Academic Medical Center, Amsterdam, Netherlands
Aging is a complex process that is coordinated by overlapping and partially independent processes often involving changes in metabolic networks. Anabolic caloric excess pathways—such as those involving insulin/IGF1 and mTOR—decrease lifespan, whereas the catabolic caloric restriction pathways—for instance those involving AMPK and sirtuin—increase lifespan. We used a genetic cross of mice (the BXD lines) and quantitative trait locus mapping to identify mitochondrial ribosomal protein S5 (Mrps5), and other members of the mitochondrial ribosomal protein (MRP) family as candidate metabolic and longevity regulators. A 50% variation in natural expression corresponds to approximately 250 days difference in lifespan. Using loss-of-function experiments in C. elegans, we validated the role of homologous MRPs in longevity via mechanisms that trigger a reduction in mitochondrial respiration and activation of the mitochondrial unfolded protein response (UPRmt). Importantly, the level of UPRmt activation correlated directly with lifespan extension. These effects were further confirmed by treatment with specific antibiotics that target bacterial and mitochondrial protein translation—for instance doxycycline and chloramphenicol. Despite the beneficial effects of antibiotics on lifespan, we also observed that the worms developed more slowly and stayed small. We demonstrated that these adverse effects are not restricted to worms, but also apply to commonly used cell lines, flies, mice, and plants. Collectively, these data expose the MRP proteins as a treatment target against age-related disease, but also call for caution with respect to antibiotic use in experimental systems (Tet-on/Tet-off) and the environment, for instance in livestock.
Hosts: Prof. Bruno Lemaitre (EPFL), Prof. Lluis Fajas (UNIL) and Prof. Kristina Schoonjans (EPFL)