title: Autophagy-mediated longevity is modulated by lipoprotein biogenesis.
abstract: Autophagy-dependent longevity models in C. elegans display altered lipid storage profiles, but the contribution of lipid distribution to life-span extension is not fully understood. Here we report that lipoprotein production, autophagy and lysosomal lipolysis are linked to modulate life span in a conserved fashion. We find that overexpression of the yolk lipoprotein VIT/vitellogenin reduces the life span of long-lived animals by impairing the induction of autophagy-related and lysosomal genes necessary for longevity. Accordingly, reducing vitellogenesis increases life span via induction of autophagy and lysosomal lipolysis. Life-span extension due to reduced vitellogenesis or enhanced lysosomal lipolysis requires nuclear hormone receptors (NHRs) NHR-49 and NHR-80, highlighting novel roles for these NHRs in lysosomal lipid signaling. In dietary-restricted worms and mice, expression of VIT and hepatic APOB (apolipoprotein B), respectively, are significantly reduced, suggesting a conserved longevity mechanism. Altogether, our study demonstrates that lipoprotein biogenesis is an important mechanism that modulates aging by impairing autophagy and lysosomal lipolysis.
authors.affiliation: a Department of Molecular Biology , Cell Biology and Biochemistry, Brown University , Providence , RI , USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Seah
authors.affiliation: b The Howard Hughes Medical Institute, The Glenn Center for Aging Research, The Salk Institute for Biological Studies , La Jolla , CA , USA.|c The Howard Hughes Medical Institute, Molecular and Cell Biology Department, Li Ka Shing Center, University of California Berkeley , Berkeley , CA , USA.
authors.forename: C Daniel
authors.initials: CD
authors.lastname: de Magalhaes Filho
authors.affiliation: a Department of Molecular Biology , Cell Biology and Biochemistry, Brown University , Providence , RI , USA.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Petrashen
authors.affiliation: c The Howard Hughes Medical Institute, Molecular and Cell Biology Department, Li Ka Shing Center, University of California Berkeley , Berkeley , CA , USA.|d Del E. Webb Neuroscience , Aging and Stem Cell Research Center, Program of Development and Aging, Sanford-Burnham Medical Research Institute , La Jolla , CA , USA.
authors.forename: Hope R
authors.initials: HR
authors.lastname: Henderson
authors.affiliation: d Del E. Webb Neuroscience , Aging and Stem Cell Research Center, Program of Development and Aging, Sanford-Burnham Medical Research Institute , La Jolla , CA , USA.
authors.forename: Jade
authors.initials: J
authors.lastname: Laguer
authors.affiliation: d Del E. Webb Neuroscience , Aging and Stem Cell Research Center, Program of Development and Aging, Sanford-Burnham Medical Research Institute , La Jolla , CA , USA.
authors.forename: Julissa
authors.initials: J
authors.lastname: Gonzalez
authors.affiliation: b The Howard Hughes Medical Institute, The Glenn Center for Aging Research, The Salk Institute for Biological Studies , La Jolla , CA , USA.|c The Howard Hughes Medical Institute, Molecular and Cell Biology Department, Li Ka Shing Center, University of California Berkeley , Berkeley , CA , USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dillin
authors.affiliation: d Del E. Webb Neuroscience , Aging and Stem Cell Research Center, Program of Development and Aging, Sanford-Burnham Medical Research Institute , La Jolla , CA , USA.
authors.forename: Malene
authors.initials: M
authors.lastname: Hansen
authors.affiliation: a Department of Molecular Biology , Cell Biology and Biochemistry, Brown University , Providence , RI , USA.|d Del E. Webb Neuroscience , Aging and Stem Cell Research Center, Program of Development and Aging, Sanford-Burnham Medical Research Institute , La Jolla , CA , USA.
authors.forename: Louis R
authors.initials: LR
authors.lastname: Lapierre
mesh_terms: D000818:Animals; D001343:Autophagy; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D031204:Caloric Restriction; D005786:Gene Expression Regulation; D020868:Gene Silencing; D007413:Intestinal Mucosa / Q000378:metabolism; D008049:Lipase / Q000378:metabolism; D008066:Lipolysis; D008074:Lipoproteins / Q000096:biosynthesis*; D008136:Longevity / Q000502:physiology*; D008247:Lysosomes / Q000378:metabolism; D014158:Transcription, Genetic; D014818:Vitellogenesis / Q000235:genetics; D014819:Vitellogenins / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D008074:Lipoproteins; D014819:Vitellogenins; D008049:Lipase
keywords: C. elegans; TOR; apolipoprotein B; autophagy; fat storage; intestine; life span; lipid metabolism; lipoprotein; vitellogenin