Date of Award

Fall 2011

Degree Type

Thesis

Degree Name

Doctor of Science (PhD)

Department

Kinesiology

Supervisor

Mark A. Tarnopolsky

Co-Supervisor

Gianni Parise

Language

English

Committee Member

Sandeep Raha

Abstract

Mitochondrial dysfunction and oxidative stress have been extensively characterized in aging. A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by studies demonstrating that the mtDNA mutator mouse, harbouring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits systemic mitochondrial dysfunction and phenocopies human aging. Epidemiological studies clearly demonstrate that endurance exercise reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline in aging remains elusive. This thesis examined the therapeutic effects of an active lifestyle in elderly individuals and forced endurance training in mtDNA mutator mouse model of aging. In older adults, a sedentary lifestyle was associated with reduced skeletal muscle mitochondrial function, dysregulated cellular redox status, and chronic systemic inflammation. Conversely, a physically active lifestyle compensated for aging-associated mitochondrial deterioration by preserving mitochondrial biogenesis, oxidative capacity, and redox status in skeletal muscle. To evaluate the systemic effects of endurance exercise, mutator mice were subjected to five months of treadmill training (15 m/min for 45 min, 3x/week). Endurance exercise conferred complete phenotypic protection and prevented premature mortality. The transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator (PGC)-1α is a critical regulator of mitochondrial biogenesis and is touted as a potential therapeutic target for aging-associated diseases. PGC-1α is dynamically regulated by post-transcriptional modification and sub-cellular compartmentalization. Endurance exercise activated PGC-1α regulated metabolic networks in the differentiated and proliferative compartments of the mutator mice, and thus promoted systemic mitochondrial biogenesis, prevented mtDNA mutations, reduced oxidative damage, attenuated telomere erosion and apoptosis markers. Mitochondrial-localized p53 facilitated mtDNA mutation repair despite the presence of defective polymerase gamma in these mice. These findings indicate that endurance exercise is an effective therapeutic approach to mitigate systemic mitochondrial dysfunction in aging, a feat that unmatched by an “exercise pill”.

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