Michelle Brandt, Senior Communication Manager, Stanford University School of Medicine asked the WineDoctors to comment on a recent article published in Nature magazine on January 19, 2010, entitled: Health benefits of red-wine chemical unclear.¹

Background. In 2007, Christopher Wesphal et al, reported that resveratrol directly activated sirtuin-1 (SIRT1). SIRT1 is a mediator of the pathways involved in calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Westphal et al. identified 3 compounds that were 1000 times more potent than resveratrol called Sirtuis compounds. These compounds are now in Phase II clinical trials for treatment of Diabetes Mellitus type II and one for cancer. A recent study published by Kay Ahn et al calls this into question.³ Specifically, Dr. Ahn and her colleagues reported that resveratrol has to be linked to a substrate or a chemical called a fluorophore to activate SIRT1. Further, in their study, the Sirtuis compounds do not directly activate sirtuin-1 without linkage to a fluorophore.

Response. Scientific literature is fraught with examples of chemicals and molecules that have beneficial effects in vitro that are not translated into clinical medicine. In translational medicine, basic science and clinical researchers work to bring hypotheses from “bench to bedside” or from a test tube with the ultimate goal of helping patients. Steps from bench to bedside include a preclinical “proof of concept” study that is a misnomer but a rigorous scientific process to form hypotheses to be tested. “Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vaccines, vitamins, minerals, or lifestyle changes. Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.

Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions:

In Phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.

In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.”⁴

A large majority of Phase III clinical trials fail.⁵ Reasons include problems in preclinical translational research: variability in the model; positive bias (i.e., positive results advance scientists’ careers); negative bias (i.e., journals are less likely to publish articles with negative conclusions) and; proving feasibility of an original approach to the treatment of disease can lead to patents and lucrative licensing agreements.⁶

In conclusion, the implications of resveratrol research are profound and broad reaching, calling into question application of the scientific method as compounds approach evaluation by the FDA. Standardization and replication trials will be required as controversy surrounds the use of compounds that promise age-defying benefits. Ethics and conflict of interest may be called into question, but the potential that medications and supplements may be on the horizon that seem to benefit humans in ways that wine consumption does offer exciting prospects for future health benefits.

1. Buchen L. Health benefits of red-wine chemical unclear. Nature News 2010 Jan 19. http://www.bioedonline.org/news/news.cfm?art=6015.

2. Jill C. Milne^1,4, Philip D. Lambert^1,4, Simon Schenk^2,4, David P. Carney¹, Jesse J. Smith¹, David J. Gagne¹, Lei Jin¹, Olivier Boss¹, Robert B. Perni¹, Chi B. Vu¹, Jean E. Bemis¹, Roger Xie¹, Jeremy S. Disch¹, Pui Yee Ng¹, Joseph J. Nunes¹, Amy V. Lynch¹, Hongying Yang¹, Heidi Galonek¹, Kristine Israelian¹, Wendy Choy¹, Andre Iffland¹, Siva Lavu¹, Oliver Medvedik¹, David A. Sinclair³, Jerrold M. Olefsky², Michael R. Jirousek¹, Peter J. Elliott¹ & Christoph H. Westphal¹ Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712-716 (29 November 2007) | doi:10.1038/nature06261; Received 3 August 2007; Accepted 17 September 2007

3. Pacholec M, Chrunyk BA, Cunningham D, Flynn D, Griffith DA, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K. Pfizer, United States. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem. 2010 Jan 8.

4. www.clinicaltrials.gov.

5. Lowenstein PR, Castro MG. Uncertainty in the translation of preclinical experiments to clinical trials. Why do most phase III clinical trials fail? Curr Gene Ther. 2009 Oct;9(5):368-74.

6. Unger EF. All is not well in the world of translational research. J Am Coll Cardiol. 2007 Aug 21;50(8):738-40. Epub 2007 Aug 6.