At last, the data are showing promising results in human studies

Wave Riding Resveratrol’s
Abundant New Research

The initial jump in resveratrol research hinged on
two seminal studies published between 2003 and 2006

By Will Block

X-51 WaveRider … Scramjet propelled
by its own shockwaves to add lift
T he phytonutrient resveratrol, was first isolated and identified in 1940 by Michio Takaoka from the dried root of white hellebore (Veratrum grandiflorum).* There was little interest in its biological activity until something known as the “French Paradox” arose in the 1990s to explain why high consumption of saturated fat by the French did not result in high levels of cardiovascular disease.


* See “Galantamine as Antioxidant” in this issue. Merry, Riddell, and Monro suggest that Moly might be black hellebore (a different species), which fits the description of the roots and flower and which was believed to be a protection against madness. (Merry WW, Riddell J, Monro DB. Homer’s Odyssey. Oxford: Clarendon Press 1886–1901.) However, more recent research points to the galantamine-containing snowdrop as the source of Moly.


While the paradox was initially associated with the consumption of red wine, researchers started to ask what in red wine could be the cause of the benefit. The answer was resveratrol. Indeed, in vitro assays showed that resveratrol might be able to protect the cardiovascular system by inhibiting platelet aggregation and LDL oxidation.2,3 Life Enhancement’s first article on resveratrol was published in July of 2000 (See “Grape Expectations”).

Rapid Research Acceleration

LEM1309growth_chart_thumb_214.gif
(click on thumbnail for full sized image)
Only 6 papers were found in the MEDLINE database from the time of Takaoka’s first paper until the end of 1989. The next decade produced 177 more, and the next decade (2000–2009) added 2909! Since 2010, in the first 3½ years of the current decade, 2669 additional papers have already been published. This constitutes an explosion in knowledge about resveratrol.


† MEDLINE is the U.S. National Library of Medicine’s® (NLM) premier bibliographic database that contains over 19 million references to journal articles in life sciences with a concentration on biomedicine.


The Age of Sirtuins

The initial jump in resveratrol research hinged on two seminal studies published between 2003 and 2006. These studies confirmed that resveratrol retarded the aging process by acting on sirtuins (Sir2 proteins—silent information regulation proteins) and that it mimicked some effects of calorie restriction (CR).4,5 This stimulated intense scientific interest in the pharmacological activities of resveratrol.

The senior author of the above two papers was David Sinclair of Harvard University’s Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. Dr. Sinclair has continued to be a leading force in resveratrol research. Life Enhancement published its first article about David Sinclair’s work in May of 2000 (“Taming the ‘Mortal Coil’ of Aging”). In their 1997 paper6 described in this article, Leonard Guarente and David Sinclair speculated that a mechanism involving runaway replication in cells is the long-sought “aging clock.” Dr. Guarente is the director of the Paul F. Glenn Lab for the Science of Aging at MIT. Thus both Drs. Sinclair and Guarente are connected through their funding source, the Glenn Foundation for Medical Research (http://glennfoundation.org/).


‡ Life Enhancement formulators Durk Pearson & Sandy Shaw were awarded the prestigious Paul F. Glenn Award, presented in 1990, for their special contribution to public education regarding biomedical aging research.


The Promise of an Antiaging Molecule

Media coverage of the scientific findings dramatically increased public awareness of the promise of resveratrol as an antiaging molecule, paving the way for the development of products containing resveratrol by the food and supplement industries. While resveratrol is found notably in grapes and in a variety of medicinal plants, the principle source of commercial resveratrol is the Japanese Knotweed, (the most concentrated source of resveratrol known). For centuries, the Chinese and Japanese pharmacopeias have used Japanese Knotweed (as well as a similar variety known as Giant Knotweed) in traditional natural med­icines. Known as Huzhang, Japanese Knotweed has long been used to improve blood flow and to control inflammatory processes.

Resveratrol’s Numerous Biological Activities

A great many biological activities have been attributed to resveratrol, including antioxidant, anti-inflammatory, anticarcinogenic, antiaging, and cardiovascular protective properties.5,7,8 The anti-inflammatory activities of resveratrol seem to be a key feature in its mode of action.

In a paper published in 1997,9 researchers suggested that the ability of resveratrol to block all three mechanisms of tumor growth—initiation, promotion, and progression—is attributable, at least in part, to its anti-inflammatory activity. This seminal paper attracted considerable interest in evaluating the anticancer effects of resveratrol. Resveratrol’s anti-inflaamatory effects were similar to those of the anti-inflammatory drug indomethacin. The edema-suppressing activity of resveratrol was much higher than expected for the in vitro inhibition of cyclooxygenase (COX) activity. This suggested that in addition to COX inhibition (resulting in relief from the symptoms of inflammation and pain), resveratrol probably has anti-inflammatory activity through other mechanisms.

Human Dose Equivalencies

In the above study,9 the anti-inflammatory activity of resveratrol could be shown in vivo at a dose of 8 mg/kg body weight/day. This dose corresponds to a human equivalent dose of about 90 mg/day for a 154 lb human, using the FDA guideline recommendations to extrapolate from effective doses in animal models to human equivalent doses. (See “Computing the Ideal Amount of Resveratrol” in the Q&A of December 2007.)

Resveratrol Overcomes Rapid Metabolism

Contrary to some criticisms about resveratrol’s bioavailability, the above study9 and other findings support the view that despite its rapid metabolism, resveratrol could have beneficial and efficacious effects in vivo at a relatively low dose. The mechanism of action and the health benefits of resveratrol have been extensively investigated in in vitro and in vivo systems with regard to antiaging and cardiovascular protective effects.

Mimicking Caloric Restriction

Resveratrol has also become a compelling topic for scientists as a molecule mimicking the effects of CR. Recently, the first human studies were published,10–16 indicating that resveratrol may have beneficial effects for humans in antiaging, metabolic, and cardiovascular health.

Resveratrol’s Rising Star

A just-published article in the July 2003 issue of the Annals of The New York Academy of Sciences reports on the emergence of resveratrol as a new supplement and food ingredient resulting from the progression of experimental data to nutritional evidence.17 Much of the outline and details of this article are derived from this paper.

In the paper’s overview, the researchers describe in great detail the translation from the in vitro mechanistic findings to the effects in humans. This translational nutrition research is critical for the long-term success of a new nutraceutical, since human studies are mandatory for the substantiation of health claims. As already stated in the article you are reading, the early in vitro findings increased the awareness of resveratrol, and a number of other in vitro studies as well as in vivo studies were initiated to evaluate the biological activity of resveratrol.

In Vitro to Animal to Human Studies

As the scientific literature has compiled, numerous animal and in vitro studies have added to the idea that resveratrol has cardioprotective benefits and may improve metabolic health by mimicking the effects of calorie restriction. In view of compelling preclinical evidence, a number of human studies investigating the effects of resveratrol on vascular and metabolic health have been initiated.

Taken together, the animal, human epidemiological, and first human intervention studies support a role of resveratrol in vascular and metabolic health. But even before this, owing to low toxicity and traditional use in Asia, resveratrol has appeared in the supplement and food product markets, emerging as a promising new health ingredient. Thus, supplementation with resveratrol may be included in nutritional and lifestyle programs aiming to reduce the risk of vascular and obesity-related problems.

Aging and Metabolic Health

Resveratrol has been shown to increase the life span of various species from invertebrates to mice.5 In mice fed a high-calorie diet, resveratrol (at a dose of only 22 mg/kg/day; 124 mg/day for a 154 lb human) was demonstrated to prevent early mortality by suppressing obesity-related metabolic disorders.18 In this study, resveratrol lowered fasting glucose, improved insulin sensitivity, and prevented liver damage, in addition to improving performance in treated animals. Despite being overweight, the resveratrol-treated mice were metabolically healthy.

The Mechanisms of Aging

As the Annals article indicates, resveratrol acts on the aging process by targeting energy/nutrient pathways proteins such as sirtuins (SIRT1), the mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK). In the beginning of the surge of interest in resveratrol, the focus was on the effect of resveratrol on sirtuins. Questions have arisen about whether sirtuins are directly or indirectly activated by resveratrol. This still needs further clarification, particularly the complex interplay between the different pathways involved. Yet, the data suggest that similarly to CR, resveratrol may act on nutrient/energy sensing systems that are considered to play key roles in the aging process.

Reduced calorie intake without malnutrition prolongs lifespan in invertebrates and rodents, as numerous studies have shown. In addition, CR has beneficial effects on diabetes, cardiovascular diseases, neurodegenerative diseases, chronic inflammation, and oxidative stress in humans.

Similarities between CR and Resveratrol

A gene evaluation study of the long-term CR mimicking effects of resveratrol on mice given a low dose of resveratrol (4.9 mg/kg/day; corresponding to a human equivalent dose of about 30 mg/day), compared to CR from middle age (14 months) to old age (30 months) was conducted.19 The results found a large overlap in the change in the gene expression profile during aging between the CR and the resveratrol-treated group in heart, skeletal muscle, and brain. Thus, CR and resveratrol retarded aging in a similar way in those tissues. At the same time, both dietary interventions also prevented age-related cardiac dysfunction. Resveratrol, at doses that can be easily achieved in humans, mimics CR to certain degrees, and thus may help prevent age-related chronic diseases.

Human Studies with Similar Resveratrol/CR Conclusions

Building on the role of resveratrol in preventing age-related metabolic and cardiovascular disturbances, several human studies have been conducted. Recently, another paper showed that the metabolic benefits observed in animal obesity models could also be translated into effects in humans.20 In this randomized double blind crossover study, resveratrol significantly reduced systolic blood pressure and improved blood glucose levels as well as insulin sensitivity in obese men receiving 150 mg/day of resveratrol for 30 days. Adding to these findings, a significant decrease in liver fat and inflammatory markers was noted, again indicating that resveratrol was able to partly mimic CR in obese humans, as previously reported in animals.

Resveratrol has also been shown to improve insulin sensitivity and glucose metabolism in subjects with impaired glucose tolerance, and overall improvement in metabolic health.

Resveratrol’s Cardiovascular Health Benefits

Back in the 1990s, following the French Paradox, studies began to demonstrate that resveratrol could benefit cardiovascular function. Since then, resveratrol has been shown to have multiple beneficial effects on the cardiovascular system, including decreasing oxidative stress, inhibiting platelet aggregation and vascular smooth muscle proliferation, decreasing vascular inflammation, and improving endothelial function. These effects have been principally ascribed to resveratrol’s antioxidant and anti-inflammatory properties, which preserve vascular function and retard atherosclerosis during the aging process.

Endothelial function improvement seems to be critical for resveratrol’s vascular benefits, owing to better regulation of vascular homeostasis resulting in reduced atherosclerotic lesions. Resveratrol inhibited early markers of endothelial dysfunction and atherosclerosis. And at low dose, it significantly inhibited the adhesion of monocytes to stimulated endothelial cells, a key step in the development of atherosclerosis.

In aged rats, resveratrol (10 mg/kg/day) reversed the age-related increase in an affective gene expression, suggesting that resveratrol may limit chronic inflammation and attenuate early atherosclerotic events. Furthermore, in a recent human ex vivo study, detrimental gene expression was significantly decreased in coronary endothelial artery cells incubated with plasma from subjects who were supplemented with 400 mg/day of resveratrol (and quercetin and grape skin extract) for 30 days.

Vascular aging has also been associated with nuclear factor dysfunction disrupting the induction of endogenous antioxidants and enzymes conferring protection from oxidative damage. Furthermore, a recent human study showed that after a single oral dose of resveratrol (100 mg) plus a grape extract enriched in polyphenol (75 mg), the activity of the nuclear factor along with its downstream targets was stimulated in isolated monocytes. Again, resveratrol significantly increased the transcriptional activity of nuclear factor target genes in endothelial cells.

Resveratrol Upregulates Nitric Oxide!

Nitric oxide (NO) is a potent vasodilator involved in the regulation of vascular homeostasis and is produced by endothelial nitric oxide synthase (eNOS). Resveratrol induced a concentration- and time-dependent upregulation of eNOS mRNA in human umbilical vein endothelial cells. At the same time, resveratrol acutely enhanced the release of NO from endothelial cells, with one paper showing that at very low doses, resveratrol increased functional eNOS protein and NO production.

In another study, when given to spontaneously hypertensive rats for 10 weeks, resveratrol preserved vascular NO production and normalized elevated blood pressure. Altogether, endothelial-related in vitro and in vivo data denote that resveratrol reduces inflammatory stress and promotes nitric oxide biosynthesis at physiologically relevant doses. Presumably, benefits in humans are associated with this mode of action.

Flow mediated dilation (FMD) is a biomarker of vascular function. In 2011, the effects of three single doses of resveratrol (30, 90, and 270 mg) on FMD of the brachial artery in humans were studied, confirming that resveratrol improves endothelial function.21 The three doses of resveratrol significantly increased FMD by 62–91%. Accordingly, resveratrol might improve endothelium-dependent vasodilation at a dose as low as 30 mg/day in humans. It is interesting to note that in a follow-up study, 75 mg/day of resveratrol taken for six weeks produced a sustained and prolonged 23% improvement in FMD.22 Another study found that, in patients with coronary artery disease, resveratrol (10 mg/day) significantly improved FMD and left ventricle diastolic function over a period of three months. This is important, because impaired endothelial vasodilator function may lead to cardiovascular disease, and an improvement in FMD has been associated with a decrease in cardiovascular adverse events. Altogether, studies to date strongly indicate that resveratrol has beneficial effects on human circulatory function.

Conversion Back to Free Resveratrol

Addressing a controversy, recent data show that resveratrol metabolites remain biologically active and could eventually be converted back to free resveratrol in the tissues.23 This means that the measurement of total resveratrol, metabolites included, is relevant to assess plasma levels after dietary intake of resveratrol. Resveratrol plasma levels in the above studies were comparable to levels that previously have shown activity in in vitro model systems.

Why You Need to Take Resveratrol Research Seriously

Interest in resveratrol continues to grow and produce significant conclusions, especially regarding its beneficial effects on aging, along with positive effects on metabolic and cardiovascular health. From the beginning, scientific findings have initiated an abundance of mechanistic and clinical research studies resulting in the launch of products focusing on age-related problems and cardiovascular health.

Moreover, many clinical trials investigating the beneficial effects of resveratrol are ongoing. According to www.clinicaltrial.gov, as of April 2013, there were 15 studies on the effects of resveratrol on the field of metabolic health and four studies in the area of cardiovascular diseases, indicating that high interest continues.

Regarding aging and metabolic problems, the experimental data indicate that resveratrol prevents pathological changes associated with high calorie intake and thus may thus provide a variety of beneficial health effects. Furthermore, as previously noted, resveratrol has been shown to reduce the deleterious effects of oxidative, inflammatory, and metabolic stress.

In the first human study of its kind, resveratrol mimicked some aspects of CR and endurance training in obese humans. Regarding cardiovascular health, there is convincing in vitro and in vivo evidence suggesting that resveratrol has beneficial effects on vascular function and on early markers of atherosclerosis. Moreover, resveratrol improves endothelial function in humans at relatively low doses.

Given the safety of resveratrol, the arguments are convincing that it is an important supplement to include in your anti-aging, health-promoting regimen.

References

  1. Takaoka, M. Phenolic substance of white hellebore (Veratrum grandiflorum Loes fil.). III. Constitution of resveratrol. Nippon Kagaku Kaishi. 1940;61:30–4.
  2. Frankel E, Waterhouse AL, Kinsella JE. Inhibition of human LDL oxidation by resveratrol. Lancet. 1993 Apr 24;341(8852):1103-4.
  3. Bertelli AA, Giovannini L, Giannessi D et al. Antiplatelet activity of synthetic and natural resveratrol in red wine. Int J Tissue React. 1995;17(1):1-3.
  4. Howitz KT, Bitterman KJ, Cohen HY et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6.
  5. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006 Jun;5(6):493-506.
  6. Sinclair DA, Guarente L. Extrachromosomal rDNA circles—a cause of aging in yeast. Cell. 1997 Dec 26;91(7):1033-42.
  7. Chachay VS, Kirkpatrick CM, Hickman IJ et al. Resveratrol—pills to replace a healthy diet? Br J Clin Pharmacol. 2011;72: 27–38.
  8. Timmers S, Auwerx J, Schrauwen P. The journey of resveratrol from yeast to human. Aging. 2012;4: 146–58.
  9. Jang M, Cai L, Udeani GO et al. Cancer chemopreventiveactivity of resveratrol, a natural product derived from grapes. Science. 1997 Jan10;275(5297):218-20.
  10. Wong RH, Howe PR, Buckley JD et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis. 2011;21: 851–6.
  11. Brasnyo P, Molnar GA, Mohas 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: 383–9.
  12. Timmers, S, Konings E, Bilet L 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: 612–22.
  13. Magyar K, Halmosi R, Palfi A et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc. 2012; 50: 179–187.
  14. Yoshino J, Conte C, Fontana L et al. Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. Cell Metab. 2012; 16: 658–64.
  15. Poulsen MM, Vestergaard PF, Clasen BF et al. High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes. 20162: 1186–95.
  16. Crandall, JP, V Oram, G Trandafirescu, et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci. 2012;67: 1307–12.
  17. Raederstorff D, Kunz I, Schwager J. Resveratrol, from experimental data to nutritional evidence: the emergence of a new food ingredient. Ann NY Acad Sci. 2013 Jul;1290(1):136-41.
  18. Baur JA, Pearson KJ, Price NL et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42.
  19. Barger JL, Kayo T, Vann JM et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One. 2008 Jun 4;3(6):e2264. doi: 10.1371/journal.pone.0002264. Erratum in: PLoS ONE. 2008;3(6). doi: 10.1371/annotation/c54ef754-1962-4125-bf19-76d3ec6f19e5.
  20. Timmers S, Konings E, Bilet L et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov2;14(5):612-22.
  21. Wong RH, Howe PR, Buckley JD et al. Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure. Nutr Metab Cardiovasc Dis. 2011 Nov;21(11):851-6.
  22. Wong RH, Berry NM, Coates AM et al. Sustained improvement of vasodilator function by resveratrol in obese adults. J Hypertens. 2012;30:e70.
  23. Hoshino J, Park EJ, Kondratyuk TP et al. Selective synthesis and biological evaluation of sulfate-conjugated resveratrol metabolites. J Med Chem. 2010 Jul 8;53(13):5033-43.


Will Block is the publisher and editorial director of Life Enhancement magazine.

Featured Product

  • Learn more about Resveratrol benefits and implementation strategies.

Ingredients in this Article

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator