Date of Award

Spring 5-15-2018

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Maintenance of NAD+ biosynthesis is critical for tissue and organ functionality during aging and disease. This dissertation addresses the role of NAMPT-mediated NAD+ biosynthesis in the age-associated decline of systemic NAD+ and its effect on the development of pathophysiologies. In the mouse hippocampus, NAD+ declines with age and effects cognitive function, leading to development of cognitive hypersensitivity. NAMPT-mediated NAD+ biosynthesis in the CA1 region of the hippocampus contributes to this dysfunction. We address the critical role for inter-tissue communication in maintenance of NAD+ biosynthesis and show the critical role of SIRT1 in deacetylating NAMPT, allowing for secretion from adipose tissue. Extracellular modulates hypothalamic NAD+ and SIRT1 function, highlighting a novel regulatory loop for systemic NAD+ biosynthesis. Lastly, NAD+ intermediate therapy is a burgeoning area of interest. Multiple human clinical trials are being conducted to understand the pharmacokinetics and safety of NAD+ intermediate supplementation. Washington University School of Medicine is conducting the first human clinical trial of nicotinamide mononucleotide, examining the effects of NMN on the cardiometabolic function. This dissertation highlights the importance for maintenance of NAD+ for tissue functionality, provides further understanding of the NAD+ biosynthetic mechanisms, and provides potential routes for treatment of aging and disease.

Language

English (en)

Chair and Committee

Shin-ichiro Imai

Committee Members

Steven Mennerick, Joseph Dougherty, Michael Bruchas, David Wozniak,

Comments

Permanent URL: https://doi.org/10.7936/K7445KWF

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