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Mitochondrial DNA mutations and aging: a case closed?

Nature Genetics volume 39, pages 445–446 (2007)Cite this article

Recent reports of premature aging in mutant mice with greatly increased rates of mitochondrial DNA mutagenesis (so-called 'mitochondrial mutator mice') appeared to confirm that accumulation of mtDNA mutations is a key mechanism of normal aging. Now, in a dramatic turnaround, a new study reports that levels of point mutations in tissues of aged normal mice are much lower than in the mutator mice, apparently ruling out a causal role in normal aging.

One of the oldest theories of why and how we age is based on the natural instability of the DNA of our genome1. This theory (in particular, the variant that refers to the genome of mitochondria) has recently experienced unprecedented swings in credibility. Initially, two groups2,3 reported that mitochondrial DNA 'mutator' mice harboring genetic defects in the proofreading exonuclease activity of mitochondrial DNA polymerase (Polgmut/mut) showed both increased mitochondrial DNA mutations and multiple symptoms of premature aging. These reports were widely interpreted (with a notable exception4) as strong evidence that mtDNA mutations were driving the aging process. However, shortly thereafter, we and others noted a striking discrepancy: the levels of mtDNA mutations in the Polgmut/mut mouse were over an order of magnitude higher than the typical mutation levels observed in aged human tissues. Furthermore, mtDNA mutation levels of the control mice, which did not age prematurely, were still higher than mutation levels in aged humans, suggesting no causal relationship to aging at all5. Now, Vermulst et al.6, on page 540 of this issue, resolve part of this paradox by using a highly sensitive mutation detection technique that gives drastically lower estimates of mtDNA mutation levels in normal aging mice than previously reported.

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Figure 1: Mitochondrial DNA mutations and aging.

Kim Caesar

References

  1. Vijg, J. Aging of the Genome (Oxford Univ. Press, New York, 2007).

    Book  Google Scholar 

  2. Trifunovic, A. et al. Nature 429, 417–423 (2004).

    Article  CAS  Google Scholar 

  3. Kujoth, G.C. et al. Science 309, 481–484 (2005).

    Article  CAS  Google Scholar 

  4. de Grey, A.D. Rejuvenation Res. 7, 171–174 (2004).

    Article  CAS  Google Scholar 

  5. Khrapko, K., Kraytsberg, Y., de Grey, A.D., Vijg, J. & Schon, E.A. Aging Cell 5, 279–282 (2006).

    Article  CAS  Google Scholar 

  6. Vermulst, M. Nat. Genet. 39, 540–543 (2007).

    Article  CAS  Google Scholar 

  7. Bielas, J.H. & Loeb, L.A. Nat. Methods 2, 285–290 (2005).

    Article  CAS  Google Scholar 

  8. Khrapko, K., Andre, P.C., Cha, R., Hu, G. & Thilly, W.G. Prog. Nucleic Acid Res. Mol. Biol. 49, 285–312 (1994b).

    Article  CAS  Google Scholar 

  9. Pallotti, F., Chen, X., Bonilla, E. & Schon, E.A. Am. J. Hum. Genet. 59, 591–602 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nekhaeva, E. et al. Proc. Natl. Acad. Sci. USA 99, 5521–5526 (2002).

    Article  CAS  Google Scholar 

  11. Zheng, W., Khrapko, K., Coller, H.A., Thilly, W.G. & Copeland, W.C. Mutat. Res. 599, 11–20 (2006).

    Article  CAS  Google Scholar 

  12. Bender, A. et al. Nat. Genet. 38, 515–517 (2006).

    Article  CAS  Google Scholar 

  13. Kraytsberg, Y. et al. Nat. Genet. 38, 518–520 (2006).

    Article  CAS  Google Scholar 

  14. Luoma, P. et al. Lancet 364, 875–882 (2004).

    Article  CAS  Google Scholar 

  15. Taylor, R.W. et al. J. Clin. Invest. 112, 1351–1360 (2003).

    Article  CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Konstantin Khrapko is in the Gerontology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. khrapko@hms.harvard.edu,

    Konstantin Khrapko

  2. Jan Vijg is in the Buck Institute for Age Research, 8001 Redwood Blvd., Novato, California 94945, USA. jvijg@buckinstitute.org,

    Jan Vijg

Authors
  1. Konstantin Khrapko
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  2. Jan Vijg
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Khrapko, K., Vijg, J. Mitochondrial DNA mutations and aging: a case closed?. Nat Genet 39, 445–446 (2007). https://doi.org/10.1038/ng0407-445

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