Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Charles M. Brenner

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a cofactor in hydride transfer reactions and consumed substrate of several classes of glycohydrolyitc enzymes, including sirtuins. NAD+, its biosynthetic intermediates, breakdown products, and related nucleotides (the NAD metabolome) is altered in many metabolic disorders, such as aging and obesity. Supplementation with the novel NAD+ precursor, nicotinamide riboside (NR), ameliorates these alterations and opposes systemic metabolic dysfunctions in rodent models. Based on the hypothesis that perturbations of the NAD metabolome are both a symptom and cause of metabolic disease, accurate assessment of the abundance of these metabolites is expected to provide insight into the biology of diseases and the mechanism of action of NR in promoting metabolic health. Current quantitative methods, such as HPLC, lack specificity and sensitivity to detect distinct alterations to the NAD metabolome. In this thesis, I developed novel sensitive, accurate, robust liquid chromatography mass spectrometry methodologies to quantify the NAD metabolome and applied these methods to determine the effects of disease states and NR supplementation on NAD+ metabolism. My investigations indicate that NR robustly increases the NAD metabolome, especially NAD+ in a manner kinetically different than any other NAD+ precursor. I provide the first evidence of effective NAD+ supplementation from NR in a healthy, 52 year old human male, suggesting the metabolic promoting qualities of NR uncovered in rodent studies are translatable to humans. During my investigation of NR supplementation, my work establishes an unexpected robust, dramatic increase in deamino–NAD+, NAAD, directly from NR, which I argue could serve as an accessible biomarker for efficacious NAD+ supplementation and the effect of disease upon the NAD metabolome. Lastly, I further establish NR as a general therapeutic against metabolic disorder by detailing its ability to oppose aspects of chronic alcoholism and diabetes mellitus.

Public Abstract

A century ago in the United States, a disease known as Pellagra ravaged areas mainly subsisting on maize. This disease was detrimental to quality of life and in some instances proved fatal. At the time, this disease was considered a major public health problem and many grant initiatives were announced to identify the cause of the disease and develop an effective treatment. Through these efforts, Pellagra was shown to be a non-infectious disease caused by a diet of maize and lard. It was cured by drinking milk and eating more animal meat. These efforts essentially eliminated the disease from high income nations. Further investigation identified the B3 vitamins commonly referred to as niacin as the anti-Pellagra components of milk and animal meat. Today, obesity, diabetes, and heart disease are prevalent in the US and areas around the world. These diseases are a new public health crisis resulting in the loss of billions of dollars and a decreased quality of life and lifespan. As it was a hundred years ago, public funds are now directed to identify effective treatments to counter these prevalent and devastating diseases. Work generously funded by the public has identified the most recently discovered B3 vitamin, nicotinamide riboside, as a health promoting compound that could treat these diseases. The goal of my thesis was to develop improved tools to answer how this vitamin works in times of health and disease. In so doing, my work further establishes this novel B3 vitamin as a health promoting compound and describes clinically relevant technologies to assess its effectiveness in future human trials.

Keywords

publicabstract, LC-MS, Metabolomics, Nicotinamide Adenine Dinucleotide, Nicotinamide Riboside

Pages

xv, 190 pages

Bibliography

Includes bibliographical references (pages 174-190).

Copyright

Copyright 2016 Samuel AJ Trammell

Included in

Genetics Commons

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