title: Iron promotes protein insolubility and aging in C. elegans.
abstract: Many late-onset proteotoxic diseases are accompanied by a disruption in homeostasis of metals (metallostasis) including iron, copper and zinc. Although aging is the most prominent risk factor for these disorders, the impact of aging on metallostasis and its role in proteotoxic disease remain poorly understood. Moreover, it is not clear whether a loss of metallostasis influences normal aging. We have investigated the role of metallostasis in longevity ofCaenorhabditis elegans. We found that calcium, copper, iron, and manganese levels increase as a function of age, while potassium and phosphorus levels tend to decrease. Increased dietary iron significantly accelerated the age-related accumulation of insoluble protein, a molecular pathology of aging. Proteomic analysis revealed widespread effects of dietary iron in multiple organelles and tissues. Pharmacological interventions to block accumulation of specific metals attenuated many models of proteotoxicity and extended normal lifespan. Collectively, these results suggest that a loss of metallostasis with aging contributes to age-related protein aggregation.
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA. Karolinska Institute, Department of Biosciences and Nutrition, S-141 83 Huddinge, Sweden.
authors.forename: Ida M
authors.initials: IM
authors.lastname: Klang
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schilling
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Sorensen
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Alexandria K
authors.initials: AK
authors.lastname: Sahu
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kapahi
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Andersen
authors.affiliation: Karolinska Institute, Department of Biosciences and Nutrition, S-141 83 Huddinge, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Swoboda
authors.affiliation: Nutrition and Metabolism Center, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Killilea
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143, USA.
authors.forename: Bradford W
authors.initials: BW
authors.lastname: Gibson
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Lithgow
mesh_terms: D000367:Age Factors; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D004032:Diet; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D066329:Protein Aggregates; D040901:Proteomics / Q000379:methods; D012995:Solubility; D013997:Time Factors
chemical_list: D029742:Caenorhabditis elegans Proteins; D002614:Chelating Agents; D066329:Protein Aggregates; D007501:Iron