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Elife. 2018 Nov 27;7. pii: e40314. doi: 10.7554/eLife.40314.

Translation attenuation by minocycline enhances longevity and proteostasis in old post-stress-responsive organisms.

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States.
2
Department of Neuroscience, The Scripps Research Institute, La Jolla, United States.
3
Department of Integrative Structural and Computational Biology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States.
4
Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States.
5
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, United States.
6
The Buck Institute for Research on Aging, Novato, United States.

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).

KEYWORDS:

C. elegans; biochemistry; chemical biology; lifespan extension; minocycline; neurodegenerative disease; protein aggregation; ribosomal load; stress signaling

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