Mitochondrial sirtuins regulate lifespan in C. elegans

Open Access
Author:
Chang, Sarah
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Wendy Hanna Rose, Thesis Supervisor
  • Ming Tien, Honors Advisor
Keywords:
  • mitochondria
  • sirtuins
  • C. elegans
  • lifespan
  • oxidative stress
  • pyruvate carboxylase
  • pyruvate dehydrogenase
Abstract:
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.