Mitochondria and Fatty Acid Homeostasis in the Aging Nervous System

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dc.contributor.advisorWildering, Willem C.
dc.contributor.authorLee, Jonathon R.
dc.contributor.committeememberTreberg, Jason R.
dc.contributor.committeememberWilson, Richard J. A.
dc.contributor.committeememberAntle, Michael C.
dc.contributor.committeememberSyme, Douglas A.
dc.date2019-11
dc.date.accessioned2019-08-26T20:51:26Z
dc.date.available2019-08-26T20:51:26Z
dc.date.issued2019-08-22
dc.description.abstractImpairments of learning and memory are among the most salient outcomes of the natural aging process. Particularly among humans who have experienced dramatic increases in lifespan over the last century, age-associated cognitive decline has become especially problematic in our increasingly elderly population. To mitigate the impact of these demographic changes, understanding of the fundamental biology that underlies the aging process is essential. The aim of the research presented in this thesis is to provide a new perspective on the foundational biological processes that contribute to age-related declines in cognitive function. In this regard, mitochondrial dysfunction and resulting oxidative stress have been widely implicated in the cellular and molecular deterioration of aging cells including neurons. Yet, how these phenomena arise and translate to the neuronal and behavioural dysfunction observed in aging animals remains an open question. The research conducted here integrates existing knowledge of biological aging with the novel idea that mechanisms surrounding lipid (dys)homeostasis play a prominent role in cognitive outcomes of aging. Using the gastropod model system Lymnaea stagnalis, the general hypothesis that deregulation of lipid homeostasis contributes to neuronal and behavioural impairment is investigated. Briefly, evidence is provided for the following ideas. 1) Neurons do not generally rely on lipids to meet energy requirements, yet mitochondrial fatty acid metabolism (β-oxidation) is important for the maintenance of metabolic reserve capacity and excess lipid management. In aging neurons, this is compromised as β-oxidation capacity declines. 2) Mitochondria are often considered the “seat of senescence”; however, plasma membrane lipid peroxidation and associated phospholipase A2 activity is involved with producing characteristics of age-related mitochondrial dysfunction, suggesting an extra-mitochondrial origin of biological aging. These changes may arise due to ailing β-oxidation capabilities in old neurons, and subsequent uncoupling of oxidative phosphorylation in a fatty acid-dependent manner. 3) β-oxidation dysfunction has wide-ranging implications for fatty acid-sensitive biological functions, such as ion channel function. The KATP potassium channels are particularly sensitive to activation by fatty acids, and directly translate β-oxidation failures to age-associated declines in neuronal excitability and long-term memory formation.en_US
dc.identifier.citationLee, J. R. (2019). Mitochondria and Fatty Acid Homeostasis in the Aging Nervous System (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/36902
dc.identifier.urihttp://hdl.handle.net/1880/110820
dc.language.isoengen_US
dc.publisher.facultyScienceen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectAgingen_US
dc.subjectMetabolismen_US
dc.subjectOxidative Stressen_US
dc.subjectFatty Aciden_US
dc.subjectExcitabilityen_US
dc.subjectMemoryen_US
dc.subjectLearningen_US
dc.subjectMitochondriaen_US
dc.subjectLymnaea stagnalisen_US
dc.subject.classificationAnimal Physiologyen_US
dc.subject.classificationBiology--Cellen_US
dc.subject.classificationNeuroscienceen_US
dc.subject.classificationPhysiologyen_US
dc.subject.classificationPsychology--Behavioralen_US
dc.titleMitochondria and Fatty Acid Homeostasis in the Aging Nervous Systemen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineBiological Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrueen_US
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