Superoxide signal orchestrates tetrathiomolybdate-induced longevity via ARGK-1 in Caenorhabditis elegans

Purpose: While reactive oxygen species (ROS) have been identified as key redox signaling agents contributing to aging process, which and how specific oxidants trigger healthy longevity remain unclear. This paper aimed to explore the precise role and signaling mechanism of superoxide (O-2(center dot-) ) in health and longevity. Methods: A tool for precise regulation of O-2(center dot-) levels in vivo was developed based on the inhibition of superoxide dismutase 1 (SOD1) by tetrathiomolybdate (TM) in Caenorhabditis elegans (C. elegans). Then, we examined the effects of TM on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the signaling mechanism for longevity induced by TM-O-2(center dot-) was screened by transcriptome analysis and tested in sod1 and argk-1 RNAi strains, sod-2, sod-3, and daf-16 mutants. Results: TM promoted longevity in C. elegans with a concomitant extension of healthy lifespan as indicated by increasing fertility and mobility and reducing lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanically, TM could precisely regulate O-2(center dot-) levels in nematodes via modulating SOD1 activity. An O-2(center dot-) scavenger Mn(III)TBAP abolished TM-induced lifespan extension, while an O-2(center dot-) generator paraquat at low concentration mimicked the life prolongation effects. The longevity in TM-treated worms was abolished by sod-1 RNAi but was not affected in sod-2 or sod-3 mutants. Further transcriptome analysis revealed arginine kinase ARGK-1 and its downstream insulin/insulin-like growth factor 1 signaling (IIS) as potential effectors for TM-O-2(center dot-)-induced longevity, and argk-1 RNAi or daf-16 mutant nullified the longevity. Conclusions: These findings indicate that it is feasible to precisely control specific oxidant in vivo and O-2(center dot)- orchestrates TM-induced health and longevity in C. elegans via ARGK-1-IIS axis.