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Translation Attenuation by Minocycline Increases Lifespan and Improves Proteostasis in Old Post-Stress-Responsive Organisms

By Gregory M. Solis, Rozina Kardakaris, Elizabeth R Valentine, Liron Bar-Peled, Alice L Chen, Megan M Blewett, Mark A McCormick, James R Williamson, Brian K Kennedy, Benjamin F Cravatt, Michael Petrascheck

Posted 19 Jul 2018
bioRxiv DOI: 10.1101/372326

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 C. 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.

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