Uncoupled respiration, metabolic stability and survival

Currently, three theories are addressing the relationship between energy metabolism and lifespan of mammals. The oldest, the "rate of living" theory, predicts that animals having a higher metabolic rate live shorter due to the higher production of radical oxygen species (ROS). ROS are highly reactive molecules which play a major pathophysiological role during aging and are generally accepted as being causal for age-related death. The recent "uncoupled to survive" hypothesis points to mitochondrial efficiency as determinant for ROS production. Uncoupled respiration, which takes place in mitochondria, e.g when heat is generated during nonshivering thermogenesis, is apparently beneficial. Notably, mitochondrial ROS formation is lowest when oxidative phosphorylation is uncoupled from ATP synthesis and energy is lost as heat. The third hypothesis suggests that not metabolic rate as such, but "metabolic stability", the capacity of metabolic networks to maintain homeostasis, could be rate-limiting for aging. We propose to experimentally test these three hypotheses in mice from the C57 BL6 strain. We specifically plan to measure energy budgets as well as ROS production over the entire lifespan of mice. We will assess lifelong time courses of food intake, body weight, assimilated energy, average daily and resting metabolic rates and will repeatedly quantify ROS production. By manipulating ambient temperature we will induce nonshivering thermogenesis and thereby uncoupled respiration. We hypothesise that mice with increased uncoupling in cold conditions life longer and produce less ROS than mice with coupled respiration but equivalent total energy turnover. Further, we plan to test whether metabolic instability impairs longevity by comparing the lifespan of mice maintained at constant temperature with that of mice exposed to shifts between cold and warm temperatures. We expect that our results will substantially contribute to the current discussion on the link between aging and energetics.