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

Area of Science:

• Molecular Biology
• Genetics
• Developmental Biology

Background:

• Intertissue RNA transport is an emerging signaling mechanism.
• Systemic RNA interference (RNAi) in C. elegans involves SID family proteins for RNA uptake and export.
• SID-1 is a dsRNA channel essential for importing extracellular RNAs in systemic RNAi.

Purpose of the Study:

• To investigate the role of RNAs as intertissue signaling molecules by modifying SID-1 function in specific C. elegans tissues.
• To understand the consequences of disrupting systemic RNA signaling pathways on organismal health and lifespan.

Main Methods:

• Genetic modification of SID-1 function in specific C. elegans tissues (intestine, muscle, neurons).
• Assessment of worm lifespan following gene overexpression or silencing.
• RNAi screening of non-coding RNA pathway components.

Main Results:

• sid-1 loss-of-function mutants showed normal health.
• Overexpression of sid-1 in intestine, muscle, or neurons led to reduced worm lifespan.
• Silencing systemic RNAi components (sid-1, sid-2, sid-5) or miRNA biogenesis proteins (PASH-1, DCR-1) attenuated lifespan reduction caused by intestinal sid-1 overexpression.
• Tissue-specific overexpression of sid-2 and sid-5 also reduced lifespan.

Conclusions:

• Systemic RNA signaling requires tight regulation.
• Disrupting this balance, termed Intercellular/Extracellular Systemic RNA imbalance (InExS), provokes a reduction in lifespan.
• These findings highlight the critical role of controlled RNA transport in maintaining organismal health.