutagenesis (American Society of Microbiology Press, Washington D. C., 1995).
Klungland, A. et al. Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc. Natl Acad. Sci. USA 96, 13300–13305 (1999).
Herrero, A. & Barja, G. 8-Oxodeoxyguanosine levels in heart and brain mitochondrial and nuclear DNA of two mammals and three birds in relation to their different rates of aging. Aging 11, 294–300 (1999).
Hamilton, M. L. et al. Does oxidative damage to DNA increase with age? Proc. Natl Acad. Sci. USA 98, 10469–10474 (2001).
Dolle, M. E., Synder, W. K., Dunson, D. B. & Vijg, J. Mutational fingerprints of aging. Nucl. Acids Res. 30, 545–549 (2002).
Prisee, K. M., Davies, S. & Michael, B. D. Cell killing and DNA damage in Chinese hamster V79 cells treated with hydrogen peroxide. Int. J. Rad. Biol. 55, 583–592 (1989).
Chance, B., Sies, H. & Boveris, A. Hydroperoxide metabolism in mammalian organs. Physiol. Rev. 59, 527–603 (1979).
National Radiation Protection Board. Living with Radiation (Reading, England, 1986).
Lieber, M. R., Ma, Y., Pannicke, U. & Schwarz, K. Mechanism and regulation of human non-homologous DNA end-joining. Nature Rev. Mol. Cell. Biol. 4, 712–720 (2003).
Takata, M. et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 17, 5497–5508 (1998).
Kraus, E., Leung, W. Y. & Haber, J. E. Break-induced replication: a review and an example in budding yeast. Proc. Natl Acad. Sci. USA 98, 8255–8262 (2001).
Roth, D. & Wilson, J. in Genetic Recombination (eds Kucherlapapti, R. & Smith, G. R.) 621–653 (American Society for Microbiology, Washington D. C., 1988).
Lieber, M. R. The biochemistry and biological significance of nonhomologous DNA end joining: an essential repair process in multicellular eukaryotes. Genes Cells 4, 77–85 (1999).
Ferguson, D. O. et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc. Natl Acad. Sci. USA 97, 6630–6633 (2000).
Karanjawala, Z. E., Grawunder, U., Hsieh, C. -L. & Lieber, M. R. The nonhomologous DNA end joining pathway is important for chromosome stability in primary fibroblasts. Curr. Biol. 9, 1501–1504 (1999).
Karanjawala, Z., Murphy, N., Hinton, D. R., Hsieh, C. -L. & Lieber, M. R. Oxygen metabolism causes chromosome breaks and is associated with the neuronal apoptosis observed in double-strand break repair mutants. Curr. Biol. 12, 397–402 (2002).
Gilley, D. et al. DNA-PKcs is critical for telomere capping. Proc. Natl Acad. Sci. USA 98, 15084–15088 (2001).
Martin, G. M., Smith, A. C., Ketterer, D. J., Ogburn, C. E. & Disteche, C. M. Increased chromosomal aberrations in first metaphases of cells isolated from the kidneys of aged mice. Israel J. Med. Sci. 21, 296–301 (1985).
Strachen, T. & Read, A. P. Human Molecular Genetics (Wiley–Liss, New York, 1999).
Vogel, H., Lim, D. -S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl Acad. Sci. USA 96, 10770–10775 (1999).
Schuler, W. et al. Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell 46, 963–972 (1986).
Okazaki, K., Nishikawa, S. -I. & Sakano, H. Aberrant immunoglobulin gene rearrangement in scid mouse bone marrow cells. J. Immunol. 141, 1348–1352 (1988).
Malynn, B. A. et al. The scid defect affects the final step of the immunoglobulin VDJ recombinase mechanism. Cell 54, 453–460 (1988).
Gu, Y., Jin, S., Gao, Y., Weaver, D. T. & Alt, F. W. Ku70-deficient embryonic stem cells have increased ionizing radiosensitivity, defective DNA end-binding activity, and inability to support V(D)J recombination. Proc. Natl Acad. Sci. USA 94, 8076–8081 (1997).
Gao, Y. et al. A targeted DNA-PKcs-null mutation reveals DNA-PK independent for Ku in V(D)J recombination. Immunity 9, 367–376 (1998).
Gu, Y. et al. Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. Proc. Natl Acad. Sci. USA 97, 2668–2673 (2000).
Adachi, N. & Lieber, M. R. Bidirectional gene organization: a common architectural motif of the human genome. Cell 109, 807–809 (2002).
Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7, 653–665 (1997).
Li, G. C. et al. Ku70: a candidate tumor suppressor gene for murine T cell lymphoma. Mol. Cell 2, 1–8 (1998).
Prince, P. R., Emond, M. J. & Monnat, R. J. Loss of Werner syndrome protein function promotes aberrant mitotic recombination. Genes Dev. 15, 933–938 (2001).
Saintigny, Y., Makienko, K., Swanson, C., Emond, M. J. & Monnat, R. J. Homologous recombination resolution defect in Werner syndrome. Mol. Cell. Biol. 22, 6971–6978 (2002).
Li, B. & Comai, L. Functional interaction between Ku and the Werner syndrome protein in DNA end processing. J. Biol. Chem. 275, 28349–28352 (2000).
Cooper, M. P. et al. Ku complex interacts with and stimulates the Werner protein. Genes Dev. 14, 907–912 (2000).
Lebel, M. & Leder, P. A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc. Natl Acad. Sci. USA 95, 13097–13102 (1998).
Burke, B. & Stewart, C. L. Life at the edge: the nuclear envelope and human disease. Nature Rev. Mol. Cell Biol. 3, 575–585 (2002).
Mukherjee, A. B. & Costello, C. Aneuploidy analysis in fibroblasts of human premature aging syndromes by FISH during in vitro cellular aging. Mech. Ageing Dev. 103, 209–222 (1998).
Martin, G. M. & Oshima, J. Lessons from human progeroid syndromes. Nature 408, 263–266 (2000).
Kanaar, R. & Hoeijmakers, J. H. J. Recombination and joining: different means to the same ends. Genes Funct. 1, 165–174 (1997).
van Gent, D. C., Hoeijmakers, J. H. J. & Kanaar, R. Chromosomal stability and the DNA double-stranded break connection. Nature Rev. Genet. 2, 196–206 (2001).
Floyd, R. A., West, M. & Hensley, K. Oxidative biochemical markers; clues to understanding aging in long-lived species. Exp. Gerontol. 36, 619–640 (2001).
Ku, H. H. & Sohal, R. S. Comparison of mitochondrial pro-oxidant generation and anti-oxidant defenses between rat and pigeon: possible basis of variation in longevity and metabolic potential. Mech. Ageing Dev. 72, 67–76 (1993).
Burt, D. W. Origin and evolution of avian microchromosomes. Cytogenet. Gen. Res. 96, 97–112 (2002).
Van den Bussche, R. A., Longmire, J. L. & Baker, R. J. How bats achieve a small C-value: frequency of repetitive DNA in Macrotus. Mamm. Gen. 6, 521–525 (1995).
Buerstedde, J. M. & Takeda, S. Increased ratio of targeted to random integration after transfection of chicken B cells. Cell 67, 179–188 (1991).
Ogburn, C. E. et al. Exceptional cellular resistance to oxidative damage in long-lived birds requires active gene expression. J. Gerontol. Biol. Sci. 56A, B468–B474 (2001).
Fernandez-Checa, J. C. Redox regulation and signaling lipids in mitochondria apoptosis. Biochem. Biophys. Res. Commun. 304, 471–479 (2003).
Blumenthal, H. T. The aging-disease dichotomy: true or false? J. Gerontol. 58A, 138–145 (2003).
Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).
Gensler, H. L. & Bernstein, H. DNA damage as the primary cause of aging. Quart. Rev. Biol. 56, 279–303 (1981).
Karanjawala, Z. E. et al. The embryonic lethality in DNA ligase IV-deficient mice is rescued by deletion of Ku: implications for unifying the heterogeneous phenotypes of NHEJ mutants. DNA Repair 1, 1017–1026 (2002).
Wallace, D. C. Mitochondrial diseases in man and mouse. Science 283, 1482–1488 (1999).
Barja, G. & Herrero, A. Oxidative damage to mitochondrial DNA is inversely related to maximum lifespan in the heart and brain of mammals. FASEB J. 14, 312–318 (2000).
Dolle, M. E. & Vijg, J. Genome dynamics in aging mice. Genome Res. 12, 1732–1738 (2002).
Parrinello, S. et al. Oxygen sensitivity severely limits replicative lifespan of murine fibroblasts. Nature Cell Biol. 5, 741–747 (2003).
Friesner, J. & Britt, A. B. Ku80- and DNA ligase IV-deficient plants are sensitive to ionizing radiation and defective in T-DNA integration. Plant J. 34, 427–440 (2003).
West, S. C. Molecular views of recombination proteins and their control. Nature Rev. Mol. Cell. Biol. 4, 435–445 (2003).
This article is dedicated to Dr. H.T. Blumenthal for his continuing contributions to pathology and gerontology. The authors would like to thank H.T. Blumenthal, R. Sohal, N. Arnheim, D. Shibata, D. van den Berg and Y. Ma for comments on the manuscript and C. Finch, A. Britt, E. Hefner, R. Lanner, C. Hsieh, J. Tower and P. Hasty for very helpful discussions. Work in the authors' laboratory is supported by the National Institutes of Health.
The authors declare no competing financial interests.
About this article
Cite this article
Lieber, M., Karanjawala, Z. Ageing, repetitive genomes and DNA damage. Nat Rev Mol Cell Biol 5, 69–75 (2004). https://doi.org/10.1038/nrm1281
Scientific Reports (2021)
Desiccation does not drastically increase the accessibility of exogenous DNA to nuclear genomes: evidence from the frequency of endosymbiotic DNA transfer
BMC Genomics (2020)
Science China Life Sciences (2020)
BMC Medical Genetics (2019)
Nature Reviews Molecular Cell Biology (2017)