title: Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan.
abstract: Genetic studies indicate that protein homeostasis is a major contributor to metazoan longevity. Collapse of protein homeostasis results in protein misfolding cascades and the accumulation of insoluble protein fibrils and aggregates, such as amyloids. A group of small molecules, traditionally used in histopathology to stain amyloid in tissues, bind protein fibrils and slow aggregation in vitro and in cell culture. We proposed that treating animals with such compounds would promote protein homeostasis in vivo and increase longevity. Here we show that exposure of adult Caenorhabditis elegans to the amyloid-binding dye Thioflavin T (ThT) resulted in a profoundly extended lifespan and slowed ageing. ThT also suppressed pathological features of mutant metastable proteins and human β-amyloid-associated toxicity. These beneficial effects of ThT depend on the protein homeostasis network regulator heat shock factor 1 (HSF-1), the stress resistance and longevity transcription factor SKN-1, molecular chaperones, autophagy and proteosomal functions. Our results demonstrate that pharmacological maintenance of the protein homeostatic network has a profound impact on ageing rates, prompting the development of novel therapeutic interventions against ageing and age-related diseases.
authors: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, California 94945, USA.
authors: Silvestre
authors: S
authors: Alavez
authors: Maithili C
authors: MC
authors: Vantipalli
authors: David J S
authors: DJ
authors: Zucker
authors: Ida M
authors: IM
authors: Klang
authors: Gordon J
authors: GJ
authors: Lithgow
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001343:Autophagy; D052160:Benzothiazoles; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008136:Longevity / Q000187:drug effects* / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism; D010243:Paralysis / Q000188:drug therapy; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D016019:Survival Analysis; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D018832:Molecular Chaperones; D011506:Proteins; D013844:Thiazoles; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C474710:heat shock factor-1, C elegans; C073702:skn-1 protein, C elegans; C009462:thioflavin T; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin