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Studies on Age-related Changes of Lipid Metabolisms

安藤, 亜由美 筑波大学 DOI:10.15068/0002000833

2021.08.02

概要

Senescence is known as a risk factor in multiple diseases such as neurodegenerative disorders and diabetes, and its physiological increase is known as aging. Therefore, studies exploring the underlying mechanisms of senescence are expected to lead to the discovery of new drug targets and biomarkers in these diseases. However, because of the multiple mechanisms contributed to the aging process, narrow down the cause of aging. Therefore, molecular network analysis have been used to understanding this process. One such type is metabolomic analysis, which provides qualitative and quantitative information regarding all metabolites in a cell, tissue, or organ. Therefore, metabolomic studies have the potential to provide valuable insights into the mechanisms of senescence and senescence-related diseases. Various reports carried out metabolic approaches to evaluate the aging organs of aged mammals, however the cause of physiological decline, i.e., senescence, with aging is still unclear.

In the first chapter, I described comprehensive analysis for hydrophilic and hydrophobic metabolites by LC/MS and GC/MS to evaluate changes in metabolism associated with aging, especially lipid metabolism about each from various organs. As a result, more than 1,000 metabolites were statistical analysis was carried out and deoxysphingolipids and ether-bound diacylglycerols were found in aged mouse tissues as age-related lipids. Deoxysphingolipids were reported to increases in the serum with the associate of neurological symptom of drug-induced adverse effect. And also increases has been reported in the plasma of metabolic syndrome and related disorders. As for the ether- linked, I speculated the cause of increases of ether-linked diacylglycerol was degradation of ethanolamine plasmalogen, which has ether-bound glycerol structure. These finding indicated that the aging-associated lipids, and their possible role in senescence could be investigated. this study will contribute to the understanding of the aging process and the prevention of accelerated aging and aging-associated diseases.

In chapter 2, I had carried out the development of an analytical method of simple and highly sensitive quantitation of eicosanoids using nano-flow liquid chromatography/mass spectrometry. Generally, simultaneous lipid analysis could not detect the picomolar level lipids. However, inflammation disease such as arteriosclerosis is deeply modulated by the picomolar and femtomolar levels of bioactive lipids called eicosanoids. However, the sample preparation processes for these lipids are laborious and time-consuming tasks, and the data quality relies largely on skill and experience. To solve these problems, I established a simple sample preparation using a phospholipid-removal solid-phase extraction column. As a results, the quantitation range achieved 0.01 – 100 ng/mL for thromboxane B2, and 0.05 – 100 ng/mL for prostaglandin E2, prostaglandin D2, prostaglandin F2, leukotriene B4, 6-keto prostaglandin F1α and 11-dehydro thromboxane B2. The minimized sample preparation contributes for the analytical robustness.

Taken together, I conclude that the changes of age-related unique lipids were possible to associate with aging related disorder, and the simple and high sensitivity with robustness was achieved which will be enable to evaluate more precise metabolism changes.

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