Tissue-specific overexpression of the double-stranded RNA transporter SID-1 limits lifespan in C. elegans

Intertissue RNA transport has emerged as a novel signaling mechanism. In C. elegans, this is conferred by the systemic RNAi pathway, in which the limiting step is the cellular import of extracellular RNAs via SID-1. To better understand the physiological role of systemic RNAi in vivo, we modified the function of SID-1 through loss-of-function mutation and tissue-specific overexpression of sid-1 in C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were reversed by silencing the components of the systemic RNAi pathway sid-1, sid-2 and sid-5, thus implicating RNA transport. Moreover, silencing the miRNA biogenesis proteins pash-1 and dcr-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Lastly, we observed that the lifespan decrease produced by tissue-specific sid-1 overexpression was dependent on the bacterial food source. Collectively, our data support the notion that systemic RNA signaling is tightly regulated, and unbalancing that process provokes a reduction in lifespan.