The Toll of SARM1/TIR1—A Novel NAD-Consuming Enzyme
Open Access
- Author:
- Argento, Ian
- Area of Honors:
- Biochemistry and Molecular Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Melanie Mc Reynolds, Thesis Supervisor
Lorraine C Santy, Thesis Honors Advisor - Keywords:
- C. elegans
NAD+
Metabolomics
Biochemistry
Longevity - Abstract:
- The discovery that nicotinamide adenine dinucleotide (NAD+) declines with age launched scrutiny into the web of metabolic pathways that produce and consume the essential cofactor. Recently, the scrutiny befalls SARM1—a novel NAD+-consuming enzyme with implications in neuronal cell death. While researchers examine the potential boon to NAD+ and neural health offered by SARM1 knockdown therapeutics, I seek to understand how SARM1 deletion affects the organism as a whole: what uncharacterized phenotypes associate with SARM1 deletion, and how do they relate to altered NAD+ metabolism? I begin my research into the SARM1 homologue TIR-1, found in C. elegans, where I examine longevity, brood-sizes, and NAD+ metabolism to characterize the health (and illness) of TIR-1 mutants. My data suggests that the evolutionarily conserved NAD+-consumer maintains health, promoting a longer lifespan and increased reproductive vitality without significantly depleting NAD+. I explore metabolomics data to understand a potential role for TIR-1 not in NAD+ consumption, but in mediating the uptake of NAD+ precursors. My research contributes to the ongoing investigation of how to protect against NAD+ imbalance and offers insight on how C. elegans TIR-1 mutants model therapeutics which target SARM1.