Date of Award

11-5-2002

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Holly Brown-Borg

Abstract

The Free Radical Theory of Aging is considered to offer a viable explanation for the phenomenon of the aging process. The rate of aging according to this concept depends on an organism’s ability to control oxidative stress within its cellular environment. The experiments in this study center around the Ames dwarf mouse, a mammalian model of aging that has demonstrated both extended life span and heightened antioxidant defense, and skeletal muscle, a tissue whose function is significantly affected under the influence of aging. Hindlimb skeletal muscle from dwarf and wild type mice at different ages was tested for its antioxidant enzyme activity, protein content, and mRNA expression along with nonenzymatic antioxidant contribution. Enzymatic and nonenzymatic antioxidants of interest were catalase (CAT), glutathione peroxidase (GPX), and glutathione (GSH). Mitochondrial hydrogen peroxide and plasma lactate concentrations were also compared between these two types of mice. Muscle used for these experiments was taken from 3-, 12-, 18-, and 24-month-old animals whose activity consisted of normal cage activity, a single 1-hour acute bout of swimming exercise, and a 6-week training period of swimming exercise to assess the influence of different metabolic states on antioxidant defense capability on this tissue. A final experiment involved an assessment of the muscle fiber composition of the gastrocnemius, a mixed fiber hindlimb muscle in mice, to correlate this determination with antioxidant defense capacity. Significant differences were often seen in GPX enzyme activity between mouse genotypes, with dwarf mice exhibiting elevated levels by comparison at older ages. This was most evident when the animals were exposed to exercise, both acute and chronic. Catalase activity and the GSH system did not often demonstrate significant differences between genotypes; however, results appeared to display an age-related influence, with antioxidant defense enhancement apparent in dwarf mice with age compared to wild type mice. Plasma lactate concentrations were significantly elevated in the wild type mice compared to the dwarf mice on a consistent basis at all ages. Despite the fact that these assays did not often portray great differences statistically between these mice across the life span, results suggest there are biological differences with regard to antioxidant defense that favor the Ames dwarf mouse.

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