"Mitochondrial biogenesis and the decline of hypoxia, oxidative stress and toxin tolerance with age"

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The Canadian population is aging. Seniors make up the fastest-growing age group and, in 2010, an estimated 4.8 million Canadians were 65 years of age or over (14.1% of the population) and that number is expected to double in the next 25 years to reach 10.4 million (23.5% of the population). Understanding the environmental factors that influence the molecular basis of aging will be crucial for healthy aging of Canadians in the near future. My NSERC Program investigates the biochemical aspects of aging, examining the molecular mechanisms of senescence and how environmental factors can either contribute to or inhibit the aging process in cells. Aging itself is associated with a high incidence of ischemic diseases (cardiac arrest, stroke) and the elderly lose the ability to cope with factors linked to these diseases including a) insufficient oxygen (hypoxia), b) oxidative stress (the production of reactive oxygen species (ROS)) and c) the ability to withstand toxins. A common feature of these stresses is mitochondrial dysfunction. Mitochondrial dysfunction has long been associated with the aging process and the onset of numerous diseases. Mitochondrial function decreases with age as the biogenesis of mitochondria declines over the lifespan of the organism. We propose to investigate the effects of a) hypoxia, b) oxidative stress and c) potentially harmful compounds identified in Canada's Chemical Management Plan on mitochondrial biogenesis and the cellular aging process. Protein factors protecting the cell from these stresses (SIRT1, HIF, NFE2L, PGC-1) will be assessed for their expression, function, changes in post-translational modifications, and effects on mitochondrial biogenesis over time in a cell senescence model. The influences of overexpression, knock down, and ablation of modification of such factors on mitochondrial biogenesis and cellular aging will be assessed. Overall, the proposed research into factors which affect cellular aging will significantly advance our understanding of this basic biological phenomenon and assist in the development and discovery of therapeutic agents that minimize the detrimental effects of aging.