The effects of mitochondrial uncoupling proteins 2 and 3 on lifespan characteristics and oxidative stress in the C57BL6 female mouse

Oxidative damage contributes to several degenerative mechanisms in physiology and is considered to be a major factor in aging [1--4]. Because calorie restriction (CR) has consistently led to significant extensions of organismal lifespan concomitant with decreased markers of oxidative stress [5], several investigations have attempted to determine if modulating specific antioxidant mechanisms will attenuate oxidative stress and extend longevity. Since the proposal of Harman's Free Radical Theory of Aging (1956), there have been several attempts to mimic the lifespan extension of CR through gene alteration using transgenic animal models. And given that mitochondria serve as a substantial source for reactive oxygen species (ROS) production [6--8], much attention has been aimed at altering mitochondrial oxidative stress. One potential mechanism that may be involved in mitochondrial oxidative stress and the generation of ROS involves uncoupling proteins (UCPs) positioned in the mitochondrial membrane. My experiments have tested the hypothesis that overexpression of UCP2 and UCP3 mimics CR with respect to reduction of ROS production and extension of lifespan. Chapter 2 describes the lifelong effect(s) of UCP2 and UCP3 at the organismal level. Lifespan characteristics were examined and compared in mice overexpressing UCP2/3 (Tg), their non-overexpressing littermates (Non-Tg) and UCP3-knockouts (UCP3KO)s relative to calorie restriction in C57BL/6J wild-type CR (WT-CR) mice and their WT littermates1. While chapter 2 addresses UCP2/3 and longevity, chapters 3 and 4 describe the effect of UCP2 on age-related hypothalamic inflammation and accrual of macromolecular oxidative damage, respectively. The results of the studies presented suggest that the physiological effect(s) in Tg mice overexpressing UCP2 and UCP3 do not mimic the CR phenotype under "basal" conditions of aging. Despite upregulation of UCP2 and UCP3 in various tissues of old CR mice, Tg mice did not alter aging mechanisms by (1) extending maximal lifespan or (2) suppressing neuroinflammation and subsequent oxidative damage. Furthermore, the absence of UCP3 did not shorten organismal longevity, nor did the absence of UCP2 appear to exacerbate age-related neuroinflammatory processes.;1Statistically meaningful lifespan characteristics were not obtained from UCP2KO C57BL6 mice due to early difficulties genotyping the UCP2KO colony (Chapt.2)...