The Saga of Red Wine and Long Life – Continued

Dov Michaeli

Posted 11/3/11 on The Doctor Weighs In

Remember resveratrol? In case you forgot, this is the chemical in the red wine that allegedly allowed the French to live happily and long despite consuming fois gras , cheeses and sweetbreads. In animal experiment the stuff extended the lifespan of mice by 40%. Imagine that if your lifespan is say, 80 years. Take the magic stuff and, voilá, you are going live to 112. Small problem: the amounts present in wine are so minuscule that to duplicate the effect in humans would require hundreds of bottles of wine, daily. Sounds like a fun way to live longer, except that your liver and heart would give out within weeks or at best, months after embarking on the debauchery.  The answer was to quickly start a company to commercialize the discovery, by synthesizing chemical analogues that would be hundreds of time more potent than the natural stuff.

The biological basis for the action of resveratrol  was shown to be activation a gene, sir2,or its human equivalent sirt1, which sits at the top of a cascade: it activates a group of proteins, sirtuins, that in turn regulate the expression of yet other genes. And those genes control the energy metabolism of the cell. Imagine, we could get the same life extension that calorie-restriction diet is supposed to accomplish, but without the agony of lifetime of 500 calories a day. Even if the calorie restriction idea is true (after all, it had been demonstrated in mice and monkeys), why would anybody go hungry for so many years? Death would come as a welcome relief.

The science of resveratrol and sirtuins seemed compelling. The life extension effect was shown in yeast, roundworms, and Drosophila fruit flies, as well as in mice. Could humans be far behind?

Those inconvenient doubting Thomases

Even at the height of the enthusiastic hype there were doubting voices who protested, initially sotto voce, that the experiments were flawed, and that the conclusions went way beyond the data. The criticism became louder as more experiments cast some doubt on the validity of the experiments and their interpretation. A paper published in Nature (Sept. 21, 2011) By British scientists, David Gems and Linda Partridge of University College London, poked a serious hole in the theory. They repeated the experiments of roundworms and fruit flies and found that if they used the proper control of genetically identical animals, which the original  experimenters did not; lo and behold, extra sirtuins did not result in life extension.

What’s the explanation? The original experiment, done in Dr. Leonard Guarente laboratory at MIT, genetically manipulated the roundworms to increase the amount of their sirtuins. But unbeknowest to them, they unintentionally introduced an additional mutation, that also caused increased longevity; elimination of that gene in the British experiment eliminated the effect of sirtuins on longevity.

Before we rush to condemn Dr Guarante, who is an eminent and very careful scientist, it is important to note that the technology available to the British scientists was not available at the time he published his papers, in 2001. Furthermore, Dr Helfand, the author of the fruit fly experiment, repeated his own experiment in 2009, using a drug to activate the sir2 gene (a much better method to control the activation of genes) and was able to reproduce his initial results.

So what’s the bottom line? Personally, I still think that sirtuins have an effect on longevity, although I am not sure that it is done through alteration of carbohydrate metabolism. Sirtuins have an effect on the expression of many genes, and it remains to be determined which ones play the critical role in life extension.

But the bigger lesson is that yet again, the checks and balances built into the conduct of scientific research proved themselves.  All experiments, all results, all claims –everything is subject to reexamination, again and again. Almost no day passes by without a paper examining and refining the theory of Evolution. Even Einstein’s Theory of General Relativity has been recently tested in a space experiment. There are no sacred cows. What other human beliefs and endeavors can claim such pursuit of integrity?

Finally, an amusing observation: In 2008 the pharmaceutical company GlaxoSmithKline paid $720 million for Sirtris, a start-up company trying to develop resveratrol-mimicking drugs that activate Salut!sirtuins. At least this time it wasn’t a bunch of crooks who laughed all the way to the bank.