Tissue-specific overexpression of systemic RNA interference components limits lifespan in C. elegans.

[Display omitted] • Tissue-specific overexpression of systemic RNAi components reduces lifespan in C. elegans. • Lifespan reduction interacts with components of systemic RNAi and microRNA pathways. • Bacterial-derived RNAs influence the magnitude of lifespan reduction. • Imbalance between intracellular and extracellular RNAs (InExS) is proposed as a mechanism. • Proper regulation of intertissue RNA signaling is important for longevity. Intertissue RNA transport recently emerged as a novel signaling mechanism. In mammals, mounting evidence suggests that small RNA transfer between cells is widespread and used in various physiological contexts. In the nematode C. elegans , a similar mechanism is conferred by the systemic RNAi pathway. Members of the S ystemic RNA I nterference D efective (SID) family act at different steps of cellular RNA uptake and export. The limiting step in systemic RNA interference (RNAi) is the import of extracellular RNAs via the conserved double-stranded (dsRNA)-gated dsRNA channel SID-1. To better understand the role of RNAs as intertissue signaling molecules, we modified the function of SID-1 in specific tissues of C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in C. elegans intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were attenuated by silencing the components of systemic RNAi sid-1 , sid-2 and sid-5, implicating systemic RNA signaling in the lifespan reduction. Accordingly, tissue-specific overexpression of sid-2 and sid-5 also reduced worm lifespan. Additionally, an RNAi screen for components of several non-coding RNA pathways revealed that silencing the miRNA biogenesis proteins PASH-1 and DCR-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Collectively, our data support the notion that systemic RNA signaling must be tightly regulated, and unbalancing that process provokes a reduction in lifespan. We termed this phenomenon In tercellular/ Ex tracellular S ystemic RNA imbalance (InExS). [ABSTRACT FROM AUTHOR]