The present invention relates to methods of increasing lifespan, delaying aging, and/or preventing or treating an age-related disease or a mitochondrialdisease in a subject, comprising inducing a nuclear-mitochondrial OXPHOS protein dyssynchrony, including inhibiting the mitochondrial translation machinery function, as well as methods forscreening agents that are able to increase lifespan, inhibit or delay aging, and/or prevent or treat an age-related disease or disorder, or a mitochondrial disease or disorder, in a subject.