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Mitochondrial sirtuins regulate lifespan in C. elegans

Author
Chang, Sarah
Published
[University Park, Pennsylvania] : Pennsylvania State University, 2016.
Physical Description
1 electronic document
Additional Creators
Hanna-Rose, Wendy and Schreyer Honors College
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Open Access.
Summary
Mitochondrial sirtuins are proteins that regulate metabolism and are emerging drug targets for metabolic and age-related diseases such as cancer, diabetes, and Alzheimer's disease. Although it is known that they are involved in metabolic regulation, how they carry out this regulation and many of their exact functions remain uncharacterized. In this study, I uncover a novel role for the mitochondrial sirtuins SIR-2.2 and SIR-2.3 in lifespan regulation using the C. elegans model. Using a genetic approach, I discovered that the mitochondrial sirtuin mutant worms surprisingly lived 25% longer than wild-type. While both overexpression of sirtuins and decreased consumption of food are known mechanisms for lifespan extension, neither decreased food intake nor upregulation of sirtuins as compensation was observed in the mitochondrial sirtuin mutants. sir-2.2 mutants display a significant increase in mitochondrial superoxide dismutase sod-3 expression. The increased lifespan of sir-2.2 mutants was further extended upon knocking down pyruvate carboxylase pyc-1 and pyruvate dehydrogenase pdh. LC-MS analysis revealed metabolic changes in sir-2.2 and sir-2.3 mutants compared to wild-type. This data suggests that SIR-2.2 and SIR-2.3 may not be redundant in function and may have different mechanisms for metabolism and lifespan regulation. These results underscore the ability of mitochondrial sirtuins to control the metabolic state of animals and reveal new metabolic pathways that can be targeted to extend lifespan.
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Dissertation Note
B.S. Pennsylvania State University 2016.
Technical Details
The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
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