HerbalEGram: Volume 9, Number 8, August 2012

by David Levine

Joseph A. Baur, PhD, a biomedical research scientist at the University of Pennsylvania’s Perelman School of Medicine, was the featured speaker at a recent New York Academy of Sciences event titled, “The Science Behind the Hype: Resveratrol in Wine & Chocolate.” The event, held June 5, 2012 in New York City, was sponsored by Science & the City and the Sackler Institute for Nutrition Science as part of a 3-part series, “The Locavore's Dilemma,” on the science of local food. In its announcement, the Academy said they chose to look at resveratrol "because early research has suggested that the benefits of resveratrol may include cancer prevention, inflammation reduction, lowering of blood sugar, as well as cardiovascular benefits. But, the studies on resveratrol are in their early days and, as with many bold, new claims made about the benefits of certain foods, it's worth looking at what the science really reveals and what we have yet to examine."

Dr. Baur opened his talk with a quote from Paracelsus, a Renaissance physician, botanist, and alchemist who said, "Wine is a food, a medicine, and a poison — it's just a question of dose." Dr. Baur explained that his own interest in resveratrol grew out of his studies in interventions that can expand human life expectancy. According to Dr. Baur’s University of Pennsylvania faculty webpage: "Age is the most important risk factor for many of the diseases affecting Western society today, including cancer, cardiovascular disease, and neurodegenerative disorders. Although the causes of aging are not known, it can be delayed experimentally in rodents by decreasing energy intake through caloric restriction, CR.”¹ The long-term goal of his research is to use models of lifespan extension, including CR, drugs, and longevity genes, to elucidate the basic mechanisms that drive aging in mammals, with the hope that this knowledge will lead to new therapeutic approaches to improve human health and longevity. 

Resveratrol is a naturally occurring polyphenol that interacts with a number of mammalian enzymes and was the most potent compound identified in a screen for activators of SIRT1, an enzyme potentially involved in the beneficial effects of CR.² Resveratrol has since been shown to extend lifespan in lower organisms, and to provide numerous health benefits in rodents, including increased insulin sensitivity, endurance, and even survival in obese mice.³ Although it was initially assumed by most researchers that these benefits result from direct activation of SIRT1, there is little experimental evidence to support this assertion, and the precise mechanism of action for resveratrol is currently a subject of much debate.⁴ Although SIRT1 activity appears to be higher in treated animals, resveratrol has other targets and does not appear to achieve the concentrations in vivo that are required to activate SIRT1 in vitro.

Dr. Baur said in his lecture that convincingly testing the effects of resveratrol in mice that lack the SIRT1 gene has not been possible because these mice have a severe phenotype including developmental defects and metabolic abnormalities. For his studies, Dr. Baur is using an inducible system to delete the SIRT1 gene in healthy adult animals, allowing a definitive test of whether resveratrol works through this enzyme. "We are testing the hypothesis that sirtuins play a critical role in mammalian CR,” said Dr. Baur, “exploring potential upstream mechanisms that could regulate their activity, and downstream effects that could account for changes in health and longevity."⁵ “Our first set of experiments has already shown that SIRT1 is required for resveratrol to increase the number of mitochondria in skeletal muscle. These structures burn fat and carbohydrates to produce chemical energy, and are thought to play an important role in aging, as well as many diseases,” said Baur, “On the other hand, we also saw hints that some of the anti-diabetic effects of resveratrol did not rely on SIRT1 at all. Clearly, no one target is going to tell the entire story here.”⁶

To give a human face to the idea of longevity, Dr. Baur showed an image of "superager" Jeanne Calment, a French woman who has the longest confirmed human life span in history, living to the age of &10000000000000122000000122 years, &10000000000000164000000164 days.  There are records that verify her age, including accounts of her meeting with artist Vincent van Gogh when he came to her hometown of Arles. Calment began smoking at age 21 and did not stop until the age of 117. In interviews with the media, Calment ascribed her longevity and youthful appearance to olive oil, which she said she poured on all her food and rubbed onto her skin, as well as to drinking port wine regularly and eating nearly one kilogram of chocolate/week.^7,8 Calment lived on her own until she was 110, rode a bicycle at over 100, and took up fencing when she was 85.

Dr. Baur told the audience that what is intriguing about people with long life spans is how healthy they are. "They do get the illnesses we associate with old age, but not until their 90s and even later." Dr. Baur showed another slide to illustrate that the plant and animal worlds also have many superagers. The bristlecone pine (Pinus spp.) has a maximum lifespan of 5,000 years, for example, while the Aldabra Tortoise's maximum lifespan is over 255 years and the Yelloweye Rockfish (Red Snapper) can live for more than 115 years.

There are 51 clinical trials of resveratrol in humans currently listed at clinicaltrials.gov in the areas of diabetes, cancer, brain injuries, and cellulite.⁹ Dr. Baur said that few of these trials have reported results yet and most of these have been safety-related. However, some past human studies have reported positive health effects of resveratrol, including improving insulin sensitivity in type 2 diabetics¹⁰ and insulin sensitivity in prediabetics and older adults.¹¹ Another study found that resveratrol improved cardiac function and lowered cholesterol in heart attack survivors and had anti-inflammatory effects in patients at high risk for cardiovascular disease who were receiving statins.¹² “While the benefits that have been reported to date are generally small, they are nevertheless important, given that most studies have lasted only weeks, and employed doses far below those used in mice,” said Dr. Baur. “A recent study by Silvie Timmers and colleagues concluded that 30 days of resveratrol treatment was sufficient to produce effects resembling caloric restriction.  Moreover, they showed that based on body mass, a 200-fold lower dose of resveratrol resulted in similar blood levels to those in resveratrol-treated mice.”¹³ “Importantly, these observations seem to refute the prediction that humans would have to consume grams of resveratrol each day to obtain any benefit to health.”

In terms of resveratrol's safety, Dr. Baur noted that acute dosing with up to 5 g per day is generally well tolerated by most individuals, but doses over 1 g per day can cause gastrointestinal side effects in some individuals.¹⁴ Since red wine typically has less than 5 milligrams of resveratrol per bottle and dietary supplements are generally below 500 mg per daily dosage, studies of supplements to date have reported only minor side effects that were not clearly related to the treatment. When asked whether it is safe to take resveratrol supplements, Dr. Baur said that larger, longer-term studies are needed before resveratrol supplements can be declared safe for human use.

Turning his attention to the health claims for dark chocolate (Theobroma cacao) — which also contains resveratrol — Dr. Baur told the audience that when compared to pure resveratrol, red wine, or its extracts, fewer studies have been conducted and most of these have been observational. Recent meta-analyses summarizing the existing literature have concluded that dark chocolate modestly reduced LDL cholesterol¹⁵ and blood pressure.¹⁶ Other studies have found a correlation between high chocolate intake and a lower risk of heart attack or stroke.¹⁷ And one study predicted that consuming 100 g a day of dark chocolate for 10 years would prevent 85 strokes or heart attacks for every 10,000 people treated.¹⁸ This model assumed elevated risk factor patients, but excluded patients who had had cardiovascular events or diabetes.

In his concluding remarks, Dr. Baur said that for both resveratrol and dark chocolate, the available data are promising, but the effect sizes are generally small and much longer-term studies are needed.

Note: There is a podcast available of Dr. Baur's talk at the New York Academy of Sciences website.

David Levine is co-chairman of Science Writers in New York and a member of the National Association of Science Writers. He has an extensive background in healthcare communications.

References

1. Joseph A. Baur, PhD: Description of research expertise. University of Pennsylvania website. Available at: www.med.upenn.edu/apps/faculty/index.php/g20000220/p8216891. Accessed July 27, 2012.
   
   
2. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191-196.

3. Agarwal B, Baur JA. Resveratrol and life extension. Ann N Y Acad Sci. 2011;1215:138-143.

4. Baur JA, Ungvari Z, Minor RK, Le Couteur DG, de Cabo R. Are sirtuins viable targets for improving healthspan and lifespan? Nat Rev Drug Discov. 2012;11(6):443-61.

5. Minor RK, Baur JA, et al. SRT1720 improves survival and healthspan of obese mice. Sci Rep. 2011;1:70.

6. Price NL, Gomes AP, Ling AJ, e al.  SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15(5):675-690.

7. Jeanne Louise Calment: the world's oldest. University of California at Davis website. Available at: http://anson.ucdavis.edu/~wang/calment.html.

8. Oldest person to ever live: Jeanne Louise Calment holds world record, living to be 122 years old. Huffington Post. May 8, 2010. Available at: www.huffingtonpost.com/2010/03/08/oldest-person-to-ever-liv_n_490828.html.
   

9. Found 51 studies with search of: resveratrol. ClinicalTrials.gov website. Available at: http://clinicaltrials.gov/ct2/results?term=Resveratrol&pg=1.
   

10. Brasnyó P, Molnár GA, Mohás M, et al . Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011;106(3):383-389.

11. Crandall JP, Oram V, Trandafirescu G, et al. Pilot Study of Resveratrol in Older Adults With Impaired Glucose Tolerance. J Gerontol A Biol Sci Med Sci. 2012.

12. Tomé-Carneiro J, Gonzálvez M, Larrosa M, et al. One-year consumption of a grape nutraceutical containing resveratrol improves the inflammatory and fibrinolytic status of patients in primary prevention of cardiovascular disease. Am J Cardiol. 2012;110(3):356-363.

13. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T,  et al. Calorie Restriction‐like Effects of 30 Days of Resveratrol Supplementation on Energy Metabolism and Metabolic Profile in Obese Humans”. Cell Metab. 2011;14(5):612-622.

14. VA Brown, KR Patel, M Viskaduraki, JA Crowell et al. Repeat Dose Study of the Cancer Chemopreventive Agent Resveratrol in Healthy Volunteers: Safety, Pharmacokinetics, and Effect on the Insulin-like Growth Factor Axis. Cancer Res. 2010;70:9003

15. Tokede OA, Gaziano JM, Djoussé L. Effects of cocoa products/dark chocolate on serum lipids: a meta-analysis. Eur J Clin Nutr. 2011;65(8):879-886.
    
    
16. Desch S, Schmidt J, Kobler D, Sonnabend M, Effect of cocoa products on blood pressure: systematic review and meta-analysis. Am J Hypertens. 2010;23(1):97-103.
    
    
17. Buijsse B, Weikert C, Drogan D, Bergmann M, Boeing H. Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults. Eur Heart J. 2010;31(13):1616-1623.
    
    
18. Zomer E, Owen A, Magliano DJ, Liew D, Reid CM. The effectiveness and cost effectiveness of dark chocolate consumption as prevention therapy in people at high risk of cardiovascular disease: best case scenario analysis using a Markov model. BMJ. 2012;344:e3657.