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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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In the Pipeline

« Pulling Molecules Apart, For Fun | Main | The Latest Sirtuin Controversy »

September 21, 2011

Big Sirtuin News

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Posted by Derek

This will be the subject of a longer post tomorrow, but I wanted to alert people to some breaking news in the sirtuin/longevity saga. It now appears that the original 2001 report of longevity effects of Sir2 in the C. elegans model, which was the starting gun of the whole story, is largely incorrect. That would help to explain the conflicting results in this area, wouldn't it? Topics for discussion in tomorrow's post will include, but not be limited to: what else do sirtuins do? Are those results reproducible? What can we now expect to come out of pharma research in the field? And what does GSK now think about its investment in Sirtris?

Comments (14) + TrackBacks (0) | Category: Aging and Lifespan | Biological News


COMMENTS

1. anchor on September 21, 2011 1:48 PM writes...

Derek : A big blow for Kevin Trudeau! I am sure that this is not the last word in the Sirtuin saga and there is more to it. I look forward to your take.

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2. dearieme on September 21, 2011 2:50 PM writes...

"When that second mutation, in a sensory neuron gene previously linked to longevity, was bred out, they found no evidence that sir-2.1 boosted lifespan." There's a real need for a new expression for that lack of evidence that results from looking very hard for evidence and coming up empty-handed, as distinct from the lack of evidence resulting from no-one having investigated the problem.

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3. Hap on September 21, 2011 3:05 PM writes...

There's plenty of time for sirtuins to pan out and for targeting them to be useful and interesting, but as the clock keeps ticking, the patents on sirtuin manipulation presumably run down. Without those and the rights of operations, the purchase of Sirtris really doesn't look good.

I also wonder whether GSK really had to spend $720M to have a chance to find out how reproducible the literature is, or if they could have worked in the field much less cheaply but with similar understanding.

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4. pete on September 21, 2011 3:28 PM writes...

I looked at the data in the Helfand lab's Aging article cited in the Nature piece. Though I'm no geneticist it would appear the issue of situin-induced lifespan increase isn't dead yet. That is, unless there's something really strange & misleading happening with the system that they're using to drive sirtuin over-expression in their Drosophila. Seems unlikely.

Nonetheless, $720 million is one of those objects that looks MUCH BIGGER when viewed in the rearview mirror.

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5. Nuclear Option on September 21, 2011 3:57 PM writes...

GSK didn't buy the literature, they bought Sirtris. I imagine the diligence effort involved more than access to PubMed.

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6. anonymous on September 21, 2011 4:27 PM writes...

@5

It wasn't.

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7. Gambler on September 21, 2011 6:18 PM writes...

Let's not forget that this entire saga was driven by not uninterested parties pushing their own agenda. I've been following this entire saga since Sir2 in yeast was tied to longevity in that system. The translation to metazoan systems always struck me as overly simplistic. Many of the PIs involved were only too happy to extrapolate their results to humans for the opportunity of a mention in the NYT and GSK bought the hype. Doesn't say much for their ability to do due diligence. Maybe their partnership with Maclaren will help them avoid making similar mistakes in the future.

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8. Zooted on September 21, 2011 9:55 PM writes...

Mind you wonks,
Resveratrol works, but I don't care how. Sirtuins or otherwise.

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9. BIll Sardi on September 21, 2011 11:45 PM writes...

Road To Longevity: Wrong Gene, Right Molecule

By Bill Sardi

Nothing new here, we’ve discussed this a couple of times in prior reports, that the road to longevity is not dependent upon a single gene, nor solely upon the Sirtuin1 survival gene, and it doesn’t require 1000 bottles of red wine to produce the same positive biological effects seen in the animal lab. But red-wine resveratrol pills are back in the headlines again today for yet another round of scientific scrutiny

“It turns out, the researchers who brought us to the longevity party may have had the wrong gene target in mind and maybe the elixir for perpetual youth is more of a low-octane mixed drink closer to that found in red wine rather than plain resveratrol juice, but we need to recognize there was no scientific or public interest in longevity pills till 2001 when MIT and Harvard researchers first identified a key gene that is activated when living organisms are placed on a limit calorie diet,” says Bill Sardi, spokesperson for Longevinex®, a leading maker of resveratrol pills.

“We can’t fault the researchers. They brought us all to the party. It’s just that when the smoke cleared, some flaws in the science now show that when the SIR2 gene (akin to the Sirtuin1 survival gene in humans) is removed from fruit flies, their lives are still significantly extended,” says Sardi. Conclusion: wrong gene target.

In a second experiment, when a prior study that employed a limited calorie diet was repeated in roundworms, only this time with a more commonly-found strain of nematodes rather than a mutated strain, life extension dwindles down from a first-quoted 15-50% to just 10-15%. It was not realized at the time that a mutated strain of roundworms would skew the results of a longevity study.

Leonard Guarente of MIT, the researcher who made the initial discovery linking Sir2 (Sirtuin1 in humans) to calorie restriction, maintains the gene target is correct it is just the amount of life extension that is in question.

He says the new findings are nothing more than a minor technical blip. An article in MIT’s Technology Review quotes Guarente to say: "It was a problem with the strain, and that has been fixed. It does not invalidate the conclusions." Guarente goes on to say that other labs have since replicated the link between Sir2 and longevity and have shown a 20 percent increase in lifespan in worms using newer methodology.

But 20% life extension is not the consistent doubling of lifespan that is commonly achieved with a calorie restricted diet in many life forms. Anything that solely targets Sirtuin1 is not a true mimic of calorie restriction.

A rodent study conducted in 2008, published in Experimental Gerontology, sheds more light on the subject. Long-term calorie restriction has been shown to significantly differentiate 831 genes in laboratory rats. A short-term experiment was conducted over a period of 12 weeks to determine to what extent and how rapidly resveratrol resembles the gene activation pattern of calorie restriction. The limited calorie diet altered 198 genes while low-dose resveratrol switched about the same number of genes (225). But when a matrix of small molecules (Longevinex®) designed to replicate the effects of red wine was used, 1711 genes were significantly changed in the short-term, and 677 of the 831 longevity genes in this species were switched in the same direction as calorie restriction. That is the closest thing to a molecular mimic of a calorie-restricted diet in animals that has been tested to date.

This experiment suggests it would require life-long adherence to a limited calorie diet or consumption of plain resveratrol to achieve the same gene pattern in long-lived rodents. However, when a matrix of low-dose small molecules was employed, the beneficial effects were realized within weeks. Consumers of plain resveratrol pills may experience health benefits but not all the longevity properties that this molecule delivers.

GlaxoSmithKline, the British-based pharmaceutical giant that purchased SRT501, a resveratrol-based developmental drug from Sirtris Pharmaceuticals for $720 million, seems to be talking out of two sides of its mouth. A statement by GSK says: "These two publications in lower-order species do not have any direct impact on the understanding of the role of sirtuins in human health and disease nor in our drug discovery efforts targeting these enzymes.” But the resveratrol-based SRT501 drug owned by GSK has been abandoned, despite all its promise.

Before you throw away your resveratrol pills, investigate these facts:

1. Resveratrol protects the heart prior to a heart attack, the only agent that has been found to do this, and turns mortal heart attacks into non-mortal events in animal experiments.

2. Resveratrol simultaneously removes cholesterol from the liver and beta amyloid plaque from the brain.

3. Resveratrol has anti-cancer properties independent of the Sirtuin1 gene and is considered the most promising anti-cancer molecule on the planet.

4. Some people suffering with an unremitting form of macular degeneration, even with the most current medicines, are beginning to find a resveratrol-based pill may bring back their lost sight.

5. The longevity pathway may actually begin with another Sirtuin family gene – Sirtuin3.

Strikingly, none of this change in the science has altered what most of the 345 resveratrol pill makers claim about their products – that the ingredients in their products activate the Sirtuin1 survival gene. “Most of these resveratrol pill companies have no scientific background and are only profiteering off of old and now outdated science,” says Sardi. #### © ResveratrolNews.com

Permalink to Comment

10. Jose on September 22, 2011 1:41 AM writes...

3. Resveratrol has anti-cancer properties independent of the Sirtuin1 gene and is considered the most promising anti-cancer molecule on the planet (aside from pixie dust and unicorn fecal pellets).

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11. drsnowboard on September 22, 2011 3:52 AM writes...

Who wants to live longer? Just opens up more decrepid and painful ways to exist and to exit in the end..

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12. NH_chem on September 22, 2011 9:28 AM writes...

Bravo to Sirtris for selling out and making lots of people lots of money. Shame on GSK. My worry is to all those employed at Sirtris. Moral cannot be too good there.....

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13. Spiny Norman on September 22, 2011 9:38 AM writes...

There's already video of Sinclair's reaction on youtube.

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14. Anonymous on September 22, 2011 11:23 PM writes...

GSK is a master of disguise and non-sense! Why didn't they listen to their scientists who were against the Sirtris science? Why are there only two managers left at Sirtris (ie: top brass)?? Looks like a mess but unfortunately will probably be forceably pushed under the rug so that all is forgotten...business as usual. Unfortunately, a lot of GSK scientists suffered from the outcome of the GSK purchase of Sirtris for ca. $750 million. Heads should roll...

Bottom line: justice always prevails in the end. Let's wait and see!

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