title: Does premature aging of the mtDNA mutator mouse prove that mtDNA mutations are involved in natural aging?
abstract: Recent studies have demonstrated that transgenic mice with an increased rate of somatic point mutations in mitochondrial DNA (mtDNA mutator mice) display a premature aging phenotype reminiscent of human aging. These results are widely interpreted as implying that mtDNA mutations may be a central mechanism in mammalian aging. However, the levels of mutations in the mutator mice typically are more than an order of magnitude higher than typical levels in aged humans. Furthermore, most of the aging-like features are not specific to the mtDNA mutator mice, but are shared with several other premature aging mouse models, where no mtDNA mutations are involved. We conclude that, although mtDNA mutator mouse is a very useful model for studies of phenotypes associated with mtDNA mutations, the aging-like phenotypes of the mouse do not imply that mtDNA mutations are necessarily involved in natural mammalian aging. On the other hand, the fact that point mutations in aged human tissues are much less abundant than those causing premature aging in mutator mice does not mean that mtDNA mutations are not involved in human aging. Thus, mtDNA mutations may indeed be relevant to human aging, but they probably differ by origin, type, distribution, and spectra of affected tissues from those observed in mutator mice.
authors.affiliation: Gerontology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. khrapko@hms.harvard.edu
authors.forename: Konstantin
authors.initials: K
authors.lastname: Khrapko
authors.forename: Yevgenya
authors.initials: Y
authors.lastname: Kraytsberg
authors.forename: Aubrey D N J
authors.initials: AD
authors.lastname: de Grey
authors.forename: Jan
authors.initials: J
authors.lastname: Vijg
authors.forename: Eric A
authors.initials: EA
authors.lastname: Schon
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008954:Models, Biological; D016296:Mutagenesis / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial