title: A DNA synthesis inhibitor is protective against proteotoxic stressors via modulation of fertility pathways in Caenorhabditis elegans.
abstract: Loss of germline precursor cells in C. elegans has previously been shown to improve protein homeostasis and extend lifespan, possibly due to reallocation of resources to somatic cells. In contrast, mutants that are sterile simply due to loss of sperm or oocyte production have a normal lifespan, often leading to the conclusion that loss of reproduction per se may have minor effects on C. elegans. We have found that inhibiting reproduction in C. elegans via the DNA synthesis inhibitor 5-fluoro-2-deoxyuridine (FUdR) improves protein homeostasis, stress resistance, and healthspan in wild-type animals. We find that FUdR is dependent on oogenesis and oocytic maturation. The effects of FUdR are dependent on FEM pathways, which regulate initiation of spermatogenesis. Loss of FEM expression leads to feminized animals that maintain arrested oocytes and are refractory to the effects of FUdR. FUdR-dependence is restored by spermatogenic signals, which trigger oocytic maturation and ovulation. Further, loss of FEM-3, a novel protein required for spermatogenesis, is sufficient to improve aspects of proteostasis. These effects are independent of previously described germline signals, including the DAF-16/FOXO, DAF-12/VDR, and HSF-1 pathways. These findings suggest that genetic or chemical inhibition of oocyte production can improve protein homeostasis in C. elegans.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd. Novato, CA 94945 USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Angeli
authors.forename: Ida
authors.initials: I
authors.lastname: Klang
authors.forename: Renuka
authors.initials: R
authors.lastname: Sivapatham
authors.forename: Karla
authors.initials: K
authors.lastname: Mark
authors.forename: David
authors.initials: D
authors.lastname: Zucker
authors.forename: Dipa
authors.initials: D
authors.lastname: Bhaumik
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Lithgow
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005298:Fertility / Q000502:physiology*; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics; D006706:Homeostasis; D013312:Stress, Physiological; D014157:Transcription Factors / Q000502:physiology; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D006360:Heat-Shock Proteins; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C075059:fem-3 protein, C elegans; C108431:hsp-16.2 protein, C elegans; C001943:5-fluorouridine; D014529:Uridine