Published online 30 March 2011 | Nature | doi:10.1038/news.2011.193

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Dying for a long life

A chemical that stains Alzheimer's-associated proteins may help cells to cope with toxic trash.

wormsWorms fed a yellow dye that stains misfolded proteins had extended lives.Carolina Biological/Visuals Unlimited/Corbis

A chemical dye that lights up the protein clumps characteristic of Alzheimer's disease also slows ageing in worms.

The lifespan-boosting effects of the dye — called Thioflavin T or Basic Yellow 1 — support the idea that the build-up of misshapen proteins underlies ageing. Drugs that recognize such toxic detritus and alert the cell's natural repair and protein-recycling systems could, therefore, be used to treat diseases of old age, says Gordon Lithgow, a molecular geneticist at the Buck Institute in Novato, California, who led the study, published today in Nature1.

Proteins are essential for almost everything a cell does, from communicating with other cells to generating energy. But sometimes proteins form the wrong three-dimensional shapes. Misfolded proteins don't function properly and, worse, tend to accumulate and gum up other cellular systems. To prevent this from happening, cells deploy 'chaperones', whose job it is to refold misshapen proteins. In more extreme cases, cells can degrade these potentially dangerous proteins.

"There's a growing appreciation that protein misfolding may be one of the very fundamental events of ageing," says Richard Morimoto, a molecular biologist at Northwestern University in Evanston, Illinois, who was not involved with the study. Worms genetically engineered to have a revved-up protein-recycling system, for instance, live longer than normal worms23.

Balancing act

Silvestre Alavez, a member of Lithgow's lab, had the idea that Thioflavin T that colours misshapen clumps of the protein amyloid-β (Aβ) — which is found in the brains of people with Alzheimer's disease — might also trigger this system.

Lithgow was sceptical that the dye could extend the lifespan of the Caenorhabditis elegans roundworms that his lab studies because the worms do not produce Aβ.

Yet small doses of Thioflavin T boosted the lifespan of roundworms by as much as 78%, Alavez found. Worms that did not receive the dye were all dead within 20 days, yet more than 80% of worms consuming a diet that included an optimum dose of Thioflavin T were still alive after the same period. However, Thioflavin T needed to be carefully measured — too large a dose proved toxic and shortened the worms' lives considerably.

Lithgow and Alavez suspect that Thioflavin T boosts lifespan by recognizing all kinds of toxic protein clumps, not just Aβ. For instance, the dye reversed the effects of mutations that cause muscle proteins to misfold, and to become paralysed at a particular temperature. Potentially toxic aggregates of proteins build up naturally in aged worms, they found, an effect that was markedly decreased in worms of a similar age fed Thioflavin T.

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"We think there may be some stabilization of misfolded proteins, and that induces the cells to take out the garbage," Lithgow says. His team also found that worms that lack genes important to dealing with misshapen proteins do not live longer when fed Thioflavin T.

Rudolph Tanzi, a neuroscientist at Massachusetts General Hospital in Boston who was not involved in the work, describes it as an "incredibly cool experiment". Scientists have traditionally focused on the build-up of proteins such as Aβ because they form visible plaques in the brain. Lately, however, scientists have realized that much smaller protein clumps do the most damage to cells. "This goes way beyond Alzheimer's disease," Tanzi says. "There may be a whole slew of protein aggregates that never show up on a pathology slide."

Drugs that mimic the effects of Thioflavin T may find their way into the clinic, Lithgow says. His team found that similar compounds, including an ingredient in the spice turmeric, lengthened the lifespans of roundworms. These chemicals or other drugs that ramp up the cell's protein recycling pathways could help treat disease of old age, such as Alzheimer's. "It's incredibly early days," Lithgow says. 

  • References

    1. Alavez, S., Vantipalli, M. C., Zucker, D. J. S., Klang, I. M. & Lithgow, G. J. Nature doi:10.1038/nature09873 (2011).
    2. Hsu, A.-L., Murphy, C. T. & Kenyon, C. Science 300, 1142-1145 (2003). | Article | PubMed | ISI | ChemPort |
    3. Morley, J. F. & Morimoto, R. I. Mol. Biol. Cell 15, 657-664 (2004). | Article | PubMed | ISI | ChemPort |
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