A study published in *Nature* (2013) reveals that mitonuclear protein imbalance is a conserved mechanism for extending lifespan. The research, led by Riekelt H. Houtkooper and Johan Auwerx, identifies mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins (MRPs) as key regulators of longevity. These proteins, when knocked down, cause an imbalance between nuclear and mitochondrial-encoded proteins, activating the mitochondrial unfolded protein response (UPRmt), which extends lifespan in both *C. elegans* and mammals. The study used a combination of mouse population genetics and RNAi in *C. elegans* to identify MRPs as longevity genes. In *C. elegans*, MRPs induce a stoichiometric imbalance between nuclear and mitochondrial-encoded OXPHOS proteins, termed "mitonuclear protein imbalance," which activates UPRmt and extends lifespan. This mechanism is shared with pathways that induce mitonuclear protein imbalance, such as the UPRmt and lifespan effects of rapamycin and resveratrol. The study also identified a quantitative trait locus (QTL) on chromosome 2 in mice associated with longevity, with genes Slc12a1, Mrps5, and Ttl showing strong correlation with lifespan. Mrps5 expression covaries with genes involved in oxidative phosphorylation (OXPHOS), suggesting a key role in longevity. The study further demonstrated that MRPs are conserved across species, linking mitochondrial ribosome function and mitonuclear protein imbalance to UPRmt, an overarching longevity pathway. Pharmacological agents such as doxycycline and chloramphenicol, which inhibit mitochondrial translation, mimic MRPs knockdown and extend lifespan by inducing mitonuclear protein imbalance. Similarly, resveratrol and rapamycin, which act on different molecular targets, also induce UPRmt and extend lifespan in *C. elegans*. The study concludes that mitonuclear protein imbalance and UPRmt represent a conserved mechanism for longevity, linking mitochondrial function to lifespan regulation. This mechanism is independent of reactive oxygen species (ROS) and mitohormesis, and is involved in multiple species, including mammals. The findings highlight the importance of mitochondrial protein synthesis and metabolism in natural lifespan regulation.A study published in *Nature* (2013) reveals that mitonuclear protein imbalance is a conserved mechanism for extending lifespan. The research, led by Riekelt H. Houtkooper and Johan Auwerx, identifies mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins (MRPs) as key regulators of longevity. These proteins, when knocked down, cause an imbalance between nuclear and mitochondrial-encoded proteins, activating the mitochondrial unfolded protein response (UPRmt), which extends lifespan in both *C. elegans* and mammals. The study used a combination of mouse population genetics and RNAi in *C. elegans* to identify MRPs as longevity genes. In *C. elegans*, MRPs induce a stoichiometric imbalance between nuclear and mitochondrial-encoded OXPHOS proteins, termed "mitonuclear protein imbalance," which activates UPRmt and extends lifespan. This mechanism is shared with pathways that induce mitonuclear protein imbalance, such as the UPRmt and lifespan effects of rapamycin and resveratrol. The study also identified a quantitative trait locus (QTL) on chromosome 2 in mice associated with longevity, with genes Slc12a1, Mrps5, and Ttl showing strong correlation with lifespan. Mrps5 expression covaries with genes involved in oxidative phosphorylation (OXPHOS), suggesting a key role in longevity. The study further demonstrated that MRPs are conserved across species, linking mitochondrial ribosome function and mitonuclear protein imbalance to UPRmt, an overarching longevity pathway. Pharmacological agents such as doxycycline and chloramphenicol, which inhibit mitochondrial translation, mimic MRPs knockdown and extend lifespan by inducing mitonuclear protein imbalance. Similarly, resveratrol and rapamycin, which act on different molecular targets, also induce UPRmt and extend lifespan in *C. elegans*. The study concludes that mitonuclear protein imbalance and UPRmt represent a conserved mechanism for longevity, linking mitochondrial function to lifespan regulation. This mechanism is independent of reactive oxygen species (ROS) and mitohormesis, and is involved in multiple species, including mammals. The findings highlight the importance of mitochondrial protein synthesis and metabolism in natural lifespan regulation.