Resveratrol: why it matters in HIV.

"Resveratrol extends the lifespan of every species we have fed it to. We are now showing that this is also possible for mice on a high-fat diet." David Sinclair, Harvard Medical School and Sirtris Pharmaceuticals (http://www.sirtrispharma.com/), a company he co-founded to commercialize resveratrol-related discoveries.

The headline stories in November 2006 about an ingredient in red wine, chocolate, and some other foods improving the health and extending the lifespan of mice fed a high-fat diet did not involve HIV--yet we need to pay attention. In animal studies, resveratrol and related substances have many effects that may reduce diabetes, cardiovascular disease, and mitochondrial damage in cells (a likely cause of many cases of neuropathy, as well as other problems), and significantly increase healthy lifespan.

No human trials have been done--and it would be impossible to get the same dose of resveratrol from red wine, for example, as was given to mice in the recent test. No one knows what dose would be needed for human benefit, as no such benefit has yet been proved (because testing in humans is much more difficult than in mice). So far resveratrol has helped animals, and at least one company is trying to change the natural molecule to optimize its use as a patented human drug.

How is this relevant to HIV? See our "Comment on HIV ..." below.

Recent Articles

Here are some places to check for more information, as of early December 2006:

* On October 31, 2006, a day before the scientific publication of the benefit of resveratrol in mice, The New York Times published an article about calorie restriction in monkeys. [1] It has been known since 1935 that animals fed a complete diet but with about 30% or 40% fewer calories will stay healthy and live longer than animals fed their usual diet. Some scientists believe that this effect evolved as a mechanism to help animals and people survive famine--and that resveratrol works by stimulating the same genetic mechanism.

* A day later (November 1), the science journal Nature published online a key study in mice [2]--and The New York Times provided a non-technical description [3], as did Forbes [4]. Atone year of age (middle age for a mouse), mice were started on an unhealthy high-fat diet (about 60% of their calories from fat); others stayed on their usual laboratory diet. Some of the mice on the high-fat diet were also given resveratrol. They did get fat, but remained healthy like the normally fed mice, and lived as long. The animals fed the high fat without resveratrol showed signs of diabetes and died months earlier.

* On November 15, the biology journal Cell published a finding that resveratrol improved mitochondrial function and protected against metabolic disease (often a precursor of diabetes) in mice. [5]

* On November 30, Nature reported a finding that other ingredients in red wine, procyanidins (not resveratrol, because the amount present is too small), were the "principal vasoactive polyphenols" in red wine--and were highest in regions where wine was prepared by traditional methods that extracted these compounds efficiently from the grapes. The paper noted that people in these regions tended to live longer. [6]

* In early December, Antioxidants and Redox Signaling published findings on how resveratrol may help protect the heart. [7]

Additional resveratrol background was compiled by the Linus Pauling Institute. [8] But as we go to press, that document was last updated in March 2005, so it does not include the recent work.

Various products containing resveratrol (and other products with procyanidins) have been sold for some time as food supplements. We have no information on their quality.

The Linus Pauling Institute background paper noted that resveratrol had been reported to inhibit the liver enzyme cytochrome P450 3A4 (also called CYP3A4), though this had not yet been tested in humans. If it does so it would increase blood levels of drugs metabolized by that enzyme; for some drugs the increase could be dangerous. [8] Grapefruit juice also inhibits the same enzyme--so if one has been cautioned to avoid grapefruit juice because of interaction with prescription drugs, one might be cautious with resveratrol as well.

Many doctors and scientists say it is too early to rush to take large doses of resveratrol supplements of uncertain quality. Some are taking it themselves, however.

Comment re HIV: Studies We Need Now, and Why We Are Unlikely to Get Them

Earlier, some researchers looked at resveratrol as a possible HIV treatment--although we have not seen any papers published on this since 2004. (To check what has been published in peer-reviewed journals and read the abstracts, visit http://www.pubmed.gov and enter "resveratrol hiv" without the quotation marks into the search bar near the top of the window, then click Go).

Today we would most want to see small trials to find out if resveratrol might help relieve certain drug side effects, or other problems resulting from HIV disease--including lipid or other metabolic abnormalities, or neuropathy, or other symptoms suspected of being caused by mitochondrial damage. Trials aiming to relieve symptoms, or normalize blood levels that are easily measured, could potentially get results fairly quickly and with a fairly small number of volunteers. This is because a measurement is always available, avoiding the need to wait for rare "events" like disease progression or death, for end-point data to be collected.

The main problem in organizing such trials is that there is little economic incentive, unless the goal is to develop a costly, proprietary drug (requiring lots of bureaucracy and generating years of delay). Today greed is usually the sine qua non of drug development within the U.S. and multinational corporate system, and this system imposes its standards on the world. Greed in medicine is prone to intolerable abuses (when companies or individuals sacrifice the health of thousands of people for the promise of more profit for themselves). Therefore it requires heavy-handed controls, which cause major administrative delays and other lost opportunities, delays and losses that are not medically or scientifically necessary. We need alternative drug development systems. But institutional abuses (such as patents on human biology [9]) make alternatives difficult.

References

Note: All of the following except [1] and [9] (which do not mention resveratrol) can be found at www.connotea.org/group/aidsnew; type "resveratrol" in the 'Search' bar, and click 'Find results'.

[1.] One for the Ages: A Prescription That May Extend Life. Michael Mason, New York Times, October 31, 2006; http://www.nytimes.com/2006/10/31/health/nutrition/31agin.html (registration required).

[2.] Baur JA, Pearson KJ, Price NL, and others. Resveratrol improves health and survival of mice on a high-calorie diet. Nature, November 16, 2006; volume 444, pages 337-342 (published electronically November 1).

[3.] Yes, Red Wine Holds Answer. Check Dosage. Nicholas Wade, New York Times, November 2, 2006; http://www.nytimes.com/2006/11/02/science/02drug.html (registration required).

[4.] Compound in Red Wine Boosts Health of Obese Mice, Forbes; http://www.forbes.com/forbeslife/health/feeds/hscout/2006/ 11/01/hscout535859.html (you may need to wait for an ad).

[5.] Lagouge M, Argmann C, Gerhart-Hines Z, and others. Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-lalpha. Cell; published ahead of print November 15.

[6.] Corder R, Mullen W, Khan NQ, and others. Oenology: red wine procyanidins and vascular health. Nature; November 30, 2006, volume 444, page 566.

[7.] Goh SS, Woodman OL, Pepe S, Cao AH, Qin C, and Ritchie RH. The red wine antioxidant resveratrol prevents cardiomyocyte injury following ischemia-reperfusion via multiple sites and mechanisms. Antioxidants and Redox Signaling, January 2009; volume 9, number 1, pages 101-103.

[8.] Higdon J and Steward WP. Resveratrol. (2005-03-04) Linus Pauling Institute at Oregon State University. http://lpi.oregonstate.edu/infocenter/phytochemicals/resveratrol/

[9.] "Astonishingly, the Federal Circuit also held that physicians (or researchers) would infringe the patent merely by thinking about the relation between homocysteine and vitamin deficiency when they analyzed an alternative homocysteine test." From "When Patents Threaten Science," Science, December 1, 2006. What was patented was to use any test to measure the amino acid homocysteine, and conclude from a high level that a vitamin B deficiency was likely. (Excessive homocysteine may be a serious risk factor for heart attack, stroke, and other cardiovascular disease--although as of November 2006 it is not officially recognized as such in the U.S. standard of care). LabCorp was ruled liable for over $2,000,000 damages for selling its own homocysteine test--and the U.S. Supreme Court dismissed the appeal, leaving the ruling standing as U.S. law.

There are many other patent-abuse examples. For a short explanation of what went wrong recently in the U.S. patent system, see "The Patent Trap," Harvard Magazine, July-August 2005, http://www.harvardmagazine.com/on-line/070575.html This article reviews the book Innovation and Its Discontents: How Our Broken Patent System Is Endangering Innovation and Progress and What to Do about It (published 2005), by Josh Lerner and Adam B. Jaffe, professor of investment banking at Harvard Business School and professor of economics at Brandeis, respectively.