Document Type

Thesis

Date of Degree

Spring 2017

Degree Name

MS (Master of Science)

Degree In

Health and Human Physiology

First Advisor

Amy Lynn Sindler

Abstract

Age-related increases in arterial stiffness are mediated in part by mitochondrial dysfunction. Sirtuin 3 (SIRT3) is a mitochondrial NAD+-dependent deacetylase that regulates mitochondrial function. SIRT3 deficiency contributes to physiological dysfunction in a variety of pathological conditions. Here, we tested the hypothesis that age-associated arterial stiffness, assessed by aortic pulse wave velocity (PWV), would be accompanied with decreased renal and aortic SIRT3 expression and activity due to decreased NAD+ levels. We further tested whether boosting NAD+ concentration with nicotinamide riboside (NR), a NAD+ precursor, for 6 months would reverse the effects of aging. Old (~26 mo, n = 9) C57BL/6 male mice had higher PWV vs. young (6 mo, n = 10) (448 ± 14 vs 382 ± 13, p < 0.005), which was associated with reduced arterial SIRT3 protein (0.365 ± 0.088 AU’s vs 1.000 ± 0.000); p < 0.05). Furthermore, SIRT3 deficient male mice demonstrated higher PWV compared to age-matched control mice (480 ± 21 n = 6 vs. 391 ±12 n = 7, p < 0.005). Aortic SIRT3 protein was negatively correlated with PWV (r=-0.7798, p < 0.005). Old mice also exhibited reduced kidney SIRT3 protein (0.73 ± 0.10 AU’s) compared to young controls (1.00 ± 0.00; p = 0.0192) and reduced NAD+ (918.6 ± 50.5 pmol/mg vs. young 1302.0 ± 56.6 pmol/mg, p = 0.0036). Old mice supplemented with NR had increased NAD+ concentration in kidney tissue (1303.0 ± 90.2 pmol/mg) however, had no effect on normalizing age-associated arterial stiffness (402 ± 18 old with NR vs 418 ± 15 old; p = 0.78). Here we show for that SIRT3 protein correlates with aortic stiffness and may be required for the maintenance of healthy arteries and for the first time that supplementation with NR, a commercially available supplement, ameliorates age-associated decreases in renal NAD+ demonstrating therapeutic potential in kidney disease.

Keywords

arterial stiffness, Kidney Disease, Nicotinamide Riboside, SIRT3

Pages

x, 40 pages

Bibliography

Includes bibliographical references (pages 35-40).

Copyright

Copyright © 2017 Alexander Lee Brodjeski

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