Resveratrol: New Evidence for a Human Health Benefit

Juvenon Health Journal volume 9 number 4 april 2010
By Benjamin V. Treadwell, Ph.D.

Today’s Internet world can provide us with a truly amazing amount of information about virtually any topic. We simply click on a search engine like Google, and we don’t even have to know how to spell our topic of interest. The computer will politely offer us the right word(s). What it can’t do, however, is evaluate the data it presents.

For example, consider what you’ll find on the health-promoting benefits of a plethora of primarily plant-derived nutrients. Besides being confusing, many of the claims are outrageous, lacking solid scientific evidence to support them. On the other hand, the potential benefits of some compounds, like resveratrol, seem to be well founded.

Tip of the Resveratrol Iceberg
For a decade or more, researchers have been studying resveratrol, the polyphenols contained in red wine and many plants. Their research, with animals and with human cells in culture, has yielded many exciting discoveries, from the compound’s supportive properties for nerve and brain tissue, to its effect on the insulin biochemical pathway (decreasing blood-glucose levels by improving insulin sensitivity), to demonstrating the compound’s capacity to extend the lifespan of some organisms.

“The potential benefits of resveratrol seem to be well founded.”

In fact, many of resveratrol’s effects on tissues mimic those produced by consuming a calorically restricted diet (which appear to relate to overall health, longevity, mental acuity and central nervous system function, etc.). But, although this research is instructive and interesting, it has largely fallen short in the sense that there has been little evidence (besides anecdotal) of positive effects from oral administration to humans. Until now.

A recently published report describes one of the first studies (conducted by a British team from Northumbria University’s Brain, Performance and Nutrition Research Centre and Newcastle University’s School of Agriculture, Food and Rural Development) to support a potential role for orally administered resveratrol in human health.

More Resveratrol in the Blood

“Many of resveratrol’s effects on tissues mimic a calorically restricted diet.”

Scientists have speculated that improved blood flow to the aging brain may help reduce age-related mental decline and improve cognition The British investigators designed an experiment to demonstrate whether resveratrol would have an effect on blood flow to the frontal lobes (problem-solving, cognitive area).

Their first question? Does the compound, trans-resveratrol, actually enter the blood stream after being ingested orally? So, the first leg of the experiment involved giving each of nine male subjects (mean age 25 years) a capsule containing either 250mg or 500mg of resveratrol.

The compound was detected in the blood within 45 minutes and was at peak concentration between 90 and 120 minutes. Now the research team, satisfied that the resveratrol did indeed enter the blood stream, was ready to test for its effects on blood flow.

More Blood to the Brain
They were aware of previous reports from animal studies, showing that resveratrol influenced blood vessel relaxation and increased blood circulation. They hoped to narrow the focus with this human study, determining whether ingested resveratrol would alter blood flow to the brain, specifically the prefrontal cortex, which is highly active during problem-solving tasks.

“Tests showed that orally ingested resveratrol entered the blood stream.”

Four men and 20 women, mean age 20 years, participated in the double-blind crossover experiment. Half of the subjects were instructed to take a coded capsule, containing either 250mg or 500mg resveratrol, and the other half were asked to take another coded capsule, an inert placebo. After a day of testing, the subjects were instructed to return in seven days at which time the capsule content would be reversed.

Total hemoglobin (oxygenated and non-oxygenated or deoxyhemoglobin) in the prefrontal cortex was measured at different times, using a non-invasive technique, Near Infrared Imaging Spectroscopy (NIRS). The results? The effects on blood flow to the brain for the resveratrol groups, 250 and 500mg doses, were similar: a significant increase in blood flow, compared to the subjects taking the placebo.

The difference was even more pronounced with respect to deoxyhemoglobin: the resveratrol group showed much higher levels of this oxygen-depleted form of hemoglobin. At first glance, this may seem contrary. But it signifies that the cells of this area of the brain are more active, thus, extracting more of the oxygen from the blood for the production of energy.

“With resveratrol, the cells of the brain’s problem-solving area seem to be more active.”

In fact, as a follow-on to the blood flow tests, the subjects were instructed to perform cognitive task and mental fatigue tests. The difference between the deoxyhemoglobin levels of the placebo and resveratrol groups was even more significant and the resveratrol group produced even higher levels than during the blood flow tests.

Encouraging Resveratrol Results
Evidence that the plant supplement seems to have at least one beneficial effect on humans, a capacity to increase blood flow to the brain, is exciting. The oxygen use findings also imply that previous animal and cell-culture work, showing that resveratrol improves mitochondrial function, may apply to humans. (Could this indicate a role for resveratrol in stimulating mitochondrial production as well?)

Another interesting correlation to earlier animal research occurred during the bioavailability testing. Sulfated and glucuronidated resveratrol – metabolized products – were identified as the major forms of the compound once it enters the blood stream. This raises the question of whether these modified resveratrol metabolites are key to eliciting some of the biological effects.

These results should encourage additional human studies with orally administered resveratrol. Perhaps it won’t be long until we learn whether it improves cognition and mental acuity over time. Or if, as previous work with animals has also indicated, this plant compound has a more global effect on the tissues of the human body, too.

A group of British investigators, from Northumbria University’s Brain, Performance and Nutrition Research Centre and Newcastle University’s School of Agriculture, Food and Rural Development, recently published “Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation” in the American Journal of Clinical Nutrition.

The article reports on the research team’s experiments to determine whether resveratrol would have any effect on blood circulation to the human brain. Previous animal studies, demonstrating the compound’s effect on stimulating the production of nitric oxide, an agent known to promote vasodilation and increased blood flow, prompted this project. The investigators also recognized the potential of improving cognitive ability in an aging population with associated decreased blood flow that may deprive the brain of nutrients.

In the first phase of the study, the team administered 250 and 500mg oral doses of resveratrol to examine uptake into the blood stream and assess bioavailability. Results showed typical pharmacokinetics: the uptake was maximal at 60 to 120 minutes after ingesting the resveratrol supplement. However, further analysis of blood samples revealed that the primary resveratrol compound was no longer the parent compound. Instead, it now largely consisted of a sulfated, and a glucuronidated form with small, but detectable quantities of the parent compound.

The second phase of the experiment involved 24 adults (mean age 20 years), who were divided into a placebo group (12 subjects) and an experimental group. Six of the experimental subjects took 250mg capsules of resveratrol, while the other six took 500mg doses.

Immediately after taking the capsules, the subjects were examined for cerebral blood flow using a non-invasive method known as a Near Infrared Spectroscopy (NIRS). The NIRS instrument measures both oxygenated (hemoglobin), and non-oxygenated (deoxyhemoglobin) blood flowing through the brain tissues. The prefrontal cerebral cortex was the target tissue as this is the major problem-solving and cognitive center of the brain.

The first half of this phase consisted of taking blood measurements every five minutes for 45 minutes. In the second half of the experiment, the subjects were presented with three cognitive tasks that were previously shown to activate the prefrontal cortex in brain imaging studies. Again, every five minutes for an additional 45 minutes, measurements were taken with the NIRS.

The results clearly showed that resveratrol increased blood flow to the brain. More importantly, they demonstrated that the deoxyhemoglobin levels were most affected by the resveratrol during the cognitive task period, which is consistent with an increase in mitochondrial activity and energy production. In other words, the research showed that orally administered resveratrol does have a significant effect on human brain activity.

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

Dr.Treadwell answers your questions.

question: There’s a lot of contradictory information out there about resveratrol and, in particular, about what the ideal amount to take per day would be. One producer of a supplement sternly warns about the dire consequences of taking more than 350mg per day (and recommends 100mg). One resveratrol researcher told me privately that he is personally taking 500mg per day.

Obviously, the reason for the contradictory information is that nobody really knows. But, based on what studies are out there, would you have a guess as to the range that makes the most sense? Thanks –

answer: You ask a very good question. Coincidentally, in this month’s Health Journal, I talk about a recent human study of a specific effect of resveratrol at 250mg and 500mg dosage.

Back to your question. My calculation, taking into consideration much of the research to date, is that 250mg per day is probably close to the optimum dose for an average weight human (150-180lbs). This is still based, in large part, on animal studies, using conversion factors to translate to human dosage. However, anecdotal evidence from humans supports the 250mg dose as well.

Benjamin V. Treadwell, Ph.D., is a former Harvard Medical School associate professor and member of Juvenon’s Scientific Advisory Board.