Severe mitochondria deficiency leads in humans to devastating degenerative disorders, but we and others found that mild reduction of mitochondrial function has pro-longevity effects. This indicates that cellular adaptation to mild metabolic stress can induce beneficial responses, which if identified may represent promising candidates to prevent or delay the development of age-associated disorders thus ultimately extending healthy lifespan. We exploits C. elegans as a powerful genetic and screening tool to unravel molecular mechanisms of mitochondrial-stress control of longevity and of mitochondria-associated diseases, with special attention revolved to the crosstalk between genetic and environmental interventions.