Mitohormesis

Mitohormesis is the phenomenon by which transient, low-to-moderate increases in mitochondrially generated reactive oxygen species (ROS — superoxide, hydrogen peroxide, and related radicals) trigger protective adaptive responses improving cellular stress resistance, metabolic health, and longevity. These ROS pulses act as intracellular signals, activating transcription factors including NRF2 and p38 MAPK, upregulating antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and inducing mitophagy. This dose-dependent, bell-shaped response was formalized by Ristow and colleagues through C. elegans and human studies linking exercise and caloric restriction benefits to ROS-dependent signaling. A 2009 PNAS trial (Ristow et al.) showed that vitamin C (1,000 mg/day) and vitamin E (400 IU/day) taken during a 4-week exercise program abolished improvements in insulin sensitivity and antioxidant defenses, implicating ROS as necessary adaptive signals. In aging, mitohormetic signaling declines alongside mitochondrial biogenesis, contributing to sarcopenia and metabolic deterioration; structured exercise — endurance and resistance training in particular — remains the best-evidenced intervention in humans, while pharmacological ROS mimetics remain investigational.