Reactive oxygen species (ROS) are continuously generated in skeletal muscle during exercise. ROS produced during exercise instigate adaptive responses that promote muscle function and metabolic health. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Both mitochondria and NADPH oxidases (NOXs) have been implicated as sources of ROS in muscle. Our studies have shown that skeletal muscle NADPH oxidase 4 (NOX4) is primarily responsible for the production of H2O2 in response to exercise. We have shown that H2O generated by skeletal muscle NOX4 during exercise promotes both mitochondrial biogenesis and antioxidant defence to enhance muscle function and prevent the oxidative damage that otherwise contributes to the development of insulin resistance. We now report that skeletal muscle NOX4 levels decline with age and that this contributes to the decline in muscle function and the development of insulin resistance . We demonstrate and that the specific deletion of NOX4 in skeletal muscle exacerbates the decline in insulin sensitivity and onset of frailty with age. Our findings point towards defective skeletal muscle redox homeostasis being instrumental in the decline in muscle function and the development of insulin resistance and frailty with age.