All ETDs from UAB

Advisory Committee Chair

Daniel L Smith

Advisory Committee Members

Shannon Bailey

Paula Chandler-Laney

Barbara Gower

Degui Zhi

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Age-related diseases continue to be a leading cause of death. One of the only replicable methods proven to decrease age-related morbidity and mortality in multiple species is calorie restriction (CR). CR is difficult for human populations to implement, and has a number of associated risks and side effects. A CR mimetic could provide the healthspan- and lifespan-extending benefits of CR without the limitations. Acarbose (ACA), an α-glucosidase and α-amylase inhibitor approved to treat type 2 diabetes in humans, was recently identified as able to extend lifespan in healthy mice. The purpose of this research was to determine the effects of ACA on physiology and metabolism of the healthy mouse and to investigate the possibility of ACA as a CR mimetic. A 6-month dose-response study was performed in both male and female C57BL/6J mice. Mice received ad libitum diets containing low, medium, or high doses of ACA, as well as a no-dose control. Male mice receiving all doses of ACA weighed less following treatment than control-fed mice and all ACA mice had less fat mass, but not lean mass. This was despite an increase in food intake with all ACA doses and no differences in daily total energy expenditure. Fecal analyses indicated ACA led to decreased carbohydrate and increased fat and protein extraction from the diet, increased fecal levels of short chain fatty acids, and less microbial diversity. Next, we investigated modification of macronutrient metabolism and inflammatory factors in mature, healthy C57BL/6J mice through four diets: 0.1% ACA, 40% CR, a diet matched in macronutrients to the calculated exposure from the previous study, and no-treatment controls. After 10 months, all ACA and CR mice weighed less than controls. ACA and CR also modified whole-body metabolism and energy expenditure. At this young age, few differences were seen among groups in circulating cytokines or in immune cells isolated from spleens and mesenteric lymph nodes, suggesting differences may not appear until an immune or inflammatory challenge is encountered. ACA results in both similar and different outcomes compared to CR and may be an effective method of improving healthspan in human populations.

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