Journal
CELL REPORTS
Volume 28, Issue 4, Pages 1050-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.06.078
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Funding
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- National Natural Science Foundation of China [31471379, 31671527]
- American Federation for Aging Research
- Larry L. Hillblom Foundation
- NIH [AG056743, AG053066, AG045835]
- Morris Scientific Discovery Award from the National Institute of General Medical Sciences of the NIH [P20GM103423, P20GM104318]
- Institutional Development Award from the National Institute of General Medical Sciences of the NIH [P20GM103423, P20GM104318]
- Impact Circle Award
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Reduced mRNA translation delays aging, but the underlying mechanisms remain underexplored. Mutations in both DAF-2 (IGF-1 receptor) and RSKS-1 (ribosomal S6 kinase/S6K) cause synergistic lifespan extension in C. elegans. To understand the roles of translational regulation in this process, we performed polysomal profiling and identified translationally regulated ribosomal and cytochrome c (CYC-2.1) genes as key mediators of longevity. cyc-2.1 knockdown significantly extends lifespan by activating the intestinal mitochondrial unfolded protein response (UPRmt), mitochondrial fission, and AMP-activated kinase (AMPK). The germline serves as the key tissue for cyc-2.1 to regulate lifespan, and germline-specific cyc-2.1 knockdown non-autonomously activates intestinal UPRmt and AMPK. Furthermore, the RNA-binding protein GLD-1 -mediated translational repression of cyc-2.1 in the germline is important for the non-autonomous activation of UPRmt and synergistic longevity of the daf-2 rsks-1 mutant. Altogether, these results illustrate a translationally regulated non-autonomous mitochondrial stress response mechanism in the modulation of lifespan by insulin-like signaling and S6K.
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