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And Thee, O Time

Back in 2003, I wrote about the paper that identified the natural product resveratrol as an activator of the sirtuin deacetylase pathway. This may well be the common thread between a host of studies on life-extending genes in model organisms and the much-publicized phenomenon of life extension through caloric restriction. In other words, if you want to live longer, but don’t feel like taking in a third fewer calories, it’s possible that activating sirtuin might do the job for you, and resveratrol is the prototype activator.
Three years ago, after first pointing out that many companies might want to run screens for sirtuin activators, I went on to speculate:
Second, there is no reason to think that resveratrol itself is an optimized molecule. It’s a great starting point, but as a medicinal chemist I can see several things I’d like to do to it immediately. Hey, fellow chemists, let’s talk shop here. . .(list of possible structural modifications follows – DBL). . .Believe me, thousands of folks like me are looking at this structure today and having these exact thoughts, and some of them are going to act on them (if someone hasn’t already.)
Third, this compound is surely being given to higher animals as we speak. I can see no reason not to start feeding it to mice in a long-term study. Mice live around two years – let’s try for three! After all, it’s already been given to rodents in other studies. (And those are just papers from the last year or two!) But as far as I can tell, none of these have allowed the mice to age to their full normal lifespan under resveratrol dosing. Time to find out!

Well, in an unusual development for my predictions, all of this is coming true. This summer, David Sinclair (who leads one of the major efforts in this area – another is led by his former boss, Leonard Guarente) published an interesting review of resveratrol’s in vivo effects. Now his group reports in Nature that resveratrol does indeed have effects in mice – very powerful effects indeed. When put on a high-fat diet, normal mice gain weight, develop diabetes and liver problems, and die early. But on the same diet along with resveratrol, the mice (although they do put on weight) show improved glucose and insulin levels, better liver function, and significantly increased lifespan. Their activity and motor abilities appear to mimic normal-diet mice, even into their extended old age. (Here’s their press release if you don’t have a Nature subscription).
And on top of this, Sinclair’s company has let it be known that they have developed improved molecules based on resveratrol, and are now taking them into the clinic. The first one is called SRT501, and I’d be very interested to know its structure. But remember that compound code – you’re going to be hearing about it again.
These are still early days. There may be penalties to pay for messing around with longevity (increased cancer rates are only the first thing that come to mind). But there may also be a revolution in progress here, something that will make the future quite different from what we’ve been imagining it will be. G. K. Chesterton would be happy – scroll down here for a discussion of the game of “Cheat The Prophet”. Is anyone ready for Cheat the Reaper?

7 comments on “And Thee, O Time”

  1. Zak says:

    There was a completely inane quote by Leon Kass about the futility of trying to seek immortality through some of these mechanisms.
    Either the NYT quoted him totally out of context (possible, I guess), or he took very modest gains in lifespan coupled with disease-resistance and somehow extrapolated that to outright immortality!
    That is one dense man.

  2. David says:

    Never mind the increased cancer risk. A Woody Allen quote springs to mind : There are worse things in life than death. Have you ever spent an evening with an insurance salesman?

  3. RKN says:

    What a great time to be a wine lover – especially Pinots, which iirc have the highest [resveratrol] of all the wine grapes. Those grown in cooler climates even more so. Daily dosing of red wine and fish oil (another PPAR agonist) alone have reduced my biological age ~ 5 years (p=0.50).
    Charles Mann wrote an interseting essay speculating on the implications of longer life.

  4. MTK says:

    Someone has been orchestrating a good PR campaign here.
    Ahead of the Nature paper and the press release there was a page 1 story on SRT1, Sinclair, and resveratrol in Monday’s Wall Street Journal.

  5. MolecularGeek says:

    I wasn’t fully awake when CNN kicked on this morning, but I think Sanjay Gupta did a segment on resveratrol this morning, too.
    And I thought the line from Woody was about attempting suicide by inhaling near an insurance agent? 😎
    MG

  6. Daniel Newby says:

    Paper: Resveratrol mimics ischemic preconditioning in the brain.

    So does that mean it’s doomed in humans? (I’m not being entirely silly.)

  7. CC says:

    I wonder if the high rate of breast cancer in Marin County, CA, has anything to do with red wine consumption?

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