Different theoretical considerations suggest that brown adipose tissue (BAT) and uncoupling proteins (UCPs) could affect aging and longevity. BAT activation leads to an increased energy expenditure and substrate oxidation which could prevent the development of obesity and related life shortening health disorders such as the metabolic syndrome. The hallmark of brown adipose tissue is the presence of UCP1 which uncouples mitochondrial respiration from ATP synthesis, thus generating heat. According to the “uncoupling-to-survive” hypothesis, an increased mitochondrial proton conductance could lead to decreased production of reactive oxygen species (ROS) which in turn could minimize oxidative damage to DNA and thus slow ageing. This hypothesis is supported by recent reports that genetic variations in human UCP genes are associated with longevity and also more directly by animal studies. We have shown that transgenic mice with ectopic expression of UCP1 in skeletal muscle mitochondria (HSA-UCP1 mice) displayed a markedly increased longevity under high fat diet feeding which was linked to a delayed obesity development and improved glucose homeostasis. We further observed a positive correlation of total energy expenditure with lifespan. Although isolated muscle mitochondria from HSA-UCP1 mice showed a decreased ROS production in vitro, we did not find evidence for decreased oxidative stress in vivo. On the contrary, we observed an increased fat metabolism in skeletal muscle of HSA-UCP1 mice which was linked to an increase in lipid peroxidation products, indicating an increased oxidative stress. This was paralleled by an induction of endogenous antioxidant defense systems and increased redox signaling. This argues for the mitochondrial hormesis hypothesis suggesting that ROS are not always detrimental to health but essential signaling molecules for health and longevity.