Mitochondria play a crucial role in cellular processes. They are where oxidative phosphorylation (OXPHOS) occurs. OXPOHS produces ATP which powers most cellular functions. Mitochondria are also regulators of other cellular processes such as apoptosis, cell cycle regulation, calcium signaling and neuronal synaptic transmission. They contain the only extra-nuclear DNA in eukaryotes. Mitochondrial DNA (mtDNA) encodes crucial components required for OXPHOS. Reactive oxygen species (ROS) are a natural byproduct of OXPHOS. In healthy states, ROS production facilitates mitochondrial cell signaling. ROS levels are kept in homeostasis by naturally occurring anti-oxidants. When dysregulated, ROS can cause mutations in mtDNA ultimately thereby decreasing ATP production capacity. Aging in humans manifests as a gradual decline in cellular functioning, leading to loss of tissue function and eventual death. The rate at which humans age and eventually die, is a complex interplay between genes and environment. Mitochondria are closely related to cellular function and their decline mirrors the aging process. These observations suggest that mitochondrial dysfunction might play a role in the aging process.Human mtDNA is exclusively transmitted from mother to child with no possibility for paternal recombination. Certain patterns of mtDNA haplotypes cluster in geographic regions. Observing these geographic differences has allowed researchers to put groups of mtDNA haplotypes into phylogenic trees that mirror human migration patterns. Epidemiologic studies have sought to associate disease patterns with mtDNA haplotype groups. Some studies of longevity have found that carriers of certain mtDNA haplotype groups are more common among aged cases than younger controls. However, these studies leave many questions unsettled. Prior studies do not account for nuclear genetic factors, have not achieved sufficient statistical power, have been unable to account for changes in age-at-death that have occurred over time and have not use time-to-event analysis.This dissertation examines that hypothesis that mtDNA Haplogroup J carriers live longer than carriers of other haplogroups. This work focuses on a newly-identified population isolate in Mid-Michigan with a well-documented pedigree. It is within this pedigree that we propose to test the Haplogroup J and longevity or lifespan association. In Chapter 1, the case for the association is presented. It covers the evidence for a stronger maternal to the heritability of longevity over a paternal contribution. It details how mitochondria could be the biologic mechanism and mtDNA genetics the observable phenomena and testable material for the heritability differences. Further this chapter presents the role of mitochondria in biologic processes and how genetic variation presented by mtDNA haplogroup differences has been demonstrated as epidemiologic risk factors in several human health states. It also details why previous studies are not in the optimal context to best address these questions.In Chapter 2, the unique characteristics of the population isolate and their pedigree database are presented. The descendants of a small group of settlers have remained in a small geographic area for the past century and a half. Since these descendants reside in the small area and often to choose to marry others within the community, the population is isolated but not closed. Isolate populations are ideal for discovering occult heritability of human health states. Chapter 3 presents a meta-analysis and pooled effect-size estimate of mtDNA Haplogroup J carriers living longer lives than carriers of other groups. The association is more pronounced in European populations. However, even when all available studies are pooled into one effect estimate, there is still insufficient power to confirm or refute that one haplogroup confers a longevity benefit in the background of many others expected in a European population. Within this epidemiologic context, I hypothesize that a population isolate is a well-suited sampling frame for studying a mitochondrial genetic association because the background nuclear-genetic and environment factors have some homogeneity. Chapter 4 presents the results the "Mitochondrial DNA patterns and Lifespan" (MDPL) study, in which I test the Haplogroup J/Lifespan hypothesis in the population isolate using several statistical measures. The study assembled a direct population of living individuals, scored their mtDNA haplogroup, ascribed their haplogroup to the most distant maternal relative in the pedigree dataset and assembled all her descendants. From the deceased mitochondrial descendants of the maternal ancestors, we created an indirect population. From the ages at death of the indirect population, I tested several metrics of increased lifespan in Haplogroup J carriers contrasted with carriers of all other haplogroups combined and assess the differences when stratified by sex.Chapter 5 presents a summary of these findings and proposed future direction. In pursuing the test of my hypothesis I discovered points for others to ponder. I present these points and discuss my thoughts to guide future studies.
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