Last month, scientists reported that dietary resveratrol, a polyphenol found in red grapes and wine, made no difference to people’s health (see May 2014 news story). However, some suggested that higher doses might, and a small study now supports that possibility. Researchers led by Agnes Flöel, Charité–Universitätsmedizin Berlin, found that six months of resveratrol supplements improved memory, hippocampal functional connectivity, and glucose metabolism in overweight older people. The results provide a basis for conducting more clinical trials on resveratrol, said Rafael de Cabo, National Institute on Aging, Baltimore, who was not involved in the study. “These researchers demonstrate with an elegant study design that resveratrol supplementation appears to improve cognition and metabolic factors associated with age,” he told Alzforum.
Resveratrol mimics a low-calorie diet. It reportedly improves spatial memory in rodents (see Wang et al., 2006) and non-human primates (see Dal-Pan et al., 2011). However, it is unclear whether such benefits extend to people. In healthy people, one-time high doses reportedly increased cerebral blood flow, but not cognitive function (see Kennedy et al., 2010). No one has evaluated whether long-term resveratrol supplementation improves memory in an older population.
To find out, first author Veronica Witte and colleagues enrolled 46 cognitively healthy people aged 50 to 80 whose body-mass index (BMI) was 25 to 30. That is the range called overweight. A body mass index of 18.5 to 24.9 is considered normal, and outright obesity starts at 30. They chose such a cohort because research suggests that this population benefits more from resveratrol (see Timmers et al., 2011). For 26 weeks, half the volunteers took 200 milligrams of the supplement per day, while the others received placebo capsules containing sunflower oil. At baseline and after treatment, the researchers tested word recall with the Auditory Verbal Learning Test, measured resting connectivity in the brain with functional magnetic resonance imaging (fMRI), and collected blood, body measurements, and vascular data.
Compared with the placebo group, the two dozen folks who took resveratrol recalled more test words at the end of the study. Functional connectivity between the hippocampus and frontal, parietal, and occipital areas was higher, as well, as was glucose metabolism. The three outcomes correlated with each other.
This suggests that resveratrol might improve cognitive function in adults, but the authors do not know whether it does so directly or works indirectly via energy metabolism, Flöel told Alzforum.
“This was a nice study that couples neuropsychological testing, fMRI analyses, and blood measurements,” said Todd Manini, University of Florida, Gainesville. While the correlations do not show causation, they suggest factors that may underlie resveratrol’s benefits to human health, he said. Manini just completed a Phase 1 trial looking at safety and metabolic outcomes of 12 weeks of resveratrol supplementation in older, overweight people (see Anton et al., 2014). He cautioned that in the German study, cognition in the placebo group declined more than he would have expected, which could contribute to a false positive.
Beau Ances of Washington University in St. Louis agreed, and said that the small number of participants coupled with the reliance on just one test of memory could also contribute. However, Ances praised the use of multiple modalities.
Given that studies have focused on resveratrol in overweight or otherwise unhealthy people, would people with a normal BMI benefit? The answer may be no, because resveratrol seems to work by resetting an off-balance metabolism, said de Cabo. However, more research will be needed to make sure. He cautions people against taking resveratrol until researchers run larger studies to find the most effective doses and decide who is likely to benefit.
Flöel and colleagues are currently running a six-month Phase 4 trial in 330 people with mild cognitive impairment to see if resveratrol affects their memory. Other trials of resveratrol are in the works for diabetes and Alzheimer’s disease (AD), including a Phase 2 from the Alzheimer’s Disease Cooperative Study that examines biomarker and cognitive changes associated with a year of resveratrol treatment in people with AD.—Gwyneth Dickey Zakaib
- Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein DL, Thiyagarajan M, Percival SS, Talcott ST, Pasinetti GM. Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer's disease. FASEB J. 2006 Nov;20(13):2313-20. PubMed.
- Dal-Pan A, Pifferi F, Marchal J, Picq JL, Aujard F. Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. PLoS One. 2011 Jan 31;6(1):e16581. PubMed.
- Kennedy DO, Wightman EL, Reay JL, Lietz G, Okello EJ, Wilde A, Haskell CF. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am J Clin Nutr. 2010 Jun;91(6):1590-7. Epub 2010 Mar 31 PubMed.
- Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink MK, Kunz I, Schrauwen-Hinderling VB, Blaak EE, Auwerx J, Schrauwen P. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011 Nov 2;14(5):612-22. PubMed.
- Anton SD, Embry C, Marsiske M, Lu X, Doss H, Leeuwenburgh C, Manini TM. Safety and metabolic outcomes of resveratrol supplementation in older adults: results of a twelve-week, placebo-controlled pilot study. Exp Gerontol. 2014 May 24;57C:181-187. PubMed.
- Ponzo V, Soldati L, Bo S. Resveratrol: a supplementation for men or for mice?. J Transl Med. 2014 Jun 3;12:158. PubMed.
- Mattison JA, Wang M, Bernier M, Zhang J, Park SS, Maudsley S, An SS, Santhanam L, Martin B, Faulkner S, Morrell C, Baur JA, Peshkin L, Sosnowska D, Csiszar A, Herbert RL, Tilmont EM, Ungvari Z, Pearson KJ, Lakatta EG, de Cabo R. Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab. 2014 Jul 1;20(1):183-90. Epub 2014 May 29 PubMed.
- Granzotto A, Zatta P. Resveratrol and Alzheimer's disease: message in a bottle on red wine and cognition. Front Aging Neurosci. 2014;6:95. Epub 2014 May 14 PubMed.
- Witte AV, Kerti L, Margulies DS, Flöel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci. 2014 Jun 4;34(23):7862-70. PubMed.