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

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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.

Change history

  • 14 April 2011

    In Fig. 4, units were corrected to μM.

References

  1. 1

    Morimoto, R. I. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427–1438 (2008)

    CAS  Article  Google Scholar 

  2. 2

    Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Porat, Y., Abramowitz, A. & Gazit, E. Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem. Biol. Drug Des. 67, 27–37 (2006)

    CAS  Article  Google Scholar 

  4. 4

    Frid, P., Anisimov, S. V. & Popovic, N. Congo red and protein aggregation in neurodegenerative diseases. Brain Res. Brain Res. Rev. 53, 135–160 (2007)

    CAS  Article  Google Scholar 

  5. 5

    Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005)

    CAS  Article  Google Scholar 

  6. 6

    Tullet, J. M. et al. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans . Cell 132, 1025–1038 (2008)

    CAS  Article  Google Scholar 

  7. 7

    Morley, J. F. & Morimoto, R. I. Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol. Biol. Cell 15, 657–664 (2004)

    CAS  Article  Google Scholar 

  8. 8

    Hsu, A. L., Murphy, C. T. & Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145 (2003)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Groenning, M. Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils—current status. J. Chem. Biol. 3, 1–18 (2009)

    Article  Google Scholar 

  11. 11

    Rodríguez-Rodríguez, C. et al. Design, selection, and characterization of thioflavin-based intercalation compounds with metal chelating properties for application in Alzheimer’s disease. J. Am. Chem. Soc. 131, 1436–1451 (2009)

    Article  Google Scholar 

  12. 12

    Drake, J., Link, C. D. & Butterfield, D. A. Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid β-peptide (1–42) in a transgenic Caenorhabditis elegans model. Neurobiol. Aging 24, 415–420 (2003)

    CAS  Article  Google Scholar 

  13. 13

    McColl, G. et al. The Caenorhabditis elegans Aβ1–42 model of Alzheimer’s disease predominantly expresses Aβ3–42 . J. Biol. Chem. 284, 22697–22702 (2009)

    CAS  Article  Google Scholar 

  14. 14

    Temussi, P. A., Masino, L. & Pastore, A. From Alzheimer to Huntington: why is a structural understanding so difficult? EMBO J. 22, 355–361 (2003)

    CAS  Article  Google Scholar 

  15. 15

    Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R. & Morimoto, R. I. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311, 1471–1474 (2006)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Zengel, J. M. & Epstein, H. F. Identification of genetic elements associated with muscle structure in the nematode Caenorhabditis elegans . Cell Motil. 1, 73–97 (1980)

    CAS  Article  Google Scholar 

  17. 17

    Anderson, P. & Brenner, S. A selection for myosin heavy chain mutants in the nematode Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 81, 4470–4474 (1984)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Ben-Zvi, A., Miller, E. A. & Morimoto, R. I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc. Natl Acad. Sci. USA 106, 14914–14919 (2009)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Chen, D., Thomas, E. L. & Kapahi, P. HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans . PLoS Genet. 5, e1000486 (2009)

    Article  Google Scholar 

  21. 21

    Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans . Nature 424, 277–283 (2003)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Walker, G. A. & Lithgow, G. J. Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2, 131–139 (2003)

    CAS  Article  Google Scholar 

  23. 23

    Li, W., Gao, B., Lee, S. M., Bennett, K. & Fang, D. RLE-1, an E3 ubiquitin ligase, regulates C. elegans aging by catalyzing DAF-16 polyubiquitination. Dev. Cell 12, 235–246 (2007)

    CAS  Article  Google Scholar 

  24. 24

    McColl, G. et al. Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans . J. Biol. Chem. 283, 350–357 (2008)

    CAS  Article  Google Scholar 

  25. 25

    Chen, D., Thomas, E. L. & Kapahi, P. HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans . PLoS Genet. 5, e1000486 (2009)

    Article  Google Scholar 

  26. 26

    Timmons, L., Court, D. L. & Fire, A. Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans . Gene 263, 103–112 (2001)

    CAS  Article  Google Scholar 

  27. 27

    McColl, G. et al. Insulin-like signaling determines survival during stress via posttranscriptional mechanisms in C. elegans . Cell Metab. 12, 260–272 (2010)

    CAS  Article  Google Scholar 

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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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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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