京都大学 / 新制・課程博士 / 博士(理学) / 甲第23043号 / 理博第4720号 / 新制||理||1676(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)准教授 秋山 秋梅, 教授 曽田 貞滋, 教授 沼田 英治 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

The main aim of this work was to compare the genotoxicity of organic extracts from different size fractions of aerosol particles (1-10 µm, 0,5-1 µm, 0,17-0,5 µm) collected by high volume cascade impactors in various localities of the Czech Republic differing in the extent of the environmental pollution (Březno - strip mine, Dobré Štěstí - highway, Praha - city center, Láz - background station). Genotoxicity was determined in acellular assay of calf thymus DNA (CT-DNA) with and without S9 metabolic activation by analysis of DNA adducts induced by extractable organic matter (EOM) from the particulate matter (PM) by 32 P-postlabeling and the ability of extracts to induce oxidative DNA damage was evaluated using the competitive ELISA test. The main finding of this work is that most of the observed genotoxicity is connected with fine particles (<1 µm). The concentration of carcinogenic polycyclic aromatic hydrocarbons (c-PAHs) in EOMs indicate that fine fractions bound the highest amount of c-PAHs in all sampling sites. This fact might be related to a higher specific surface of this fraction as compared with a course fraction and a higher mass as compared with a condensational fraction. As for aerosol mass, both fine and condensational fractions are effective carriers of c-PAHs. Similarly, the DNA...

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<p>Aging erodes motivation, cognition, sensory modalities and physical capacities, effectively depleting quality of life. Declining sensory, cognitive and motor function are reliable biomarkers of aging and mortality risk. These declines are associated with dysregulation of systemic and cellular processes. We developed a complex dietary supplement (DSP) designed to ameliorate five mechanisms of aging (oxidative processes, inflammation, mitochondrial function, insulin resistance and membrane integrity). Remarkably, normal mice fed the DSP retained youthful functionality into old ages, reflecting slower aging rates. Marked improvements in motor function, memory capacity, spatial learning, muscle strength, visual acuity, olfaction, fecundity and important behavioral functions were observed in aging supplemented mice. Conversely, untreated control animals showed age-related declines in all of the above. Functional improvements were associated with reduced oxidative damage, elevated mitochondrial activity, positive cellular energy balance, improved glucose tolerance, boosted neurotransmitters, greater synaptic density and higher neuronal numbers throughout the brain. A 30% reduction in cancer rates was also documented for DSP treated p53+/- mice. The vast functional benefits greatly exceed the modest longevity extension (11%) in normal supplemented mice. For aging humans, maintaining functionality and performance into later years may provide greater socioeconomic and health benefits than simply prolonging lifespan. Implications of these findings extend to common age-related pathologies including dementia and neurodegenerative diseases, diabetes, cancer, sarcopenia and age-related macular degeneration. Although identifying the role of specific ingredients remains outstanding, results provide proof of principle that complex dietary cocktails can powerfully ameliorate biomarkers of aging and modulate mechanisms considered ultimate goals for aging interventions.</p> / Doctor of Philosophy (PhD)