Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice

We find that homozygous inactivation of mclk1, the mouse ortholog of clk-1, yields embryonic stem cells that are protected from oxidative stress and damage to DNA

Xingxing Liu; Ning Jiang; Bryan Hughes; Eve Bigras; Eric Shoubridge; Siegfried Hekimi

2005

Scholarcy highlights

  • The power of using the genetic approach to elucidate the mechanisms of aging has been underscored by the possibility of identifying long-lived mutants in invertebrate animal models of aging
  • In addition to the absence of ubiquinone and the mitochondrial respiration defect observed previously, we have characterized a number of additional phenotypes of mclk1−/− embryonic stem cells, including slow cell multiplication, reduced tendency to differentiate in the presence of low levels of leukemia inhibitory factor, low levels of basal and induced reactive oxygen species measured by dye-dependent fluorescence, and resistance to apoptosis induced by the ROS-generating compound menadione
  • Given our observations of low levels of oxidative stress and DNA damage in mclk1−/− cells, and the fact that reducing clk-1 activity prolongs the lifespan of nematodes, it was of interest to test the effect of reducing the activity of mclk1 on the lifespan of mice
  • If the phenotypic effects of reduced clk-1/mclk1 activity observed in worms and in ES cells are entirely mediated by a reduction of the level of ubiquinone, we should not expect to observe an effect on the lifespan of the heterozygous mice
  • We find that reducing the activity of mclk1 reduces ROS levels, oxidative stress, and oxidative damage in mouse cells, and prolongs the lifespan of whole animals
  • Our results with mclk1 strengthen the generality of the observation that resistance to oxidative stress accompanies increased lifespan
  • It is possible that reduction of mclk1 expression might bring about an undetected minor reduction of ubiquinone levels, or a reduction in particular cell types, or during particular physiological conditions, that could be favorable for longevity by increasing resistance to damage at significant times and/or places

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