Speaker: Dr. Siegfried Hekimi
Date: Friday 27th, January 2012
Time: 12 noon
Location: HSC 1A5
Title: Taking a good look at free radicals in the aging process
Abstract
The oxidative stress theory of aging postulates that aging results from the accumulation of molecular damage caused by mitochondrial reactive oxygen species (ROS) generated during normal metabolism. In the nematode C. elegans several mutations in mitochondrial proteins lead to a substantial increase in longevity. clk-1 encodes an enzyme necessary for ubiquinone biosynthesis, isp-1 and nuo-6 encode subunits of the mitochondrial respiratory chain, and sod-2 encodes the main mitochondrial superoxide dismutase. We have investigated the involvement of ROS metabolism in the mechanisms of longevity of these mutants. Our findings indicate that the longevity of these mutants is not the result of lower accumulation of oxidative damage. Rather we find that their mitochondria display an enhanced generation of ROS, a property that we find to be necessary and sufficient for their increased longevity. We speculate that these ROS act as signaling molecules that modulates gene expression, a hypothesis that we are currently investigating further.
In mice, we have found that reduced activity of the mitochondrial enzyme MCLK1, which is necessary for ubiquinone biosynthesis, prolongs lifespan. In young Mclk1+/- mutants, in which MCLK1 levels are reduced two-fold, we observe a reduction of mitochondrial electron transport and an increase in mitochondrial ROS generation and oxidative stress. Surprisingly, this condition appears to improve several biomarkers of aging measured in 23 months old animals, including mitochondrial function, serum isoprostanes and 8-OHdG, liver fibrosis and plasma ALT levels. Furthermore, Mclk1+/- were found to be partially resistant in models of age-dependent pathologies, including cerebral vascular damage, infection and cancer. To understand this phenomenon we sought to identify protective pathways that could be stimulated by increased mitochondrial ROS in these mutants. We found that enhanced mitochondrial ROS in cells or animals with reduced MCLK1 expression stabilize the hypoxia-inducible factor HIF-1α, a transcriptional regulator of a variety of protective mechanisms, including the immune response, whose activity appears to be enhanced and protective against age-related damage in Mclk1+/- mutants.
I will seek to articulate a model that reconciles our observations with the large dataset that has been at the basis of the oxidative stress theory of aging and that reveals a strong correlation between oxidative stress and aging. I propose that ROS are tightly associated with the aging process because they play a role in mediating a stress response to age-dependent damage. This could generate the observed correlation between aging and ROS without implying that ROS damage is the earliest trigger or even a main cause of aging.
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