title: C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins.
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.
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: edward_anderson@brown.edu.
authors: Edward N
authors: EN
authors: Anderson
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: markcork@yahoo.com.
authors: Mark E
authors: ME
authors: Corkins
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: jia-cheng_li@brown.edu.
authors: Jia-Cheng
authors: JC
authors: Li
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: komudis@gmail.com.
authors: Komudi
authors: K
authors: Singh
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: sade.parsons@gmail.com.
authors: Sadé
authors: S
authors: Parsons
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: timothy.tucey@monash.edu.
authors: Tim M
authors: TM
authors: Tucey
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: altar_sorkac@brown.edu.
authors: Altar
authors: A
authors: Sorkaç
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: huiyan_huang@brown.edu.
authors: Huiyan
authors: H
authors: Huang
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: m.dimitriadi@herts.ac.uk.
authors: Maria
authors: M
authors: Dimitriadi
authors: Department of Genetics, Harvard Medical School and Glenn Labs for Aging Research, Boston, MA 02115, USA. Electronic address: david_sinclair@hms.harvard.edu.
authors: David A
authors: DA
authors: Sinclair
authors: Department of Neuroscience, Brown University, 185 Meeting Street, Providence, RI 02912, USA. Electronic address: anne_hart@brown.edu.
authors: Anne C
authors: AC
authors: Hart
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D005467:Floxuridine / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects*; D009997:Osmotic Pressure / Q000187:drug effects*; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; C108831:daf-16 protein, C elegans; D005467:Floxuridine; D037761:Sirtuins
keywords: C. elegans; FOXO; FUdR; Hormesis; Hypertonic stress; Sirtuin