Date of Award

Spring 1-1-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Douglas R. Seals

Second Advisor

Robert S. Mazzeo

Third Advisor

Matthew B. McQueen

Fourth Advisor

Thomas J. LaRocca

Fifth Advisor

Christopher L. Gentile

Abstract

Cardiovascular diseases (CVD) remain the leading cause of mortality in modern societies. Age is the major risk factor for CVD due largely to adverse changes to arteries. Two key features of arterial aging that increase CVD risk are the development of vascular endothelial dysfunction, characterized by reduced nitric oxide (NO)-mediated endothelium-dependent dilation (EDD), and large elastic artery stiffness. These adverse functional changes are driven by increased oxidative stress and inflammation.

Trehalose is a naturally occurring disaccharide with antioxidant and anti-inflammatory properties that protects against aging in lower organisms. Moreover, oral trehalose treatment improves NO-mediated EDD and reduces arterial stiffness in old mice. However, the efficacy of trehalose to reverse arterial aging in humans is unknown. The goal of this dissertation was to test the hypothesis that oral trehalose supplementation would improve resistance and/or conduit artery NO-mediated EDD in healthy MA/O adults, and that improvements would be related to reduced inflammation and oxidative stress. A secondary hypothesis was that trehalose supplementation would decrease large elastic artery stiffness in this same population.

Thirty-two men and postmenopausal women aged 50-77 years consumed 100g/day of trehalose or maltose (energy equivalent control disaccharide without the reported health benefits of trehalose) for 12 weeks (randomized, double-blind). Resistance artery NO-mediated EDD increased with trehalose in subjects remaining weight-stable, and this was associated with evidence of decreased endothelial cell inflammation. Contrastingly, trehalose did not modify conduit artery EDD or oxidative stress. These findings indicate that trehalose may be a novel therapy for reducing vascular inflammation and improving resistance but not conduit artery EDD in MA/O adults able to maintain stable body mass.

In a secondary protocol of the parent investigation, large elastic artery stiffness was assessed in 31 healthy adults 50-77 years before and after 12 weeks of oral trehalose or maltose supplementation (100g/day). Trehalose was not effective for reversing arterial stiffness in this population.

These studies indicate that although trehalose has heterogeneous effects on different aspects of arterial aging and its caloric content poses challenges, this may be an effective intervention for the primary prevention of CVD by reversing resistance artery EDD in healthy MA/O adults.

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