The Effects of Resveratrol on Our Brain and Body (Part 2)

Today, we have Part II of our series on Resveratrol, and we start with a new study that shows that Resveratrol appears to triple the rate of age-related brain shrinkage.

Does resveratrol help with inflammation? In humans, the evidence of an anti-inflammatory effect is sparse and conflicting. About half of the studies show a modest anti-inflammatory effect, but the other half failed to find any. The proof, however, is in the pudding. What about clinical effects on inflammatory disease?

In rats and mice, resveratrol can help ameliorate the effects of experimentally-induced periodontitis, the inflammatory gum disease. However, it appears to have no effect on the progression of chronic periodontitis in human sufferers. Resveratrol may help with the inflammatory bowel disease ulcerative colitis, though. A pilot study of 500 mg a day of resveratrol for six weeks resulted in significantly decreased disease activity and elevated quality of life compared to placebo.

What about inflammatory joint diseases? One pilot study of 500 mg a day of resveratrol for knee osteoarthritis found a decrease in pain within a month, but there was no control group. So, the change can’t really be attributed to starting the supplements.

However, a second pilot study, a randomized, double-blind, placebo-controlled trial, found that the same dose taken as an “add on” to an anti-inflammatory drug significantly improved pain and function within a month in mild-to-moderate knee osteoarthritis sufferers––more than adding a placebo. The one clinical study of rheumatoid arthritis had a control group but no placebo, though there were objective signs of improvement in disease activity after taking 1,000 mg a day for three months.

Resveratrol may also be beneficial to combat menopausal symptoms. Resveratrol has some estrogenic activity. Although it doesn’t appear to help with hormonal migraines, it does appear to help with a couple symptoms of PCOS, polycystic ovary syndrome. RESHAW—Resveratrol for Healthy Ageing in Women—is the longest study of effects of resveratrol supplementation in postmenopausal women. Those randomized to 75 mg of resveratrol twice a day suffered significantly fewer physical menopausal symptoms, including aches and pains, and a general improvement in overall well-being compared to placebo.

The RESHAW study also looked at bone loss prevention. Unfortunately, though animal studies show protective effects on bone tissue, a meta-analysis of human studies on resveratrol supplementation to improve bone quality found no significant effect on bone health markers or bone mineral density of the spine, hip, or overall skeleton. A similar story was found for cognitive effects.

Most studies on resveratrol for brain function in animal models show positive outcomes, but meta-analyses of human studies show no significant effect on memory, processing speed, executive function, or global cognitive performance, which led reviewers to suggest that resveratrol may be a “cognitive enhancer for mice only.” Most human cognition studies found no effect or mixed results—higher performance on some tasks, but lower performance on others, compared to placebo, resulting in a “lack of interpretable cognitive effects.”

Some have suggested the discrepancy between the animal models and the clinical data is that the rodents were massively dosed––up to a gram per kilogram of body weight a day, which would be like giving people an entire bottle of high-dose resveratrol supplements at once. Or, ironically, it could be the opposite, where the doses researchers gave people were too large. A dose-response study found that human cerebral blood flow was maximally boosted by the lowest dose of resveratrol tested––75 mg a day. So, when the RESHAW study was developed, that was the dose they used, given twice a day.

RESHAW was primarily designed to test the effects of resveratrol on cognitive performance. Interim analyses at 14 weeks and a year looked promising, leading the researchers to conclude that their findings “support the adoption of resveratrol as a low-cost, effective intervention to help counteract the age- and menopause-related accelerated cognitive decline in our ageing population.” However, by the end of the two-year study, it’s not clear if the apparent benefit in overall cognition survives adjustment for multiple comparisons––meaning there were so many cognitive outcomes tested that the few treatment differences may well have arisen through chance.

What about cognitive benefit for those who really need it? Observational studies find wine drinkers tend to get less dementia, but it’s hard to disentangle the social, cognitive, and personality factors that accompany a wine-drinking habit. So, researchers decided to put resveratrol to the test for Alzheimer’s disease.

A randomized, double-blind, placebo-controlled pilot out of Cornell in 2006 kicked things off with a bang. Patients with mild-to-moderate Alzheimer’s disease who were randomized to a 5 mg resveratrol concoction twice a day ended up with significantly better cognition after three months compared to placebo. There was a greater than expected deterioration in the placebo group, though, suggesting this may have just been a fluke––especially since an attempt to replicate the study with the same dose for a year failed to find any effects of statistical significance. Maybe the researchers just didn’t use a high enough dose?

More than a hundred patients with mild to moderate Alzheimer’s were randomized to placebo or an escalating dose of resveratrol starting at a hundred times the dose of the previous study—500 mg once a day and ending at a 1,000 mg twice a day. After a year, there were no significant improvements in cognition or the performance of activities of daily living compared to placebo. Instead, there was a significant acceleration of brain volume loss. At the end of the study, there was triple the brain volume loss (3 percent versus 1 percent) in the resveratrol group. And the only other randomized, double-blind, placebo-controlled trial to date found the same thing: no significant cognitive benefits and the same tripling of age-related brain shrinkage. The authors tried to somehow spin this as a positive, like hey—maybe that’s just decreased brain swelling, but as a team of researchers wrote in an understatement of the year, “It is difficult to reconcile these effects as potentially beneficial.”

In our final story of the series, we discover how Resveratrol supplements may blunt some of the positive effects of exercise training.

If you have a condition that might benefit from resveratrol supplementation, like diabetic foot ulcers, or ulcerative colitis, or menopausal pains, and want to give resveratrol a try, are there any concerns––aside from the cost, which can exceed $10 a day?

Well, although a meta-analysis of studies of resveratrol found no overall effect on LDL cholesterol levels, a couple studies found that resveratrol sometimes increased LDL levels––up to 25 percent over placebo. As cardiovascular disease is by far the leading killer of diabetics, as well as other conditions for which you might take it, if you do try resveratrol, please make sure to have your cholesterol closely monitored.

The scientific literature regarding resveratrol and cardiovascular health in general is said to be “replete with conflicting information and controversy.” There are no human studies on cardiovascular disease outcomes, but an often-overlooked study found that resveratrol caused atherosclerosis in rabbits. The study, entitled “Resveratrol promotes atherosclerosis in hypercholesterolemic rabbits,” found that the hardening of the arteries of bunnies fed dietary cholesterol was worsened by resveratrol. But, negative or null findings are often marginalized by the resveratrol research community; so, you rarely hear about them.

Though there are no long-term safety data, 450 mg a day has been considered a safe dose, at least in the short term, for a 60 kg person (that’s about 130 pounds). But supplementation at higher doses could be potentially toxic. Daily doses of resveratrol in excess of a gram commonly cause mild to moderate gastrointestinal symptoms, such as nausea, diarrhea, and abdominal pain, as well as “anal itchiness.” Unexpected renal toxicity with cases of severe kidney failure were noted in a five-gram-a-day study, but this was in the context of a cancer that is particularly hard on the kidneys.

Two studies, however, found that so-called “safe” levels of resveratrol (at 150 to 250 mg a day) may blunt some of the positive effects of exercise training. In rodents, resveratrol supplementation decreases cardiovascular risk factors and improves cardiovascular function and physical capacity. But, when it was put to the test in older men (with an average age of 65), the exact opposite was found. Specifically, combining resveratrol with athletic training abolished the reduction in blood pressure, cholesterol, and triglycerides normally associated with exercise, had a more artery-constricting effect than a dilating one, and led to a significantly lower increase in aerobic fitness. Rodents on resveratrol get enhanced exercise performance, but in people, the resveratrol induced a 45 percent lower increase in maximum aerobic capacity compared with those taking a sugar pill. For all of their working out, the resveratrol was undercutting their effort. An apparent impairment in peak aerobic power was also noted in young men following high-intensity interval training on resveratrol compared to placebo.

A recent review overreacted to these data by suggesting “foods containing resveratrol should not be consumed during exercise.” But to even reach the lower dose of 150 mg, you’d have to eat more than a 100 pounds of grapes a day. (Though, I suppose, if you did manage to stuff in a hundred pounds of grapes, it might indeed be a little impairing.)

The exercise impairment with resveratrol supplements does make sense, though, given its purported mechanism. Sirtuin activation by resveratrol is thought to occur via the activation of the body’s fuel gauge, AMPK, by interfering with energy production in the mitochondria powerplants in our cells. Mouse cells react by increasing mitochondria to compensate, but human cells apparently do not. So, the energy-dimming effect of resveratrol may explain why the effects of exercise are impaired.

What works in animals may not necessarily work in people. Thus, concluded one review, the hype regarding resveratrol may “turn out to be nothing more than a slight-of-hand marketing device using peer-reviewed, published, non-human research as a cover.” Although some, like Dr. Oz, have recommended resveratrol as a life-extending “miracle molecule,” given that evidence-based responses are sparse-and-controversial, such “claims, innuendo, and hyperbole” are said to be “atrocious.”

The fitness-blunting exercise study of older adults was supported in part by a manufacturer of resveratrol supplements. To their credit, the researchers responded to an angry letter from a supplement company consultant that, “It is our opinion that we, as scientists, have a responsibility to report what we find and not to twist our findings to fit the commercial interests.”