RNA Transfer Between Cells is Tightly Regulated, and Disruption Shortens Life Span

It is not always the case that genetic alterations that shorten life span are interesting: there are many ways to break a complex system, and only some of those breakages are relevant to the dysfunction of aging. Researchers here explore the transfer of RNA between cells in nematode worms, showing that too much RNA uptake causes reduced life span. Is this relevant to aging, however? Most likely only if this set of regulatory processes become changed in maladaptive ways in later life. Otherwise, this is just another one of the countless different ways to break the complex regulatory systems of a living organism.

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 Systemic RNA Interference Defective (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 RNA (dsRNA)-gated 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.

Link: https://doi.org/10.1016/j.gene.2023.148014

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