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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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April 1, 2011

Live Long and Prosper (and Be Bright Yellow at the Same Time)

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Posted by Derek

I'll freely admit to being very interested in research on aging and lifespan. It's a great subject from a scientific (and philosophical) point of view, but perhaps the prospect of turning 50 years old next year has something to do with it, too (not that that age seems anywhere near believable from my end).

Model organisms such as nematodes and fruit flies have already helped identify a number of highly conserved pathways that affect lifespan, many of them having to do with nutrient sensing and various insulin-related pathways. But there are other possibilities. One hallmark of aging at the cellular level is an accumulation of protein defects, chiefly misfolded and chemically modified proteins that apparently are difficult to clear out.

A new paper in Nature takes an alarmingly direct route to investigating potential therapies for this pathway. The researchers looked at small molecules that are known to bind tightly to insoluble protein aggregates and fibrils like amyloid. And what sort of compounds are we sure bind tightly to such things? Why, the sorts of dyes used to selectively stain them for histopathology slides, what else? (See, I told you that this was a rather forceful approach).

But it certainly seems to have paid off. As it turns out, treating nematodes (roundworms, C. elegans) with the dye Thioflavin T (also known as ThT or Basic Yellow 1) extends their lives quite significantly - up around a 60% increase in both median and maximal lifespan. Several other related benzazole compounds were also tried, which produced lifespan extension of up to 40%, and at much lower concentrations.

There are some nematode strains with known defects in protein handling - they produce extra amyloid or polyglutamine proteins, which eventually paralyze them and kill them off. Treating these with the dye had a significant lowering effect on the number of paralyzed nematodes, and the protein aggregrates in their muscle tissue were much lower as well. Similar effects were seen in several other mutant strains that had been used as markers of protein homeostasis.

A number of RNAi and immunological experiments (this is a very data-rich paper, by the way) indicated that ThT's effects depend on several known protein regulators and chaperones. In particular, a strain with a defective heat-shock factor 1 (HSF-1) gene showed no effects with ThT treatment at all, and neither do nematodes with an RNA knockdown of SKN-1 (also known to be implicated in stress responses and longevity). Taken together, these folks really do seem to have found a way to enhance the protein homeostasis functions of living cells, and this seems to have a very beneficial effect on their aging process.

Very interesting work, and very thoroughly followed up on, as it should be. I would be absolutely certain that similar experiments are underway in other species as we speak - I'd go straight to mice, personally, and not neglect some of the mutantmouse strains with protein-handling defects of their own, and compare them to mice that overexpress or underexpress HSF-1 itself. (I can't find any references to SKN-1 mutant mice). Those would be excellent experiments, but I'll bet that I'm not the only one who thinks so. In fact, I'll clean my lab bench off with my tongue if the people who did these studies haven't already thought of them, too.

Oh, and just one more thing: as my wife pointed out to me when I told her about this paper, the FDA was just making headlines the other day by recommending that more study be given to any possible links between food dyes and hyperactivity (though stopping short of recommending any warning at this time, due to lack of convincing evidence). On the basis of this latest work, though, I'm starting to wonder if we're not putting enough dyes in our food. . .

Comments (34) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. anchor on April 1, 2011 9:56 AM writes...

A very through paper indeed! People from Indian sub-continent have been using "Turmeric", whose active component is curcumin, that is responsible for its yellow color. Curcumin, which is a diketone and is phenol derived also has some anti-oxidant properties. Wonder if any studies related to its reduction of oxidative stress properties are known.

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2. luysii on April 1, 2011 10:01 AM writes...

WRTfood dyes and hyperactivity this is another example of the FDA caving again, just as they did with the fraudulent silicone causes autoimmune disease bonanza for the plaintiff's bar (thank you, Oprah). Back than, Kessler never said that silicone actually did anything (just that they were looking into it), but this stopped the use of silicone for needed medical uses such as ventriculoperitoneal shunts for hydrocephalus for a time.

At least there aren't medical uses for food dyes. A while back you had something about methylene blue and Alzheimer's disease. Methylene blue is another such dye used by neurohistologists -- it stains Nissl substance -- which is basically rough endoplasmic reticulum and ribosomal RNA (not a toxic protein aggregate). Remember that neurons are huge protein synthetic machines, with a huge volume (when you consider that some of their axons can be a meter long) to fill with proteins-- which is basically what the rough endoplasmic reticulum does. There is so much rough ER that methylene blue stains it. However, Nissl substance can in no way be considered a toxic protein aggregate -- so be careful.

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3. NoDrugsNoJobs on April 1, 2011 10:06 AM writes...

#1 - Curcumin is a nice example, I believe there have been studies in mice showing its ability to break up amyloid aggregates. Though with amyloid plaques, its not clear where you want to interfere with the process. The problem is for curcumin is, I believe, pretty low bioavailability. I have seen supplements that contain some sort of CYP-inhibitor that putatively increases the bioavailability. Of course, it would mess with metabolism of lots of other stuff as well so....Interesting topic, thanks Derek.

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4. Curious Wavefunction on April 1, 2011 10:22 AM writes...

An early important paper on curcumin and its effect on reducing amyloid load both in vitro and in vivo.

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5. CMCguy on April 1, 2011 10:23 AM writes...

Wasn't some of the earliest med chem based on dye derivatives so cycling back in time?

I can foresee a possible outcome "Live longer, risk cancer" as most dyes may promote mutagensis is some in vivo or in vito model and regardless of potential therapeutic window will be a big barrier. Again there exists liability issues that are a large determent to transition of bench science to markets products and climate make for extreme risk. Perhaps less of an hindrance if something actually works but side affects like colored urine or observed skin tinting has derailed a few drugs in the past.

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6. Rick on April 1, 2011 10:34 AM writes...

Ah yes, this reminds me of one of my favorite chemists of all time, Paul Ehrilich. Every few years, people discover that dyes stick to proteins (imagine that!!!) and then use the latest tools to analyze what happens when dyes (rather indiscriminately, I should add) stick to proteins. It's a kind of neat story that just keeps on giving and becomes fresh with each retelling.

By the way, since people on this blog seem to really like Sirtris ;), I'd like to point out that the stilbene in resveratrol, their wonder drug for aging, is an isostere for one of the oldest and most common types of dyes out there, the azo dyes. Unfortunately, the azo form of resveratrol is no good as a dye (no interesting color) and I'm not sure it'll be much better as a fountain of youth. Azo dyes were also the source of Ehrlich's early antibiotic discoveries that led to the sulfanilamide class of antibiotics.

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7. Carl Bussjaeger on April 1, 2011 11:16 AM writes...

Oooooooh Kay.

I'm not a chemist, won't pretend to be, but reading this I took it to be an April Fools day gag. But reading comments...

I should be taking this seriously?

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8. sgcox on April 1, 2011 11:28 AM writes...

Figure 3 is very alarming for me. Other compounds give the same life extention at 1 nM (!!!) and no dose responce whatsoever. My first thought was that 50 uM dosage of ThT can easily contain 1 nM contamination of whatever it might be there.
It looks like the paper belongs to "What If Those Wonderful Results Are Wrong?" post

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9. MoMo on April 1, 2011 12:18 PM writes...

Good paper and it points out the family of bioreductive thiazoles that are useful against reactive oxygen species, among others. Not too far from the structure of thiamine as well, so take your B vitamins!

But I differ on the comment made by LUYSII. Go search the literature on Yellow #5 and you will see 98% of the research was done in Europe and is banned there as well. Papers galore show the effects on children and hyperactivity, but it was funny, no to few papers published in the US, and the ones that were support dyes in foods. Why is that? Are only Europeans affected by hyperactivity and food dyes?

Because such dyes are added to your foods to make you want to eat them, as all processed foods are scientifically manipulated to make you eat. Then once the hyperactivity starts a second drug can be used to treat the effects of the first drug-methylphenidate, Ritalin, is the drug of choice here.

Excellent paper showing the effects of bioreductive heterocycles, but Big Pharma stays away from them and simpler natural products and their derivatives.

That leaves them for the rest of us!

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10. johnnboy on April 1, 2011 12:43 PM writes...

Thioflavin T also fluoresces under UV light, so you'd be a sensation while kicking it on the dancefloor at 100 year old.
But if the yellow color doesn't suit your skin tone, Congo Red , which also binds amyloid, might be more You.

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11. Nate on April 1, 2011 12:54 PM writes...

@6: I came here to mention Ehrlich and his "magic bullet"!

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12. Dr. Manhhatan on April 1, 2011 1:03 PM writes...

And just in time for all of those brightly colored jelly beans! Who knew they might help you live longer?

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13. Nick K on April 1, 2011 1:05 PM writes...

The take-home message of this paper seems to be that you can live to 150 if you're happy to look like Homer Simpson.

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14. Anonymous on April 1, 2011 1:29 PM writes...

@7
If you're looking for an April Fools gag, look here:
http://www.ozonesolutions.com/journal/2011/ozone_beer_reverse_aging/

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15. Rick on April 1, 2011 1:49 PM writes...

#8 sgcox,
Weird dose response curves (too shallow, too steep) are pretty much the norm for dyes. Having spent more time than I'd like to admit doing protein binding kinetics on what turned out to be dyes, I've concluded it's the result of their promiscuous protein binding plus their tendency to stick to themselves. That's what makes them good dyes! Try getting a Hill constant out of that.

One other very important point. Many chemical libraries-for-sale, the kind small biotechs and some academic labs like to buy because their cheap and plentiful, are absolutely CHOCK FULL of dyes. There's enough there to keep Nature Drug Discovery publishing breathless reports on small molecules that do amazing things for quite a while...

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16. bbooooooya on April 1, 2011 2:20 PM writes...

Following after Marx, "You're only as old as the woman you feel"

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17. Imaging guy on April 1, 2011 2:34 PM writes...

@15.Rick

I am interested in your comment.Do you know any published paper on that subject?

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18. Carl Bussjaeger on April 1, 2011 3:01 PM writes...

@14: I'm willing to believe that one. It's long been known that beer makes women younger and more attractive. Especially near closing time.

:^)

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19. Rick on April 1, 2011 3:10 PM writes...

#17 Imaging guy,
The few papers I've seen on this subject are many decades old and unfortunately, I don't have any at my fingertips. However, I did a quick PubMed Search and came up with the following reviews with promising-sounding titles/abstracts that might enable you to work your way back to the original research.

Biotech Histochem. 2009;84(4):139-58
Biotech Histochem. 2001 May;76(3):137-61
Biochim Biophys Acta. 1981 Aug 27;655(1):82-8

For people with current experience with this problem, you might also want to surf over to the Society for Biomolecular Screening web page and see what that gets you.

As far as the prevalence of dyes, azo and otherwise, in commercial chemical libraries, my best advise is just to look at the catalogs themselves.

Hope this helps.

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20. RKN on April 1, 2011 4:22 PM writes...

Model organisms such as nematodes and fruit flies...

I am more than a bit incredulous that nematodes are a good model for human aging. The expected average lifespan of an (American) human is ~1500 times greater than that a typical nematode. I expect that the explanation for that difference will eventually find its basis in the important differences in the molecular networks of the two species, the understanding of which will also be critical to pharmacological approaches to slow aging in humans.

I understand that for a number of other reasons, though, nematodes make swell critters for genetic experiments!

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21. Geo guy on April 1, 2011 8:32 PM writes...

This almost sounds like stopping earthquakes with a bunch of seismographs. I know it isn't, but this just strikes me as funny in a twisted inverted effect-and-cause way.

It would be even funnier if the effect were strongest with gentian violet. Prince would like that.

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22. Chinabonding on April 2, 2011 1:25 AM writes...

So we'll be 80 for fifty years...AND yellow?!

I dont feel as bad about leaving gobs of debt to future generations
who will be 25 for fifty years and tanned.

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23. barry on April 2, 2011 8:26 AM writes...

As Rick (#15 notes) that binding curve isn't drug-like. It has been reported that Thioflavin-T forms micelles http://www.ncbi.nlm.nih.gov/pubmed/16125973 That (plus the binding curve) should alarm anyone who has read any of Shoichet's papers. This is not a drug lead.

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24. metaphysician on April 2, 2011 9:15 AM writes...

*cough* So the future will be Dune, where people take drugs to live longer that change the color of their body?

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25. cancer_man on April 3, 2011 3:38 AM writes...

Sirtris shall set ye free...

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26. Marc on April 3, 2011 10:52 AM writes...

There's not really a clear mouse homologue pf skn-1. Closest thing is Nfe2l1/2/3.

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27. Phil on April 3, 2011 1:06 PM writes...

Just because one dye has positive effects doesn't mean all of them do. I hope that conclusion was written tongue-in-cheek.

That said, most dyes are polyaromatic and many are hydroquinones (or similar structures), which are anti-oxidants (like the turmeric example). Makes some sense.

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28. anon on April 4, 2011 1:04 PM writes...

I'm getting me a bunch of yellow M&M's and living forever!

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29. SSpiffy on April 4, 2011 4:10 PM writes...

Add 60% to my lifespan at the cost of being yellow? Call me Homer!

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30. Hap on April 4, 2011 5:26 PM writes...

Big flat aromatic things scream "intercalator" to me - it depends on where they end up, charge, etc. but that might be a problem down the line.

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31. Jonadab on April 4, 2011 8:09 PM writes...

> links between food dyes and hyperactivity

It's almost easier to list things people *haven't* blamed hyperactivity on than all the things that they have so accused.

On the other hand, even *if* this one particular yellow dye turns out to be medically useful for humans (which is a rather large step yet from the nematodes), that doesn't necessarily imply that other dyes are good -- though I tend to think the majority of our diet-related health problems might have less to do with a few dyes here and there than with the fact that as a society we've almost completely stopped eating vegetables. Call me crazy, but that seems like it could be relevant.

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32. Jonadab on April 5, 2011 5:03 AM writes...

> I am more than a bit incredulous that
> nematodes are a good model for human aging.

I was going to say, let me know if they get it to work (and by "work" I mean significant extension of lifespan) in mammals.

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33. Design Monkey on April 5, 2011 11:33 AM writes...

While some people are painting worms yellow, in Soviet Russia...

Ethylthiobenzymidazol hydrobromide - bemitil/meprotan - approved official drug, nootropic, immunomodulator, antioxidant, regenerative and all other blahblah.

One should take that with grain of salt, still structure is from about the same ballpark.

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34. Morten G on April 8, 2011 3:53 PM writes...

Curcumin is a Michael acceptor, right? (asks the structural biologist)
Wouldn't that react with a number of things? On the other hand Warfarin is pretty specific for VKOR...

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