Regulatory dynamics of energy metabolism in living cells entails a coordinated response of multiple enzyme networks that operate under non-equilibrium conditions. Here we show that mitochondrial dysfunctions associated with the aging process significantly modify nonlinear dynamical signatures in free radical generation/removal, thereby altering energy metabolism in liver cells. We support our data with a plausible biochemical mechanism for modified bioenergetics that involves uncoupling protein-2 that is up-regulated in aged cells as an adaptive response to mitigate increased oxidative stress. Combining high spatial and temporal resolution imaging and bio-energetic measurements, our work provides experimental support to the hypothesis that mitochondria manifest nonlinear dynamical behavior for efficiently regulating energy metabolism in intact cells, and any partial or complete reduction in this behavior would contribute to organ dysfunctions including the aging process and other disease processes.Complexity in a dynamic system is characterized by mutually interacting components (nonlinear network dynamics), hypersensitivity to initial conditions (deterministic chaos), and longterm memory processes (power-law scaling) (1, 2). Because of the fact that multiple enzymes, cofactors, and signaling molecules contribute to efficient cell survival amid spatially/temporally varying stimuli, metabolic networks in a living cell are unique biological candidates for studying the role that complexity plays in regulatory enzyme kinetics. Mitochondria serve dual roles in cellular metabolism; that is, as the hub of cellular energetics as well as the centers of programmed cell death (3). The mitochondrial theory of aging postulates that intracellular reactive oxygen species (ROS) 2 produced during normal cellular metabolism cumulatively contributes to the progressive damage of macromolecules and, hence, to organ dysfunction that collectively define aging in organisms (4 -6). Earlier studies in isolated mitochondria from young/aged animals were unable to provide a realistic picture since they ignored physiologically relevant regulatory cross-talks between mitochondria and cytosol/nucleus. On the other hand lifespan measurements at the whole animal level may indicate specific conditions (such as calorie restriction) in which lifespan can be increased or decreased, but they do not give any clue on the cellular mechanism involved in the aging process per se. It is, therefore, imperative to develop strategies to probe single-cell responses that can report the mitochondrial dynamics in relation to other relevant metabolic networks in living cells rather than in isolated conditions. Furthermore, it is possible to dissect single cell responses under controlled perturbations, and one can obtain mechanistic insights into the complex dynamics of metabolic networks in living cells. With this motivation we sought to ask how the aging process contributes to modifications in subtle dynamics in metabolic networks and how these modifications dete...