A pair of RNA binding proteins inhibit ion transporter expression to maintain lifespan

Regulation of lifespan by transcription factors has been well established. More recently, a role for RNA binding proteins (RBPs) in regulating lifespan has also emerged. In both cases, a major challenge is to determine which regulatory targets are functionally responsible for the observed lifespan phenotype. We recently identified a pair of neuronal RBPs, exc-7/ELAVL and mbl-1/Muscleblind, which in Caenorhabditis elegans display synthetic (nonadditive) lifespan defects: single mutants do not affect lifespan, but exc-7; mbl-1 double mutants have strongly reduced lifespan. Such a strong synthetic phenotype represented an opportunity to use transcriptomics to search for potential causative targets that are synthetically regulated. Focus on such genes would allow us to narrow our target search by ignoring the hundreds of genes altered only in single mutants, and provide a shortlist of synthetically regulated candidate targets that might be responsible for the double mutant phenotype. We identified a small handful of genes synthetically dysregulated in double mutants and systematically tested each candidate gene for functional contribution to the exc-7; mbl-1 lifespan phenotype. We identified 1 such gene, the ion transporter nhx-6, which is highly upregulated in double mutants. Overexpression of nhx-6 causes reduced lifespan, and deletion of nhx-6 in an exc-7; mbl-1 background partially restores both lifespan and healthspan. Together, these results reveal that a pair of RBPs mediate lifespan in part by inhibiting expression of an ion transporter, and provide a template for how synthetic phenotypes (including lifespan) can be dissected at the transcriptomic level to reveal potential causative genes.