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Wednesday, November 28, 2007

The Longevity Pill?

Drugs much more powerful than the resveratrol found in red wine will be tested to treat diabetes.

By Emily Singer
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Revving up resveratrol: A new class of drugs 1,000 times more potent than resveratrol, the compound thought to underlie the health benefits of red wine, shows promise in treating diabetes.
Credit: Technology Review

A novel group of drugs that target a gene linked to longevity could provide a way to turn back the clock on the diseases of aging. The compounds are 1,000 times more potent than resveratrol, the molecule thought to underlie the health benefits of red wine, and have shown promise in treating rodent models of obesity and diabetes.

Human clinical trials to test the compounds in diabetes are slated to begin early next year, according to Sirtris Pharmaceuticals, based in Cambridge, MA, which developed the drugs. "As far as I'm aware, this is the first anti-aging molecule going into [testing in] man," says David Sinclair, a biologist at Harvard Medical School, in Boston, and cofounder of Sirtris. (See "The Enthusiast.") "From that standpoint, this is a major milestone in medicine."

The new drugs target an enzyme called SIRT1, which belongs to a class of proteins known as sirtuins that have been shown to lengthen life span in lower organisms. Sinclair and others theorize that activating these enzymes, which play a role in cell metabolism, mimics the effects of caloric restriction--a low-calorie but nutritionally complete diet that dampens disease and boosts longevity in both invertebrates and mammals.

For several years, scientists have been on the hunt for a drug that could bring the benefits of caloric restriction without the strict diet. (See "The Fountain of Health.") Last fall, Sinclair and his colleagues took a first step when they showed that mice given resveratrol, a molecule that activates SIRT1, stayed healthy when fed high-fat foods. (See "A Life-Extending Pill for Fat Mice.") But there was a catch: mice were dosed with the human equivalent of more than 1,000 wine bottles' worth of the compound, an amount not possible for humans to imbibe or take in pill form.

Now a team at Sirtris, led by CEO Christoph Westphal, has identified a group of compounds that activate SIRT1 1,000 times more potently than resveratrol does. According to findings published today in the journal Nature, the compounds bind to the enzyme and dramatically increase its activity. Because the new compounds are more powerful, much lower doses are likely needed to achieve the same beneficial effects. "We believe doses needed in humans for the novel compounds are probably on the order of hundreds of milligrams, similar to many marketed drugs," says Westphal.

The Sirtris team focused initial animal tests on type 2 diabetes, a disease that results from the impaired ability to use insulin, and whose risk increases with aging. They found that the drugs improved insulin sensitivity and blood glucose levels in three rodent models: diet-induced obese mice, genetically obese mice, and a rat model of type 2 diabetes. "Theoretically, this is a perfect drug," says Charles Burant, head of the Michigan Metabolomics and Obesity Center at the University of Michigan, in Ann Arbor. "Animals seem to have no change in weight, yet they have improved metabolic status."
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  • Resveratrol
    jsstubbs on 11/28/2007 at 3:15 PM
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    Your artilce is not accurate in its statement that resvertrol is not available in pill form in the amounts given to mice in the Harvard study released about a year ago.  A human could take 3 pure 500 mg pills per day to reach the equivalent amount.  There is also growing evidence that resveratrol is effective in Much lower doses than this.  You have to remember that if natural Resveratrol can effectively be delivered in manageable quantities,this hurts Sirtris's business model.  It is in their best interest to say that Resveratrol is weak and that humans should only take their product.  My guess is that the truth will come out soon; that resveratrol is effective in smaller doses than Sirtis would want you to believe.
    Rate this comment: 12345
    • Re: Resveratrol
      posttoasties on 11/29/2007 at 11:17 AM
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      The above commenter misses the point.  Resveratrol is an effective natural substance, but it does not achieve the 30% life-extension in humans that have been observed in other species.

      The Sirtis compounds are NOT Resveratrol at all. They are other activators that stimulate Sirtuins to a far greater degree than Resveratrol will ever be able to achieve on its own.

      The other problem with buying off-the-shelf Resveratrol is that it is a non-regulated "supplement".  You don't know how much of the compound you're purchasing from any of the hippy-dippy vitamin manufacturers, no matter what the label says. Resveratrol is especially vulnerable to oxidation, so it is difficult if impossible to know if what you're buying is even bio-available.

      Give me an FDA-approved Sirt1 stimulator, please! If it from Guarente's lab it will be the real deal.
      Rate this comment: 12345
      • Re: Resveratrol
        jsstubbs on 11/30/2007 at 12:07 AM
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        Sirtris compound, SRT501 is resveratrol and it has been found to effectively treat type 2 diabetes in mice - just as the novel compounds treated type 2 diabetes in mice (and which are 1000 times more powerful than resveratrol and SRT501). The question is, do humans need substances 1000 times more powerful than resveratrol/SRT501.  Reseratrol/SRT501 treats diabetes in mice - what else does resveratrol/SRT501 treat?
        Rate this comment: 12345
      • resveratrol study dosages
        rlindsl on 11/30/2007 at 12:09 AM
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        200mg per kilogram in many of the studies. Doing the math for my body weight puts me at about sixteen grams to achieve similar plasma concentrations It is metabolized very quickly, in a few hours. The main contaminant in the herb source is a laxative. And it comes from China... reason to worry on several levels! very happy to hear about the new class, plan to ultramarathon with it.
        Rate this comment: 12345
    • Re: Resveratrol
      drs on 06/05/2008 at 12:35 PM
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      RED WINE, SPECIFICALLY FROM A MODERATELY HARSH CLIMATE [NY,MO,CHILE, NOT CALIFORNIA!], 1 GLASS EVERY OTHER DAY IS ADEQUATE [NO MORE,TO PROTECT THE LIVER]AND THE CHEAPER THE WINE, THE MORE RESVERATROL. START NOW, RESULTS IN 2-4 WK. WHY WAIT FOR THE FDA TO OK EXPENSIVE PHARMACEUTICALS IN 5-7 YR. YOUR MITOCHONDRIA WILL THANK YOU!
      Rate this comment: 12345
    • Resveratrol
      MolBioGurl on 07/21/2008 at 12:41 PM
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      What is less known, or at least advertised, is that resveratrol does not actually increase Sirt1 activity against its natural substrate at all.  It was found and published in 2005 that the observed increase in Sirt1 activity  due to resveratrol was dependent on the fluorophore attached to the substrate (1).  In other words, resveratrol increases Sirt1 activity only against a synthetic substrate, not against substrates generated by your cells.  Thus, while resveratrol does appear to possess life prolonging properties, at least in some of the tested animals, it does not do so through Sirt1.  This is something else I don't think we will find advertised on resveratrol distributor's sites.  In order for Sirtris to market their other Sirt1 "stimulators" they'd best show it works on natural substrates.

      1. Margie T. Borra, Brian C. Smith, and John M. Denu. "Mechanism of Human SIRT1 Activation by Resveratrol"
      The Journal Of Biological Chemistry Vol. 280, No. 17, April 29, pp. 17187–17195, 2005
      Rate this comment: 12345
  • Tests of resveratrol supplements
    bioinvestigator on 11/29/2007 at 4:35 PM
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    Consumer Lab, an independent dietary supplement   evaluation organization, published a report on 13 November 2007 on the popular resveratrol supplements. They stated that there exists a wide range in quality, dose, and price among products evaluated. The actual amount of resveratrol contained in the capsules range from 2.2mg for Revatrol, which claimed to have 400mg of "Red Wine Grape Complex", to a high of 500mg for Biotivia Transmax, which is consistent with the amount claimed on the product's label. Prices per 100mg of resveratrol ranged from less than $.30 for products made by Biotivia, Jarrow, and Country life, to a high of $45.27 for the Revatrol brand. None of the products tested were found to have significant levels of heavy metals or other contaminants
    Rate this comment: 12345
  • Resveratrol
    davtho66 on 11/29/2007 at 6:17 PM
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    am not sure about chocolate but a friend of mine told me that he had started taking resveratrol based on a doctors suggestion about six weeks ago. My friend was experiencing chronic fatigue
    and was having trouble sleeping. I asked him how it was working out and he said that he was taking a type of resveratrol called biotivia transmax and that after two weeks the results were subtle but undeniable. He said that he had more energy during the day, was more alert throughout the day and was sleeping less but waking up more refreshed. So based on his experience I decided to give it a try. I have had similiar results after just one week. It is only recently that I have heard about it anti-aging benefits.
    There is something to this resveratrol, I have no idea if I will live longer but I can tell you that I am living better now.
    Rate this comment: 12345
  • The Wrong Track?
    rajnz on 12/01/2007 at 2:12 AM
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    The thing that Sirtris Pharmaceuticals is not advertising, as they have put a lot of research into compounds that activate sirtuins, is that sirtuin blockers maybe far more life prolonging that sirtuin enhancers. At least that’s what Valter Longo found in yeast in 2005. Putting in an extra copy of the SIR2 gene increased the lifespan of yeast by 30% but knocking it out altogether increased it by 600%.
    If we achieved the same feat in humans our lifespans would be about 5 centuries!
    Rate this comment: 12345
  • Problems with receptor Blockers
    foolingreens on 12/04/2007 at 1:36 PM
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    Competitively blocking a receptor with a natural substance and completely blocking it are unfortunately two very different things. Witness the recent problems with Avandia. There are many natural substances that competitively block the PPAR site without adverse effects but when completely blocked with Avandia there were significant and serious side effects. Unfortunately these did not come to light until the drug was already in wide spread use. This news is exciting but there is still the need to be cautious
    Rate this comment: 12345
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