title: Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans.
abstract: Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Folick
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Holly D
authors.initials: HD
authors.lastname: Oakley
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Armstrong
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, A-8010, Austria.
authors.forename: Manju
authors.initials: M
authors.lastname: Kumari
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Sanor
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.affiliation: Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ortlund
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, A-8010, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. wmeng@bcm.edu.
authors.forename: Meng C
authors.initials: MC
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism; D008136:Longevity / Q000235:genetics / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D029742:Caenorhabditis elegans Proteins; C000594562:LBP-8 protein, C elegans; D018832:Molecular Chaperones; C505159:NHR-49 protein, C elegans; C559127:NHR-80 protein, C elegans; D018160:Receptors, Cytoplasmic and Nuclear; C569694:LIPL-4 protein, C elegans; D008049:Lipase