期刊
MECHANISMS OF AGEING AND DEVELOPMENT
卷 154, 期 -, 页码 30-42出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2016.01.004
关键词
C. elegans; FUdR; Hypertonic stress; FOXO; Sirtuin; Hormesis
资金
- NIH Office of Research Infrastructure Programs [P40 OD010440]
- Ellison Medical Foundation
- National Institutes of Health [R01GM78171, R01NS055813, P01NS66888]
Moderate stress can increase lifespan by hormesis, a beneficial low-level induction of stress response pathways. 5'-fluorodeoxyuridine (FUdR) is commonly used to sterilize Caenorhabditis elegans in aging experiments. However, FUdR alters lifespan in some genotypes and induces resistance to thermal and proteotoxic stress. We report that hypertonic stress in combination with FUdR treatment or inhibition of the FUdR target thymidylate synthase, TYMS-1, extends C. elegans lifespan by up to 30%. By contrast, in the absence of FUdR, hypertonic stress decreases lifespan. Adaptation to hypertonic stress requires diminished Notch signaling and loss of Notch co-ligands leads to lifespan extension only in combination with FUdR. Either FUdR treatment or TYMS-1 loss induced resistance to acute hypertonic stress, anoxia, and thermal stress. FUdR treatment increased expression of DAF-16 FOXO and the osmolyte biosynthesis enzyme GPDH-1. FUdR-induced hypertonic stress resistance was partially dependent on sirtuins and base excision repair (BER) pathways, while FUdR-induced lifespan extension under hypertonic stress conditions requires DAF-16, BER, and sirtuin function. Combined, these results demonstrate that FUdR, through inhibition of TYMS-1, activates stress response pathways in somatic tissues to confer hormetic resistance to acute and chronic stress. C. elegans lifespan studies using FUdR may need re-interpretation in light of this work. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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