A life-extending molecule to dye for: fluorescent revelations

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  • Published: Apr 1, 2011
  • Author: David Bradley
  • Channels: UV/Vis Spectroscopy
thumbnail image: A life-extending molecule to dye for: fluorescent revelations

Worm's end

Worms live longer if protein homeostasis is maintained by adding a dye molecule to their diet, according to new study. The dye molecule Thioflavin T precludes the kind of protein misfolding that, in humans, leads to aging effects and Alzheimer's disease.

The research by an international team from Sweden and the USA investigated how aging might be slowed and lifespan extended in the biomedical researcher's favourite worm Caenorhabditis elegans by exposing it to the dye molecule. They used fluorescence and absorption studies to assess exposure and results.

Silvestre Alavez, Maithili Vantipalli, David Zucker, Ida Klang and Gordon Lithgow of the Buck Institute for Research on Aging, in Novato, California. Institute graduate students involved are also associated with the Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California (Zucker) and the Karolinska Institute, Center for Biosciences at NOVUM, in Huddinge, Sweden (Klang) explain how the failure of protein homeostasis in metazoan species leads to cascades of protein misfolding and the accumulation of insoluble fibres and aggregates of proteins, including the kind of substances present in Alzheimer's disease, the amyloids. Researchers have previously shown that common "stain" compounds used in medical laboratories and biomedical research can slow such protein misfolding cascades.

Now, the international team has demonstrated how one of those stain compounds, the dye Thioflavin T, ThT, can bind to amyloids and so profoundly slow the aging process in adult C. elegans. The presence of ThT, known formally as (4-(3,6-dimethyl-1,3-benzothiazol-3-ium-2-yl)-N,N-dimethylaniline chloride), also suppressed the toxicity of beta amyloids. The effect apparently depends on changes affecting 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. However, it is surely the effect on lifespan of dosing with ThT that will be of most interest to medical science: at low doses given throughout the nematodes' adult life at the sub-toxic dose, life extension of 60% was possible. Assuming three-score years and ten, that would represent an increase in lifespan for a human to 112 years. That's a molecule to dye for, surely?

"These compounds have a particular chemical structure that allows them to interact with protein aggregates in vitro, particularly those related to neurodegenerative diseases," Alavez told SpectroscopyNOW. "My idea was that if such a thing could also happen in vivo they could interact with proteins prone to aggregate and in consequence modulate the rate of protein aggregation, a process that has been claimed to be a determinant of aging and age-related diseases."

Alavez adds that, "These compounds have been frequently used to stain beta amyloid plaques and to quantify protein aggregation in vitro because they undergo a blue shift in the spectrum when they bind to protein aggregates. Additionally due to their fluorescent nature they could be used to characterize proteins prone to aggregate by co-localization experiments."

Other highly pigmented dye molecules also have a life-extending effect because of their ability to bind to protein aggregate. Curcumin, the yellow substance found in turmeric, the powdered root of the ginger-like plant Curcuma longa. Rifampicin an antibiotic originally derived semi-synthetically from the microbe Amycolatopsis rifamycinica also increased lifespan, although to a lesser extent (up to 45%), the team says. Combining ThT and curcumin did not have an additive effect on C elegans lifespan, the team adds.

Life-extending drugs?

Importantly in terms of drug development, the team tested various pharmacological compounds with similar structural features to ThT but different known physiological profiles. 2-(2-hydroxyphenyl)-benzoxazole (HBX),2-(2-hydroxyphenyl) benzothiazole (HBT) and 2-(2-aminophenyl)-1H-benzimidazole (BM) also showed a marked ability to increase lifespan (up to about 40 percent) but at much lower doses than ThT. The team initially had the notion that these molecules might be acting as dietary restriction mimetics and so extending lifespan through the well-known association with certain forms of dietary restriction that also suppress protein aggregation and increase lifespan. However, early tests ruled out this possibility as the effect of dietary restriction is too small to account for the large life extension seen with ThT.

Should the work be extensible to higher animals and even humans, then it could offer a new kind of therapy for a host of health issues. The team concludes that, "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." They add that, "Small stress response mimetic molecules that target protein homeostatic mechanisms may provide opportunities for intervention in ageing and age-related disease."

"We are currently collaborating with Researchers at the Barshop Institute in San Antonio, Texas to look for the effect of these compounds in some neurodegenerative diseases and also exploring its potential beneficial effects on different kinds of cells," Alavez told us.

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

Photo by David Bradley. Worms live longer if protein homeostasis is maintained by adding a dye molecule to their diet, according to new study. The dye molecule Thioflavin T precludes the kind of protein misfolding that, in humans, leads to aging effects and Alzheimer's disease.
What would seniors give for a molecule to dye for?

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