Moderation of mitochondrial respiration mitigates metabolic syndrome of aging

Significance The efforts toward minimizing oxidative stress and maintaining mitochondrial energy metabolism for promoted healthy aging are at the forefront of current research on aging. We have characterized a treatment that, by reversible inhibition of mitochondrial respiration in mice through cytochrome c oxidase (CcO), markedly improves mitochondrial bioenergetics and delays the lead health concerns associated with aging in mice. We demonstrated that chronic moderate inhibition of CcO reduces ATP synthesis, promotes mitochondrial biogenesis and mitophagy, subsequently decreases ROS production and mitochondrial decay, and rectifies vital cellular energy metabolism regulators, thus, effectively refining energy homeostasis and curbing obesity and glucose irregularities linked to aging.