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

•FUdR extends lifespan of C. elegans adapted to hypertonic stress conditions.•FUdR increases resistance to acute hypertonic stress, thermal stress, and anoxia.•Effects of FUdR are primarily somatic in this context.•FUdR acts via thymidylate synthase inhibition and impacts FOXO, sirtuins, and DNA rep...

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Published in:Mechanisms of ageing and development 2016-03, Vol.154, p.30-42
Main Authors: Anderson, Edward N., Corkins, Mark E., Li, Jia-Cheng, Singh, Komudi, Parsons, Sadé, Tucey, Tim M., Sorkaç, Altar, Huang, Huiyan, Dimitriadi, Maria, Sinclair, David A., Hart, Anne C.
Format: Article
Language:English
Subjects:
Animals
C. elegans
Caenorhabditis elegans - genetics
Caenorhabditis elegans - metabolism
Caenorhabditis elegans Proteins - genetics
Caenorhabditis elegans Proteins - metabolism
DNA Repair - drug effects
Floxuridine - pharmacology
Forkhead Transcription Factors - genetics
Forkhead Transcription Factors - metabolism
FOXO
FUdR
Hormesis
Hypertonic stress
Longevity - drug effects
Osmotic Pressure - drug effects
Sirtuin
Sirtuins - genetics
Sirtuins - metabolism
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Summary:•FUdR extends lifespan of C. elegans adapted to hypertonic stress conditions.•FUdR increases resistance to acute hypertonic stress, thermal stress, and anoxia.•Effects of FUdR are primarily somatic in this context.•FUdR acts via thymidylate synthase inhibition and impacts FOXO, sirtuins, and DNA repair pathways.•FUdR use should be avoided in C. elegans stress or aging studies, or when different genotypes are compared. 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.
ISSN:0047-6374
1872-6216
DOI:10.1016/j.mad.2016.01.004