While aging impacts most, if not all, living organisms, the molecular mechanisms behind this phenomenon are not completely understood. Here, I aimed to further describe the intricate relationship between genetics and diet in aging, focusing on touch receptor neuron aging processes in the model nematode, Caenorhabditis elegans. I specifically tested the hypotheses that (1) age-related touch receptor neuron morphological changes are associated with whole organism health, (2) intrinsic (i.e. genetic) and extrinsic (i.e. nutritional) factors can influence these morphological changes, and (3) specific cellular signaling processes underlie these morphological changes. To this end, this dissertation has three components: (1) the impact of insulin signaling disruption on neuron morphology and protein aggregation in a model of Huntington’s Disease; (2) establishment of Alaskan nutraceutical treatments that extend lifespan and offset age-related decline in neuron and whole organism health; and (3) description of mechanisms driving Alaskan nutraceutical treatment effects using RNA sequencing to target subsequent experiments. In all three of these components, I measured markers of whole organism health (e.g. lifespan, motility, endogenous reactive oxygen species) and markers of touch receptor neuron health (e.g. neuron morphology, mechanosensation). Together, this dissertation demonstrated that lifespan-extending interventions (e.g. decreased insulin signaling, Alaskan nutraceutical treatments) improved mechanosensation and, interestingly, differentially modulated development of age-related neuron morphological changes. That beneficial treatments increased the occurrence of posterior neuron process branching and/or decreased the occurrence of several anterior cell soma morphologies (e.g. soma outgrowths) suggests that some morphologies are representative of successful defense of the cell against age-related deterioration, while others are markers of cellular dysfunction. These results support the idea that multiple cellular signaling pathways are involved in aging of touch receptor neurons, and thus, there are multiple mechanisms for promoting health with age at the cellular level.
Thesis (Ph.D.) University of Alaska Fairbanks, 2016
Table of Contents
Chapter 1: General Introduction -- 1.1 Biology of aging -- 1.2 Brain and neuron aging -- 1.3 Genetic determinants of aging -- 1.4 Nutritional aging interventions -- 1.5 References cited -- Chapter 2: A Dual Role of the Insulin Signaling Pathway in the Aging of Healthy and Proteotoxically Stressed Mechanosensory Neurons -- 2.1 Abstract -- 2.2 Introduction -- 2.3 Materials and methods -- 2.3.1 Strains -- 2.3.2 Worm maintenance -- 2.3.3 RNA interference treatments -- 2.3.4 Lifespan analysis -- 2.3.5 Mechanosensory response assay -- 2.3.6 Neuron morphology imaging -- 2.3.7 Protein aggregate quantification and data analysis -- 2.4 Results -- 2.4.1 Neuron and systemic RNAi knockdown of insulin signaling proteins alters polyQ0 and polyQ128 C. elegans lifespan -- 2.4.2 Decreased insulin signaling through RNAi knockdown influences healthy mechanosensory neuron morphology and function -- 2.4.3 Touch response, mechanosensory neuron morphology, and protein aggregate accumulation are affected by insulin signaling in a model strain of Huntington’s disease pathogenesis -- 2.4.4 RNAi knockdown of daf-2 returns polyQ128 mechanosensory neuron morphology to healthy levels -- 2.5 Discussion -- 2.5.1 Summary of findings -- 2.5.2 Extending understanding of the influence of insulin signaling on healthy aging mechanosensory neurons -- 184.108.40.206 daf-2 insulin receptor -- 220.127.116.11 age-1 PI3 kinase and other insulin signaling molecules -- 18.104.22.168 daf-16 -- 2.5.3 Distinctive outcomes of daf-2 RNAi in the proteotoxically stressed Huntington’s disease model strain -- 22.214.171.124 daf-2 -- 126.96.36.199 age-1 PI3 kinase and other insulin signaling molecules -- 188.8.131.52 daf-16 -- 2.5.4 daf-2 RNAi uniquely changes distribution of polyQ128 aggregate load -- 2.5.5 Neurons aging under extreme aggregate challenge exhibit differences from natural aging -- 2.6 Acknowledgements -- 2.7 References cited -- Chapter 3: Differential Mechanosensory Neuron Aging Trajectories and Lifespan Extension Following Medicinal Alaskan Berry and Fungal Treatments in Caenorhabditis elegans -- 3.1 Abstract -- 3.2 Introduction -- 3.3 Materials and methods -- 3.3.1 C. elegans strains and maintenance -- 3.3.2 Berry and fungus extract preparation -- 3.3.3 Biochemical quantification of extracts -- 3.3.4 Berry and fungus treatment administration -- 3.3.5 Lifespan analysis -- 3.3.6 Motility measurement -- 3.3.7 Reactive oxygen species quantification -- 3.3.8 Fecundity measurement -- 3.3.9 Mechanosensory neuron aging assay -- 3.3.10 hsp16-2::GFP gene expression assay -- 3.4 Results -- 3.4.1 Standardization of Alaskan plant and fungus extracts -- 3.4.2 Alaskan berry and fungus treatments extend C. elegans lifespan -- 3.4.3 Alaskan berry and fungus treatments improve healthspan -- 3.4.4 Alaskan berry and fungus treatments differentially alter mechanosensory neuron aging -- 3.5 Discussion -- 3.6 Acknowledgements -- 3.7 References cited -- Chapter 4: Neuronal Aging in Caenorhabditis elegans is Modulated via Distinct Cellular Signaling and Genetic Mechanisms: Insights from Alaskan Berry and Fungal Treatments -- 4.1 Abstract -- 4.2 Introduction -- 4.3 Materials and methods -- 4.3.1 C. elegans strains and maintenance -- 4.3.2 Berry and fungus extract preparation and treatment administration -- 4.3.3 Transcription factor activation assays -- 4.3.4 RNA extraction and sample preparation -- 4.3.5 RNA sequencing and analysis -- 4.3.6 RNA interference treatment -- 4.3.7 Touch receptor neuron morphology and touch response analysis -- 4.4 Results -- 4.4.1 Alaskan lowbush cranberry activates DAF-16/FOXO late in life -- 4.4.2 Alaskan lowbush cranberry modulates DAF-16 to extend lifespan and influences touch receptor neuron aging -- 4.4.3 Alaskan blueberry and chaga treatments differentially impact the transcriptome -- 4.4.4 Cytoskeleton- and metabolism-mediating candidate genes impact aging touch receptor neuron morphology and function -- 4.5 Discussion -- 4.6 Acknowledgements -- 4.7 References cited -- Chapter 5: General Conclusions -- 5.1 Summary of findings -- 5.2 Proteostasis in aging neurons -- 5.3 Nutritional impacts on insulin signaling and DAF-16/FOXO activity -- 5.4 Aging phenotypes of anterior versus posterior touch receptor neurons -- 5.5 Environmental factors in medicinal food efficacy -- 5.6 Final conclusions -- 5.7 References cited.
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