RRC ID 59409
Author Solis GM, Kardakaris R, Valentine ER, Bar-Peled L, Chen AL, Blewett MM, McCormick MA, Williamson JR, Kennedy B, Cravatt BF, Petrascheck M.
Title Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms.
Journal Elife
Abstract Aging impairs the activation of stress signaling pathways (SSPs), preventing the induction of longevity mechanisms late in life. Here, we show that the antibiotic minocycline increases lifespan and reduces protein aggregation even in old, SSP-deficient Caenorhabditis elegans by targeting cytoplasmic ribosomes, preferentially attenuating translation of highly translated mRNAs. In contrast to most other longevity paradigms, minocycline inhibits rather than activates all major SSPs and extends lifespan in mutants deficient in the activation of SSPs, lysosomal or autophagic pathways. We propose that minocycline lowers the concentration of newly synthesized aggregation-prone proteins, resulting in a relative increase in protein-folding capacity without the necessity to induce protein-folding pathways. Our study suggests that in old individuals with incapacitated SSPs or autophagic pathways, pharmacological attenuation of cytoplasmic translation is a promising strategy to reduce protein aggregation. Altogether, it provides a geroprotecive mechanism for the many beneficial effects of tetracyclines in models of neurodegenerative disease.
Editorial note:This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
Volume 7
Published 2018-11-27
DOI 10.7554/eLife.40314
PII 40314
PMID 30479271
PMC PMC6257811
MeSH Animals Caenorhabditis elegans / drug effects* Caenorhabditis elegans / physiology* Longevity / drug effects* Minocycline / metabolism* Protein Aggregation, Pathological / prevention & control Protein Biosynthesis / drug effects* Protein Synthesis Inhibitors / metabolism* Proteostasis / drug effects* Ribosomes / drug effects Ribosomes / metabolism
IF 7.551
Times Cited 10
C.elegans tm1978 tm4525