X-Message-Number: 27816
Date: Wed, 5 Apr 2006 18:28:29 -0700 (PDT)
From: Doug Skrecky <>
Subject: aging may have no direct connection to nuclear DNA damage

[Mitochondrial DNA may be another matter.]

Mutat Res. 2006 Feb 9; [Epub ahead of print]
Increased genomic instability is not a prerequisite for shortened
lifespan in DNA repair deficient mice.
  Genetic defects in nucleotide excision repair (NER) are associated with
premature aging, including cancer, in both humans and mice. To
investigate the possible role of increased somatic mutation accumulation
in the accelerated appearance of symptoms of aging as a consequence of
NER deficiency, we crossed four different mouse mutants, Xpa(-/-),
Ercc6(Csb)(-/-), Ercc2(Xpd)(m/m) and Ercc1(-/m), with mice harboring
lacZ-reporter genes to assess mutant frequencies and spectra in different
organs during aging. The results indicate an accelerated accumulation of
mutations in both liver and kidney of Xpa defective mice, which correlated
with a trend towards a decreased lifespan. Until 52 weeks, Xpa deficiency
resulted mainly in 1-bp deletions. At old age (104 weeks), the spectrum
had undergone a shift, in both organs, to G:C-->T:A transversions, a
signature mutation of oxidative DNA damage. Ercc1(-/m) mice, with their
short lifespan of 6 months and severe symptoms of premature aging,
especially in liver and kidney, displayed an even faster lacZ-mutant
accumulation in liver. In this case, the excess mutations were mostly
genome rearrangements. Csb(-/-) mice, with mild premature aging
features and no reduction in lifespan, and Xpd(m/m) mice, exhibiting
prominent premature aging features and about 20% reduction in lifespan,
did not have elevated lacZ-mutant frequencies. It is concluded that while
increased genomic instability could play a causal role in the mildly
accelerated aging phenotype in the Xpa-null mice or in the severe
progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice
with defects in transcription-related repair do not depend upon increased
mutation accumulation.

Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):17993-8. Epub 2005 Dec 6.
Somatic mtDNA mutations cause aging phenotypes without affecting reactive
oxygen species production.
  The mitochondrial theory of aging proposes that reactive oxygen species
(ROS) generated inside the cell will lead, with time, to increasing
amounts of oxidative damage to various cell components. The main site for
ROS production is the respiratory chain inside the mitochondria and
accumulation of mtDNA mutations, and impaired respiratory chain function
have been associated with degenerative diseases and aging. The theory
predicts that impaired respiratory chain function will augment ROS
production and thereby increase the rate of mtDNA mutation accumulation,
which, in turn, will further compromise respiratory chain
function. Previously, we reported that mice expressing an error-prone
version of the catalytic subunit of mtDNA polymerase accumulate a
substantial burden of somatic mtDNA mutations, associated with premature
aging phenotypes and reduced lifespan. Here we show that these
mtDNA mutator mice accumulate mtDNA mutations in an approximately linear
manner. The amount of ROS produced was normal, and no increased
sensitivity to oxidative stress-induced cell death was observed in mouse
embryonic fibroblasts from mtDNA mutator mice, despite the presence of a
severe respiratory chain dysfunction. Expression levels of antioxidant
defense enzymes, protein carbonylation levels, and aconitase enzyme
activity measurements indicated no or only minor oxidative stress in
tissues from mtDNA mutator mice. The premature aging phenotypes in mtDNA
mutator mice are thus not generated by a vicious cycle of massively
increased oxidative stress accompanied by exponential accumulation of
mtDNA mutations. We propose instead that respiratory chain dysfunction
per se is the primary inducer of premature aging in mtDNA mutator mice.

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