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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Change history
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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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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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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DOI: https://doi.org/10.1038/nature09873
