title: Proteomic analysis of age-dependent changes in protein solubility identifies genes that modulate lifespan.
abstract: While it is generally recognized that misfolding of specific proteins can cause late-onset disease, the contribution of protein aggregation to the normal aging process is less well understood. To address this issue, a mass spectrometry-based proteomic analysis was performed to identify proteins that adopt sodium dodecyl sulfate (SDS)-insoluble conformations during aging in Caenorhabditis elegans. SDS-insoluble proteins extracted from young and aged C. elegans were chemically labeled by isobaric tagging for relative and absolute quantification (iTRAQ) and identified by liquid chromatography and mass spectrometry. Two hundred and three proteins were identified as being significantly enriched in an SDS-insoluble fraction in aged nematodes and were largely absent from a similar protein fraction in young nematodes. The SDS-insoluble fraction in aged animals contains a diverse range of proteins including a large number of ribosomal proteins. Gene ontology analysis revealed highly significant enrichments for energy production and translation functions. Expression of genes encoding insoluble proteins observed in aged nematodes was knocked down using RNAi, and effects on lifespan were measured. 41% of genes tested were shown to extend lifespan after RNAi treatment, compared with 18% in a control group of genes. These data indicate that genes encoding proteins that become insoluble with age are enriched for modifiers of lifespan. This demonstrates that proteomic approaches can be used to identify genes that modify lifespan. Finally, these observations indicate that the accumulation of insoluble proteins with diverse functions may be a general feature of aging.
authors: The Interdisciplinary Research Consortium on Geroscience, The Buck Institute for Research on Aging, Novato, CA 94949, USA.
authors: Pedro
authors: P
authors: Reis-Rodrigues
authors: Gregg
authors: G
authors: Czerwieniec
authors: Theodore W
authors: TW
authors: Peters
authors: Uday S
authors: US
authors: Evani
authors: Silvestre
authors: S
authors: Alavez
authors: Emily A
authors: EA
authors: Gaman
authors: Maithili
authors: M
authors: Vantipalli
authors: Sean D
authors: SD
authors: Mooney
authors: Bradford W
authors: BW
authors: Gibson
authors: Gordon J
authors: GJ
authors: Lithgow
authors: Robert E
authors: RE
authors: Hughes
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008136:Longevity / Q000235:genetics*; D013058:Mass Spectrometry; D040901:Proteomics; D034622:RNA Interference; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate; D012995:Solubility; D013194:Staining and Labeling
chemical_list: D029742:Caenorhabditis elegans Proteins; D012269:Ribosomal Proteins; D012967:Sodium Dodecyl Sulfate