title: Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span.
abstract: Stabilization of the hypoxia-inducible factor 1 (HIF-1) increases life span and health span in nematodes through an unknown mechanism. We report that neuronal stabilization of HIF-1 mediates these effects in Caenorhabditis elegans through a cell nonautonomous signal to the intestine, which results in activation of the xenobiotic detoxification enzyme flavin-containing monooxygenase-2 (FMO-2). This prolongevity signal requires the serotonin biosynthetic enzyme TPH-1 in neurons and the serotonin receptor SER-7 in the intestine. Intestinal FMO-2 is also activated by dietary restriction (DR) and is necessary for DR-mediated life-span extension, which suggests that this enzyme represents a point of convergence for two distinct longevity pathways. FMOs are conserved in eukaryotes and induced by multiple life span-extending interventions in mice, which suggests that these enzymes may play a critical role in promoting health and longevity across phyla.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Leiser
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Hillary
authors.initials: H
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Rossner
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Fletcher
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Leonard
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Primitivo
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Rintala
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Fresnida J
authors.initials: FJ
authors.lastname: Ramos
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Dana L
authors.initials: DL
authors.lastname: Miller
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004032:Diet; D007422:Intestines / Q000201:enzymology*; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010105:Oxygenases / Q000235:genetics / Q000502:physiology*; D055550:Protein Stability; D034622:RNA Interference; D011985:Receptors, Serotonin / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; D010105:Oxygenases; D011985:Receptors, Serotonin; D014157:Transcription Factors; D014365:Tryptophan Hydroxylase; C541178:HIF-1 protein, C elegans; C583069:HLH-30 protein, C elegans; C104425:serotonin 7 receptor; C020066:dimethylaniline monooxygenase (N-oxide forming)