Phenylalanyl-tRNA synthetase balances longevity and immunity by downregulating endogenous mitochondrial double-stranded RNAs

Here, we show that dsRNAs and their regulation by dsRNA-binding proteins are key determinants of the fine balance between aging and immunity in Caenorhabditis elegans and cultured human cells. We find elevated levels of dsRNAs with organismal aging and cellular senescence.

We identify a moonlighting function for phenylalanyl-tRNA synthetase, FARS-1/FARSA, as a key factor necessary and sufficient for extending lifespan by directly binding to and downregulating dsRNAs, in particular, mitochondrial dsRNAs. FARS-1/FARSA possesses a previously unrecognized dsRNA-binding domain that mediates these effects separately from its canonical role in translation. Genetic inhibition of fars-1/FARSA upregulates immune response-related genes and enhances innate immunity through regulating the levels of mitochondrial dsRNAs.