title: Diet-derived advanced glycation end products or lipofuscin disrupts proteostasis and reduces life span in Drosophila melanogaster.
abstract: Advanced glycation end product (AGE)-modified proteins are formed by the nonenzymatic glycation of free amino groups of proteins and, along with lipofuscin (a highly oxidized aggregate of covalently cross-linked proteins, sugars, and lipids), have been found to accumulate during aging and in several age-related diseases. As the in vivo effects of diet-derived AGEs or lipofuscin remain elusive, we sought to study the impact of oral administration of glucose-, fructose-, or ribose-modified albumin or of artificial lipofuscin in a genetically tractable model organism. We report herein that continuous feeding of young Drosophila flies with culture medium enriched in AGEs or in lipofuscin resulted in reduced locomotor performance and in accelerated rates of AGE-modified proteins and carbonylated proteins accumulation in the somatic tissues and hemolymph of flies, as well as in a significant reduction of flies health span and life span. These phenotypic effects were accompanied by reduced proteasome peptidase activities in both the hemolymph and the somatic tissues of flies and higher levels of oxidative stress; furthermore, oral administration of AGEs or lipofuscin in flies triggered an upregulation of the lysosomal cathepsin B, L activities. Finally, RNAi-mediated cathepsin D knockdown reduced flies longevity and significantly augmented the deleterious effects of AGEs and lipofuscin, indicating that lysosomal cathepsins reduce the toxicity of diet-derived AGEs or lipofuscin. Our in vivo studies demonstrate that chronic ingestion of AGEs or lipofuscin disrupts proteostasis and accelerates the functional decline that occurs with normal aging.
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens 15784, Greece.
authors.forename: Eleni N
authors.initials: EN
authors.lastname: Tsakiri
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens 15784, Greece.
authors.forename: Kalliopi K
authors.initials: KK
authors.lastname: Iliaki
authors.affiliation: Institute of Nutrition, Department of Nutritional Toxicology, Friedrich Schiller University Jena, 07743 Jena, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Höhn
authors.affiliation: Institute of Nutrition, Department of Nutritional Toxicology, Friedrich Schiller University Jena, 07743 Jena, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Grimm
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens 15784, Greece.
authors.forename: Issidora S
authors.initials: IS
authors.lastname: Papassideri
authors.affiliation: Institute of Nutrition, Department of Nutritional Toxicology, Friedrich Schiller University Jena, 07743 Jena, Germany. Electronic address: tilman.grune@uni-jena.de.
authors.forename: Tilman
authors.initials: T
authors.lastname: Grune
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Athens 15784, Greece. Electronic address: itrougakos@biol.uoa.gr.
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Trougakos
mesh_terms: D000375:Aging / Q000187:drug effects*; D000418:Albumins / Q000737:chemistry; D000818:Animals; D030801:Animals, Genetically Modified; D002401:Cathepsin B / Q000096:biosynthesis / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics; D056668:Cathepsin L / Q000096:biosynthesis / Q000378:metabolism; D004032:Diet; D004331:Drosophila melanogaster / Q000378:metabolism*; D005632:Fructose / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D017127:Glycation End Products, Advanced / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006031:Glycosylation; D008062:Lipofuscin / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008136:Longevity / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D017510:Protein Folding / Q000187:drug effects*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012266:Ribose / Q000737:chemistry; D015854:Up-Regulation
chemical_list: D000418:Albumins; D017127:Glycation End Products, Advanced; D008062:Lipofuscin; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D005632:Fructose; D012266:Ribose; D002401:Cathepsin B; D056668:Cathepsin L; D002402:Cathepsin D; D046988:Proteasome Endopeptidase Complex; D005947:Glucose
keywords: AGE; ALS; Advanced glycation end products; Aging; BSA; C-L; CML; CT-L; Cathepsin; Drosophila; Frc; Free radicals; GAPDH; Glc; LF; Lipofuscin; Lysosome; N(ε)-(carboxymethyl)lysine; PN; Proteasome; RAGE; ROS; Rib; T-L; UPS; advanced glycation end product; autophagy–lysosome system; bovine serum albumin; caspase-like; chymotrypsin-like; fructose; glucose; glyceraldehyde-3-phosphate dehydrogenase; lipofuscin; proteostasis network; reactive oxygen species; receptor for AGEs; ribose; trypsin-like; ubiquitin–proteasome system