Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice.
Inactivation of the Caenorhabditis elegans gene clk-1, which is required for ubiquinone biosynthesis, increases lifespan by an insulin signaling-independent mechanism. We find that homozygous inactivation of mclk1, the mouse ortholog of clk-1, yields ES cells that are protected from oxidative stress and damage to DNA. Moreover, in the livers of old mclk1(+/-) mice, hepatocytes that have lost mclk1 expression by loss of heterozygosity undergo clonal expansion, suggesting that their resistance to stress allows them to outcompete cells that still express the gene. mclk1(+/-) mice, whose growth and fertility are normal, also display a substantial increase in lifespan in each of three different genetic backgrounds. These observations indicate that the distinct mechanism by which clk-1/mclk1 affects lifespan is evolutionarily conserved from nematodes to mammals and is not tied to a particular anatomy or physiology.
Liu
Xingxing
X
Department of Biology, McGill University, H3A 1B1, Montreal, Quebec, Canada.
Jiang
Ning
N
Hughes
Bryan
B
Bigras
Eve
E
Shoubridge
Eric
E
Hekimi
Siegfried
S
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D003433:Crosses, Genetic; D004249:DNA Damage / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D004625:Embryo, Nonmammalian; D019143:Evolution, Molecular; D022781:Hepatocytes / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D019656:Loss of Heterozygosity / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D006899:Mixed Function Oxygenases; D018384:Oxidative Stress / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014451:Ubiquinone / Q000096:biosynthesis* / Q000235:genetics
C104339:CLK-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D014451:Ubiquinone; D006899:Mixed Function Oxygenases; C434481:Coq7 protein, mouse