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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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July 23, 2013

Resveratrol: What's It Do For Mitochondria?

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Posted by Derek

I've been meaning to blog about this new paper in PLOS Biology on resveratrol's effects on mitochondria. It's suggesting that the results previously reported in this area cannot be reproduced, namely the idea that resveratrol increases mitochondrial biogenesis and running endurance. In fact, says this new paper, the whole mechanistic story advanced in this field (resveratrol activates SIRT1, which activates the coactivator PGC1, which cranks up the mitochondria) is wrong. SIRT1 has, they say, the opposite effect: it decreases PGC1 activity, and downregulates mitochondria.

That's an interesting dispute, and leads to all kinds of questions about who's wrong (because someone certainly appears to be). But there's another issue peculiar to this new paper. It now says that there are no reader comments, but for a couple of days there was one, which went into detail about how various Western blots appeared to have been performed sloppily and with confusing control lanes. I have no idea how well substantiated these objections were, and I have no idea why they have disappeared from the paper. It's all quite peculiar.

Comments (15) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. Cell Biologist on July 23, 2013 10:05 AM writes...

I would not blog about this new paper. As you can see, the blots are of very poor quality. The reviewers did a poor job.

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2. sgcgox on July 23, 2013 10:16 AM writes...

There is another recent resveratrol story:

http://www.sciencedaily.com/releases/2013/07/130722071955.htm

(I posted this link in a comment to another post, sorry for duplication)

Permalink to Comment

3. Mike P on July 23, 2013 10:40 AM writes...

For those interested, one more recent article covering the same study as sgcgox's link:

http://www.theatlantic.com/health/archive/2013/07/study-anti-aging-antioxidant-actually-seems-to-undo-effects-of-exercise/277993/

Permalink to Comment

4. Lane Simonian on July 23, 2013 11:20 AM writes...

Certain antioxidants under certain conditions can become pro-oxidants. That is the case with resveratrol. Depending on age, gender, and extent of the exercise, it is possible that resveratrol rather than counteracting the oxidation produced by stressful exercise is actually increasing it.

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5. alig on July 23, 2013 11:47 AM writes...

@2 This is yet another paper showing that antioxidants are harmful if you are exercising. The radicals that form during the oxidative stress are beneficial to health. Stop taking antioxidants if you want to benefit from exercise.

Permalink to Comment

6. Geneticist on July 23, 2013 11:50 AM writes...

Cell Biologist -

Sure, some of the blots are a little ugly, and I'd prefer to see a little more of the surrounding membrane. In general though, they're pretty clear, and not obviously fraudulent - certainly sufficient to support the scientific point being made.

Do you have a more concrete objection? Which part do you think is insufficient to support the authors' claims?

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7. Old Surfer Dude on July 23, 2013 12:06 PM writes...

Lane
Can you provide some examples where certain antioxidants can become pro-oxidants based on age, gender, and extent of the exercise?

Permalink to Comment

8. Lsne Simonian on July 23, 2013 4:18 PM writes...

There are studies on resveratrol as a potential oxidant (mainly in the presence of copper ions) and studies on strenuous exercise as a cause of oxidation, but I cannot find any studies directly linking the two. The best I can do is to suggest how they might work in tandem. Exercise and resveratrol both activate AMPK. Normally this is positive for human health (AMPK and the biochemistry of exercise: implications for human health and disease). But under conditions of oxidative stress, AMPK increases mitochondrial dysfunction by activating p38 MAPK which leads to the production of peroxynitrites (and may increase the presence of copper ions). So normally exercise and resveratrol would act as antioxidants, but perhaps together they work as oxidants.

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9. Sweden Calling on July 23, 2013 4:32 PM writes...

Resveratrol is dirtier than clozapine....it's been reported to hit numerous targets. Just sayin

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10. Lane Simonian on July 23, 2013 4:44 PM writes...

But the important question is does resveratrol affect the right targets or the wrong targets. And under certain circumstances can the right targets become the wrong targets.

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11. bob sacamano on July 23, 2013 9:45 PM writes...

coming soon:

Comment Retraction Watch.com (or perhaps it's already here)

Permalink to Comment

12. anonymous on July 23, 2013 11:02 PM writes...

"Move along....nothing to see here....move along".
Signed, Christoph

Permalink to Comment

13. Anonymous on July 24, 2013 2:04 PM writes...

I would agree with Sweeden Calling, Resveratrol is a very dirty compound. Probably developing molecules against targets that are beneficially affected by resveratrol could be a way out.

About the paper Mike P suggested: Nowhere in the paper do the authors quantify resveratrol's availability in the blood/plasma. This compound has a very variable/erratic absorption/bioavailability ( a fact that even the authors mention in the paper) from the available OTC formulations... which necessitates a quantification. Nor do they show increases in Sirt1 (a target which resveratrol supposedly activates). Hence, I am not sure I believe in their observations.


I agree with Lane, maybe an effect similar to scientifically abject concept of hormesis?

Permalink to Comment

14. V on July 25, 2013 12:12 PM writes...

Anonymous: Probably developing molecules against targets that are beneficially affected by resveratrol could be a way out.


Well, that exact solution is where the story gets painful as there's been an outstanding $720M bet on just such a target since 2008.

Otherwise, I'm in full agreement with you on this paper -- not a particular fan of this piece of work.

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15. Paul Brookes on July 26, 2013 8:21 AM writes...

Sorry for not posting this sooner, I was out of town all week and got behind on my reading.

The comment I originally left at PLoS Biology was removed. The editors contacted me to say they'd like to remove it, which I protested on the grounds that it didn't breach their comment policy, but they ignored me and did it anyway. That's why we're lucky to have sites like PubPeer (http://www.pubpeer.com/publications/D2A46528724F9B59FD58693CA41560) which allow this stuff to remain in the open while the journals do whatever it is they do behind the scenes. As you'll see from the comment, the western blot data in this paper is a little sloppy.

The response of the NY Times columnist who ran the big hoopla news story about this, has been to completely ignore me. Similarly, a number of other news outlets who jumped on the media bandwagon about this paper have not responded to requests to modify their stories to indicate the original paper may be flawed. I guess the headline "oops we may have over-hyped something" doesn't have a good ring to it?

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