Differences of oxidative damage in the brain of short- and long-lived Nothobranchius furzeri strains

BACKGROUND: The turquoise killifish (Nothobranchius furzeri), while being reported as the vertebrate with the shortest lifespan in captivity, includes many strains that diverge in their lifespans. Underlying mechanisms for these differences are believed to occur in part at the level of mitochondria, which contribute to aging through their role in energy metabolism and oxidative stress. METHODS: We used the short-lived GRZ strain and the longer-lived MZCS-222 strain to determine whether lifespan divergence is associated with distinct mitochondrial maintenance, oxidative damage, and mitigating pathways in the brain. Killifish brain homogenates were analyzed through western blots, RT-qPCR and enzymatic assays. RESULTS: In these two strains, we report that mitochondrial content declined with age in GRZ individuals, whereas it remained stable in MZCS-222 fish. The longer-lived strain also exhibited age-related increases in SOD1 and SOD2 at the protein level, suggesting enhanced antioxidant defenses. In contrast, GRZ showed an early upregulation of pink1 and bax, consistent with putative increased mitophagy and apoptotic signaling in response to mitochondrial stress, whereas MZCS-222 showed an increase in pink1 expression while maintaining stable levels of bax, indicating a possible control of mitochondrial quality through mitophagy only. CONCLUSION: Together, these findings indicate that lifespan divergence in N. furzeri is associated with distinct mitochondrial aging trajectories, supporting that enhanced antioxidants defenses and mitochondrial quality control contribute to the preservation of brain mitochondrial homeostasis and increased longevity.