NDUFS2 and inborn mitochondrial metabolism disorder: Clearly there is an association of normal aging with a degree of ETC impairment, but this impairment is not as severe as that seen in models of primary mitochondrial diseases or in embryonic lethal complete knockouts of essential ETC components like Ndufs2. Interventions like caloric restriction, exercise, and metformin treatment have all been associated with increased life or healthspan as well as a mild degree of mitochondrial ETC activity impairment that is thought to trigger a beneficial stress response.