Abstract

Proper control of lipid metabolism in the endoplasmic reticulum, lipid bodies, peroxisomes and mitochondria is essential for longevity regulation. However, the molecular mechanisms linking longevity and lipid metabolism in these organelles have not been defined prior to studies described here. The establishment of such mechanisms operating in chronologically aging yeast was the objective of my thesis.
To develop a tool for quantitative monitoring of the age-related dynamics of changes in the cellular and organellar lipidomes of chronologically aging yeast, I was able to solve the inherent limitations of the currently used methods for lipidomic analysis (including the limitations characteristic of mass spectrometry-based techniques) by devising a survey-scan electrospray ionization mass spectrometry method for quantitative lipidomics. This novel method enables within a very limited period of time and using a very low number of cells to resolve, unequivocally identify and accurately quantitate all molecular forms of lipid species composing yeast lipidome and the majority of molecular forms of lipid species composing the lipidome of cultured human cells.
Using a combination of the functional genetic, cell biological, electron and fluorescence microscopical, proteomic, lipidomic, and metabolomic analyses, I established three molecular mechanisms linking longevity and lipid metabolism confined to the endoplasmic reticulum, lipid bodies, peroxisomes and mitochondria. One of these mechanisms underlies the ability of a caloric restriction diet to extend longevity of
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chronologically aging yeast by specifically remodeling the metabolism of neutral lipids in the endoplasmic reticulum, lipid bodies and peroxisomes. The other mechanism underlies the ability of lithocholic acid, a novel anti-aging compound that my research enabled to identify, to extend yeast chronological life span by targeting the longevity-defining aspects of lipid metabolism confined to the endoplasmic reticulum, lipid bodies and peroxisomes. The third mechanism underlies the ability of lithocholic acid to extend yeast chronological life span under caloric restriction conditions by remodeling lipid metabolism in the mitochondrial membrane, thereby altering the repertoire of membrane lipids in mitochondria and influencing several longevity-defining processes confined to these organelles.