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Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan

Nature volume 472, pages 226–229 (2011)Cite this article

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Abstract

Genetic studies indicate that protein homeostasis is a major contributor to metazoan longevity1. Collapse of protein homeostasis results in protein misfolding cascades and the accumulation of insoluble protein fibrils and aggregates, such as amyloids2. 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 culture3,4. 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.

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Figure 1: Amyloid-binding compounds extend C. elegans lifespan.
Figure 2: ThT and curcumin rescue a paralysis phenotype and slow protein aggregation in vivo.
Figure 3: Dependency of ThT suppression of protein aggregation-associated paralysis on protein homeostasis factors.
Figure 4: ThT enhancement of lifespan depends on HSF-1 and SKN-1 transcription factors but not on DAF-16.

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  • 14 April 2011

    In Fig. 4, units were corrected to μM.

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Acknowledgements

We thank A. A. Gerencser for expert assistance with the confocal microscopy; A. M. Cuervo, M. S. Gill, M. Lucanic, J. Campisi, S. Melov, V. Lunyak and P. Kapahi for suggestions on the manuscript, members of the G.J.L. and P. Kapahi laboratories for helpful discussion and members of the Paper Polishing Club. Nematode strains were provided by the Ceanorhabditis Genetics Center, funded by the National Institutes of Health (NIH) National Center for Research Resources. CF2189 was a gift from C. Kenyon’s laboratory. This work was supported by grants from the Larry L. Hillblom Foundation and the NIH (UL1024917, supporting the Interdisciplinary Research Consortium on Geroscience and 1R01AG029631-01A1). G.J.L. is supported by the NIH AG21069, AG22868, AG029631-01A1, ES016655, the Larry L. Hillblom Foundation and UL1 RR024917. S.A. was supported by the U19AGO231222 from the Longevity Consortium.

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Authors and Affiliations

  1. Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, 94945, California, USA

    Silvestre Alavez, Maithili C. Vantipalli, David J. S. Zucker, Ida M. Klang & Gordon J. Lithgow

  2. Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, 94901, California, USA

    David J. S. Zucker

  3. Department of Biosciences and Nutrition, Karolinska Institute, Center for Biosciences at NOVUM, Hälsovägen 7, S-141 83 Huddinge, Sweden

    Ida M. Klang

Authors
  1. Silvestre Alavez
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  2. Maithili C. Vantipalli
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  5. Gordon J. Lithgow
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Contributions

S.A. planned and designed the project with consultation and support from G.J.L. All the data were collected by S.A. and M.C.V., with assistance from D.J.S.Z. and I.M.K. S.A. and G.J.L. wrote the paper with contribution from all authors.

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Correspondence to Silvestre Alavez or Gordon J. Lithgow.

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The authors declare no competing financial interests.

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Alavez, S., Vantipalli, M., Zucker, D. et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature 472, 226–229 (2011). https://doi.org/10.1038/nature09873

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