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Mech Ageing Dev. 2016 Mar;154:30-42. doi: 10.1016/j.mad.2016.01.004. Epub 2016 Feb 22.

C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins.

Author information

1
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: edward_anderson@brown.edu.
2
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: markcork@yahoo.com.
3
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: jia-cheng_li@brown.edu.
4
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: komudis@gmail.com.
5
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: sade.parsons@gmail.com.
6
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: timothy.tucey@monash.edu.
7
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: altar_sorkac@brown.edu.
8
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: huiyan_huang@brown.edu.
9
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: m.dimitriadi@herts.ac.uk.
10
Department of Genetics, Harvard Medical School and Glenn Labs for Aging Research, Boston, MA 02115, USA. Electronic address: david_sinclair@hms.harvard.edu.
11
Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: anne_hart@brown.edu.

Abstract

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.

KEYWORDS:

C. elegans; FOXO; FUdR; Hormesis; Hypertonic stress; Sirtuin

PMID:
26854551
PMCID:
PMC4789167
[Available on 2017-03-01]
DOI:
10.1016/j.mad.2016.01.004
[Indexed for MEDLINE]
Free PMC Article

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