Supplementation with resveratrol, systematic chemical name trans-3,5,4′-trihydroxystilbene, is still one of the most important weapons we have against aging. However, not all supplements are the same. This blog will teach you everything you need to know about the way resveratrol works, about the sometimes contradictory outcomes of trials, and the most effective way to use it.

In 1939, Japanese biochemist Michio Takaoka discovered resveratrol and its analogues, including pterostilbene, while analyzing phytochemical substances from the plant Veratrum grandiflorum.[1] Decades later, in the 1960s, another Japanese scientist identified resveratrol in the roots of Japanese knotweed (Polygonum cuspidatum).[2] Today, the supplements industry still utilizes extracts from this plant.

In a Western diet, red wine and red grape juice are probably the best sources of resveratrol. A liter of red wine can provide about 2 milligrams of resveratrol.[3] In addition, resveratrol is also found in peanuts and peanut butter,[4] cacao, berries, and nuts. Through these sources, a healthy diet can provide approximately 0.1-1 milligram of resveratrol per day.

A diet consisting of organically grown produce may provide a bit more resveratrol than conventionally grown crops. Plants produce resveratrol as a defense against insects, viruses and fungi.[5] In conventional agriculture, farmers use pesticides to combat most of these factors, which are not allowed in organic farming. As a result, organically grown crops may contain a few percent, and sometimes even tens of percent, more resveratrol than their conventionally grown counterparts.

In 1997, American chemists from the University of Illinois published a study in the journal Science which revealed an impressive range of potential health benefits associated with resveratrol.[6] Resveratrol was not only found to be an antioxidant, but it also inhibited inflammation. Resveratrol was shown to prevent the development of cancer and stimulate the development of immune cells. After the publication of the Science paper, thousands of studies into the biological effects of resveratrol followed.

David Sinclair enters the building

Some of the most influential studies on resveratrol include publications from the molecular biologist David Sinclair. Sinclair, affiliated with Harvard Medical School, studies the role of a group of enzymes – the sirtuins, to be precise – in slowing down aging processes. In 2003, Sinclair and his colleagues published a study in Nature showing that resveratrol extended the lifespan of yeast cells in a way that, at least at the molecular level, closely resembled the way yeast cells live longer when given fewer nutrients.[7] Resveratrol stimulated sirtuin activity, just like caloric restriction. The precise mechanism is not yet known.

A year later, in 2004, Sinclair published another article in Nature.[8] In this publication, Sinclair demonstrated that resveratrol also slowed down aging in fruit flies and nematodes. In 2006, Sinclair and his co-workers published yet another study in Nature.[9] In this publication, they describe how supplementation with resveratrol keeps obese mice healthy and even gives them a lifespan that comes close to that of healthy mice.

The Sinclair studies inspired researchers worldwide to thoroughly study the anti-aging effects of resveratrol. In animal studies and, to a lesser extent, in human research, scientists found evidence of positive effects of resveratrol on a wide range of age-related conditions in the heart and blood vessels, skeleton, reproductive organs, muscle tissue, and brain.[10]

Human trials, conflicting results

In the years that followed, dozens of trials were published in which medical scientists tried to determine whether resveratrol supplementation had a positive effect on a variety of chronic conditions. These studies have consistently produced different outcomes, likely due to the varying doses and methods of administration used.

For example, when Danish researchers gave a group of diabetics 150 milligrams of resveratrol daily for 4 months, they saw no positive effects.[11] When they increased this dose to 1000 milligrams per day, small negative effects were observed, such as a slight increase in the blood levels of ‘bad cholesterol’ LDL.

There are also trials with more positive outcomes. In these trials, researchers usually tested doses ranging from 150 to 900 milligrams per day. In a recent trial published in Complementary Therapies in Medicine in 2022, for example, type-2 diabetics were given 200 milligrams of resveratrol daily. [12] The researchers noted a mild improvement in glucose metabolism and a decrease in the production of inflammatory factors. In a meta-study published by Chinese endocrinologists from Southeast University in Nutrition & Metabolism, supplementation with less than 100 milligrams of resveratrol per day was found to have no effect, while supplementation with higher doses generally did ameliorate diabetic symptoms.[13] In this category of trials, the studies in which researchers administered doses of 1000 milligrams or more were less convincing than the trials in which the daily administered dose remained somewhere between the range of 100 to 1000 milligrams.

In almost all studies where various concentrations have been tested, there is an optimal concentration range in which resveratrol has positive health effects. At lower concentrations, resveratrol has no effect, while at higher concentrations it may have negative side effects. In in vitro research, for example, resveratrol stimulates Natural Killer Cells to eliminate cancer cells at concentrations of 1.5-3 micromoles.[14] These concentrations can be found in the blood after taking approximately 200-400 milligrams of resveratrol. However, higher concentrations of resveratrol, on the order of several tens of micromoles, inhibit the activity of Natural Killer Cells.

Side effects

Resveratrol appears to not have any serious side effects even at high doses. Trials have been published in which users took resveratrol in doses of 1500-5000 milligrams per day, but even in those cases, there were no serious adverse effects. However, at doses of more than 500-1000 milligrams per day, some users may experience mild gastrointestinal side effects such as stomach pain, flatulence, soft stool, and diarrhea.[15]

Which supplement?

In this blog, we have highlighted a few challenging issues associated with the use of resveratrol. Firstly, it became clear that it is not possible to consume enough resveratrol through regular foods to achieve positive health effects. Supplements are therefore necessary.

A second problem is the dosage. The cells in the tissues of the small intestine, where resveratrol is absorbed, quickly convert resveratrol into non- and less-active compounds. As a result, only a fraction of the ingested resveratrol ultimately will organs, tissues and cells elsewhere in the body.

To some extent, users can solve this problem by resorting to high doses. But even this strategy, cannot prevent the resveratrol molecules that reach the blood from quickly being converted into inactive compounds. Moreover, the use of high doses of resveratrol briefly may leads to a level at which resveratrol may have some adverse effects.

Biochemists and pharmacologists have developed several solutions to this problem. One approach is the creation of supplements that not only contain resveratrol, but also substances that slow down the conversion of resveratrol.[16] One of these substances is piperine, a substance found in black pepper.[17] [18] Piperine inhibits an enzyme in the small intestine that deactivates resveratrol.

Another interesting phytochemical in this regard is quercetin. When resveratrol is administered in combination with quercetin, the bioavailability of resveratrol increases. The enzymes that convert resveratrol into less active compounds also convert quercetin. Because these enzymes have a preference for quercetin, simultaneous administration of both substances can lead to a higher resveratrol level.[19]

Another approach, which can be applied effectively in combination with co-administration with piperine and quercetin,[20] is the pre-packaging of resveratrol in small, fatty particles based on phospholipids. Application of this technology ensures that after ingestion of a relatively small dose of resveratrol, it is present in the bloodstream for several hours at effective but non-toxic concentrations.[21] [22]

In addition to the use of these advanced technologies, there is another way to enhance the anti-aging effects of resveratrol. But that’s something for a subsequent blog.

[1] Takaoka, M. (1939). trans-3,5,4′-trihydroxystilbene, a new phenolic compound, from Veratrum grandiflorum. Journal of the Chemical Society of Japan, 60, 1090-1100.

[2] Nonomura, S. et al. (1963). Chemical constituents of Polygonaceous plants. I. Studies on the components of Kojokon (Polygonum cuspidatum). Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan, 83, 988-90.

[3] Weiskirchen, S. et al. (2016). trans-3,5,4′-trihydroxystilbene: How much wine do you have to drink to stay healthy? Advances in Nutrition, 7(4), 706-18.

[4] Sanders, T. H. et al. (2000). Occurrence of trans-3,5,4′-trihydroxystilbene in edible peanuts. Journal of Agricultural and Food Chemistry, 48(4), 1243-6.

[5] Song, P. et al. (2021). Natural phytoalexin stilbene compound trans-3,5,4′-trihydroxystilbene and its derivatives as anti-tobacco mosaic virus and anti-phytopathogenic fungus agents. Scientific Reports, 11(1), 16509.

[6] Jang, M. et al. (1997). Cancer chemopreventive activity of trans-3,5,4′-trihydroxystilbene, a natural product derived from grapes. Science (New York, N.Y.), 275(5297), 218-20.

[7] Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425(6954), 191-6.

[8] Wood, J. G. et al. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 430(7000), 686-9.

[9] Baur, J. A. et al. (2006). trans-3,5,4′-trihydroxystilbene improves health and survival of mice on a high-calorie diet. Nature, 444(7117), 337-42.

[10] Zhou, D. D. et al. (2021). Effects and mechanisms of trans-3,5,4′-trihydroxystilbene on aging and age-related diseases. Oxidative Medicine and Cellular Longevity, 2021, 9932218.

[11] Kjær, T. N. et al. (2017). No beneficial effects of trans-3,5,4′-trihydroxystilbene on the metabolic syndrome: A randomized placebo-controlled clinical trial. The Journal of Clinical Endocrinology and Metabolism, 102(5), 1642-51.

[12] Mahjabeen, W., Khan, D. A., & Mirza, S. A. (2022). Role of trans-3,5,4′-trihydroxystilbene supplementation in regulation of glucose hemostasis, inflammation and oxidative stress in patients with diabetes mellitus type 2: A randomized, placebo-controlled trial. Complementary Therapies in Medicine, 66, 102819.

[13] Zhu, X. et al. (2017). Effects of trans-3,5,4′-trihydroxystilbene on glucose control and insulin sensitivity in subjects with type 2 diabetes: systematic review and meta-analysis. Nutrition & Metabolism, 14, 60.

[14] Li, Q., Huyan, T., Ye, L. J., Li, J., Shi, J. L., & Huang, Q. S. (2014). Concentration-dependent biphasic effects of resveratrol on human natural killer cells in vitro. Journal of Agricultural and Food Chemistry, 62(45), 10928-35.

[15] Cottart, C. H. et al. (2014). Review of recent data on the metabolism, biological effects, and toxicity of resveratrol in humans. Molecular Nutrition & Food Research, 58(1), 7-21.

[16] Vesely, O. et al. (2021). Enhancing bioavailability of nutraceutically used trans-3,5,4′-trihydroxystilbene and other stilbenoids. Nutrients, 13(9), 3095.

[17] Johnson, J. J. et al. (2011). Enhancing the bioavailability of trans-3,5,4′-trihydroxystilbene by combining it with piperine. Molecular Nutrition & Food Research, 55(8), 1169-76.

[18] Bailey, H. H. et al. A randomized, double-blind, dose-ranging, pilot trial of piperine with trans-3,5,4′-trihydroxystilbene on the effects on serum levels of trans-3,5,4′-trihydroxystilbene. European Journal of Cancer Prevention, 30(3), 285-90.

[19] Jaisamut, P. et al. (2021). Enhanced oral bioavailability and improved biological activities of a quercetin/ trans-3,5,4′-trihydroxystilbene combination using a liquid self-microemulsifying drug delivery system. Planta Medica, 87(4), 336-46.

[20] Guseva, D. A. et. (2015). Influence of trans-3,5,4′-trihydroxystilbene and dihydroquercetin inclusion into phospholipid nanopatricles on their bioavailability and specific activity. Biomeditsinskaia Khimiia, 61(5), 598-605.

[21] Gausuzzaman, S. A. L. et al. (2022). A QbD Approach to design and to optimize the self-emulsifying resveratrolphospholipid complex to enhance drug bioavailability through lymphatic transport. Polymers, 14(15), 3220.

[22] Li, T. P. et al. (2017). Physical and pharmacokinetic characterizations of transresveratrol (t-Rev) encapsulated with self-assembling lecithin-based mixed polymeric micelles (saLMPMs). Scientific reports, 7(1), 10674.