Abstract
Although there is a consensus that mitochondrial function is somehow linked to the aging process, the exact role played by mitochondria in this process remains unresolved. The discovery that reduced activity of the mitochondrial enzyme CLK-1/MCLK1 (also known as COQ7) extends lifespan in both Caenorhabditis elegans and mice has provided a genetic model to test mitochondrial theories of aging. We have recently shown that the mitochondria of young, long-lived, Mclk1(+/-) mice are dysfunctional, exhibiting reduced energy metabolism and a substantial increase in oxidative stress. Here we demonstrate that this altered mitochondrial condition in young animals paradoxically results in an almost complete protection from the age-dependent loss of mitochondrial function as well as in a significant attenuation of the rate of development of oxidative biomarkers of aging. Moreover, we show that reduction in MCLK1 levels can also gradually prevent the deterioration of mitochondrial function and associated increase of global oxidative stress that is normally observed in Sod2(+/-) mutants. We hypothesize that the mitochondrial dysfunction observed in young Mclk1(+/-) mutants induces a physiological state that ultimately allows for their slow rate of aging. Thus, our study provides for a unique vertebrate model in which an initial alteration in a specific mitochondrial function is linked to long term beneficial effects on biomarkers of aging and, furthermore, provides for new evidence which indicates that mitochondrial oxidative stress is not causal to aging.
Highlights
Duces reactive oxygen species (ROS),2 that mitochondrial components are damaged by ROS, that mitochondrial function is progressively lost during aging, and that the progressive accumulation of global oxidative damage is strongly correlated with the aged phenotype
As young Mclk1ϩ/Ϫ mice display a variety of mitochondrial phenotypes, we concluded that MCLK1 carries out another, yet unidentified mitochondrial function in addition to its hydroxylase function in UQ biosynthesis
We have shown that no UQ phenotype could be evidenced in Mclk1ϩ/Ϫ mutants compared with isogenic controls at 23 months of age; that is, at a time at which we observe a substantial reduction in the appearance of biomarkers of aging
Summary
Animals—All of the mice were housed in a pathogen-free animal facility at McGill University and were given a standard rodent diet and water ad libitum. All of the mice used in the experiments comparing animals of different ages (3, 12, and 23 months) were F1 hybrid progeny generated by crossing mice of two different pure inbred strains These animals were produced by mating Mclk1ϩ/Ϫ males from the original knock-out background (129S6) to females on a pure BALB/c background. Liver mitochondria were isolated by standard differential centrifugation according to detailed procedures described elsewhere [30]. Determination of Oxidative Damage—Lipid peroxidation was determined in cytosolic and mitochondrial fractions of liver by the indirect measurement of free malondialdehyde (MDA) using a standard published method with some modifications [31]. The level of protein carbonyl contents in liver tissues was determined with the Protein Carbonyl Assay kit (Cayman Chemical) according to the manufacturer’s instructions. The linear regression was obtained from ln(Rm) ϭ ln(R0) ϩ ␣t and the mortality rate doubling time, a measure of the rate of aging, was estimated from the slope as described [33]
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