The study investigates the role of mitochondrial ribosomal proteins (MRPs) in longevity regulation. Using mouse population genetics and RNAi in *C. elegans*, the authors identify *MrpS5* and other MRPs as key regulators of metabolic and longevity pathways. Knockdown of MRP genes triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response (UPRmt). Specific antibiotics targeting mitochondrial translation and ethidium bromide, which impair mitochondrial DNA transcription, mimic MRP knockdown and extend lifespan by inducing mitonuclear protein imbalance. Additionally, resveratrol and rapamycin, which act on different molecular targets, also induce mitonuclear protein imbalance, UPRmt, and lifespan extension in *C. elegans*. These findings suggest that MRPs form an evolutionarily conserved protein family that links mitochondrial ribosome function and mitonuclear protein imbalance to UPRmt, a common longevity pathway across species. The study highlights the importance of mitochondrial translation and metabolism in natural lifespan regulation and provides a potential therapeutic target for aging-related diseases.The study investigates the role of mitochondrial ribosomal proteins (MRPs) in longevity regulation. Using mouse population genetics and RNAi in *C. elegans*, the authors identify *MrpS5* and other MRPs as key regulators of metabolic and longevity pathways. Knockdown of MRP genes triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response (UPRmt). Specific antibiotics targeting mitochondrial translation and ethidium bromide, which impair mitochondrial DNA transcription, mimic MRP knockdown and extend lifespan by inducing mitonuclear protein imbalance. Additionally, resveratrol and rapamycin, which act on different molecular targets, also induce mitonuclear protein imbalance, UPRmt, and lifespan extension in *C. elegans*. These findings suggest that MRPs form an evolutionarily conserved protein family that links mitochondrial ribosome function and mitonuclear protein imbalance to UPRmt, a common longevity pathway across species. The study highlights the importance of mitochondrial translation and metabolism in natural lifespan regulation and provides a potential therapeutic target for aging-related diseases.