In addition to improved glucose metabolism ...

Resveratrol Ups Memory Performance
… Along with improved hippocampal functionality in healthy older adults

By Will Block

R emember the “French Paradox”? It was the question raised at the end of the 20th century about why the high-fat diet of the French did not cause more heart disease. Data collected as far back as 1997 indicate that phenolic compounds (stilbenes, catechins, anthocyanins) found in red wine exhibit properties that may account in part for the fact that moderate drinking of red wine over a long period of time can protect against coronary heart disease.1 Resveratrol is a stilbene. Other epidemiological evidence indicated that moderate consumption of alcohol, particularly in the form of red wine, reduces the risk of neurodegenerative diseases such as Alzheimer’s disease (AD).2-4

Resveratrol Back in Time

The history of resveratrol — found as an active ingredient in red grapes, peanuts, berries, and several other food plants — meanders back to the Ayurveda, the ancient Indian treatise on the “science” of longevity.5 The first known use of grape extracts for human health can be dated to 2500 BC or earlier. Grape (Vitis vinifera L.) juice was the chief component of “darakchasava” (fermented juice of red grapes), a well-known Indian herbal preparation prescribed principally as a cardiotonic, having an energizing effect on the action of the heart. Using high-performance liquid chroma­tography analysis, it has now been shown that the main components of darakchasava are the polyphenols resveratrol and pterostilbene, which account for its numerous medicinal properties.

Forward to Japan

In modern times, resveratrol was first identified by a Japanese researcher in 1940 as a constituent of the roots of white hellebore (Veratrum grandiflorum O. Loes),6 and later in the dried roots of Polygonum cuspidatum, called Ko-jo-kon in Japanese, or knotwood, today. High in resveratrol content, these herbs found use for gonorrhea favus, athlete’s foot (tinea pedis), and hyperlipidemia.7

Resveratrol Retards the Aging Process

The initial leap in resveratrol research was propelled by two groundbreaking studies published in 2003 and 2006, respectively. These studies confirmed that resveratrol retarded the aging process by acting on sirtuins (Sir2 proteins — silent information regulation proteins) and that it mimicked some de-aging effects of caloric restriction (CR).8,9 These papers stimulated powerful 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 a 1997 paper10 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.

* In 1990, Durk Pearson and Sandy Shaw were the recipients of the Paul F. Glenn Award of the American Aging Association, a professional society, for their educational activities, directed to the public via books, articles, radio, and television, concerning aging research and its practical implications.

Resveratrol Addresses Mechanisms that Increase Memory

It has often been reported that dietary habits such as caloric restriction — or nutrients that mimic these effects — may exert beneficial effects on brain aging. Resveratrol has been shown to increase memory performance in primates; however, interventional studies in older humans are lacking. Until now.

Inflammation plays a major role in the pathogenesis of a wide variety of diseases including cardiovascular diseases, cancer, diabetes, autoimmune diseases and AD (see “Foiling Cytokine Storms with Cholinergics” in the December 2014 issue). Agents that can suppress inflammation thus have a potential in moderating the symptoms of the disease. Resveratrol is one of these.

(click on thumbnail for full sized image)

Resveratrol exhibits antioxidant and anti-inflammatory activities and thus may have potential in the treatment of many disorders (Fig. 1). Microarray analysis has also shown that resveratrol differentially modulates the expression of many genes in multiple cell-signaling pathways.

Resveratrol and Memory Performance — Potential Mechanisms

In a new paper, researchers tested whether resveratrol would enhance memory performance in older adults, and addressed potential mechanisms underlying this effect.11 Twenty-three healthy overweight older individuals who successfully completed 26 weeks of resveratrol intake at 200 mg/day (plus 320 mg quercetin for increased bioavailability) were pairwise matched to 23 participants who received placebo (total n=46, 18 females, 50 – 75 years). Before and after the intervention/control period, the subjects underwent memory tasks and neuroimaging to assess volume, microstructure, and functional connectivity (FC) of the hippocampus, a key region implicated in memory functions. In addition, anthropometry, glucose and lipid metabolism, inflammation, neurotrophic factors, and vascular parameters were assayed. The researchers found that resveratrol caused a significant positive effect on the retention of words over a 30-minute period, compared with placebo, with a high degree of accuracy. In addition, resveratrol led to significant increases in hippocampal FC, decreases in glycated hemoglobin (HbA1c) and body fat, and increases in leptin compared with placebo (see Fig. 2).

Figure 2. Changes in glycated HbA1c and leptin.

A. Note the significant decrease in fasting HbA1c after resveratrol (black bar, n = 21) compared with placebo (gray bar, n = 21).

B. Leptin concentrations significantly increased after resveratrol (black striped bar, n = 23) and decreased after placebo (gray striped bar; n = 23).

C. In the resveratrol group, decreases in HbA1c correlated significantly with increases in FC (n = 21). Triangles show median changes in FC within a significant cluster in the left medial prefrontal cortex (outlined in red) using the left posterior hippocampus as seed in relation to changes in HbA1c. Line indicates regression fit.

Increases in FC between the left posterior hippocampus and the medial prefrontal cortex correlated with increases in retention scores and with decreases in HbA1c. Altogether, this study provides initial but powerful evidence that supplementary resveratrol improves memory performance in association with improved glucose metabolism and increased hippocampal FC in older adults. These findings offer the basis for the increased use of resveratrol to maintain brain health during aging.

Getting on the MAP

In 1999, a paper was published suggesting that resveratrol from wine could have neuroprotective benefits.12 These benefits were attributed to MAP kinases, types of enzymes that are involved in numerous aspects of signal transduction in the cells. Phosphorylation of two particular kinases (ERK1/2) have been related to the synaptic changes at the basis of memory and learning processes.

These findings on resveratrol-induced activation of MAP kinases in human neuronal-like cells, along with previously published epidemiological studies which have demonstrated an inverse relationship between moderate wine intake and dementia, suggest that wine (but not alcohol, per se) may have a positive effect on nerve cells.

Then in 2002, building on prior work showing that free radical generation is associated with cognitive impairment in rats, resveratrol was shown to significantly prevent cognitive impairment through the use of passive avoidance paradigms, elevated plus maze, and the closed field activity test.13 The researchers noted a rise in brain glutathione in resveratrol treated rats.

Resveratrol Prevents Cognitive Deficits

In conclusion, the researchers found that resveratrol could prevent cognitive deficits as well as the oxidative stress caused by streptozotocin, a brain toxic substance, in rats. This, they noted, indicates its potential in the treatment of neurodegenerative diseases such as AD. Defense against streptozotocin was again shown in 2009, when research demonstrated that resveratrol could prevent memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats.14

Resveratrol Clears Amyloid Beta in Alzheimer’s Disease

Resveratrol does not inhibit amyloid beta (Aβ) production, because it has no effect on the Aβ-producing enzymes beta- and gamma-secretases. However, research shows that it instead promotes intracellular degradation of Aβ via a mechanism that involves the proteasome. Proteasomes are located in the nucleus and the cytoplasm of cells. Their main function is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Indeed, the resveratrol-induced decrease of Aβ could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing.15 These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in AD.

Resveratrol for Neuropreservation

AD is a complex and multifactorial neurodegenerative disease. However, it is certain that it involves the cholinergic system. With this in mind, researchers administered colchicine, a microtubule-disrupting agent, thereby causing loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation.16

Colchicine impaired cognitive functions in both the Morris water maze task and the elevated plus-maze task. However, chronic treatment with resveratrol (10 and 20 mg/kg, given orally) for a period of 25 days, beginning 4 days prior to colchicine injection, significantly improved the colchicine-induced cognitive impairment. There was also a significant decrease in acetylcholinesterase activity, i.e., acetylcholine was not broken down, while depleted glutathione was restored. These results indicated that resveratrol has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress.

Protection against Traumatic Brain Injury

Resveratrol also demonstrated neuroprotective results in another study involving rats subject to hippocampal damage and behavioral deficits subjected to bruise injury.17 A single dose of resveratrol given at 100 mg/kg of body weight immediately after induction of traumatic injury significantly ameliorated the trauma-induced neuron loss in hippocampal brain regions of rats. Additionally, treatment with resveratrol decreased anxiety and increased cortex/hippocampus-dependent memory of animals subjected to blunt head trauma.

Amyotrophic Lateral Sclerosis (ALS)

In yet another study, resveratrol promoted neuronal survival in a mouse model of AD and tauopathies (a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain).18 Resveratrol reduced neurodegeneration in the hippocampus, prevented learning impairment, and decreased the acetylation of the known SIRT1 substrates PGC-1alpha and p53, thereby protecting against neurodegeneration. In addition to AD, the researchers thought that resveratrol might be valuable for amyotrophic lateral sclerosis (aka, Lou Gehrig’s Disease).

Among other memory enhancing papers are those showing that resveratrol:

  • Protects mice against spatial learning loss from ethanol consumption19

  • Protects against neuroinflammation and deficits in working memory in aged mice20

  • Increases spatial memory performance, motor mechanisms, working memory in primates (lemurs)21

  • Prevents alcohol-induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in rats22

  • Confers lasting protection against neuronal damage23

  • Protects rats from Aβ-induced neurotoxicity by the reduction of lipid peroxidation24

  • Reduces obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet25

  • Lessens oxidative damage and ameliorates cognitive impairment in the brain of senescence-accelerated mice26

  • Prevents homocysteine-induced vascular and neural defects27

  • Improves learning and memory in normally aged mice by promoting brain-derived neurotrophic factor (BDNF) synthesis28

  • Proffers neuroprotective effects and prevents cognitive impairment after chronic cerebral hypoperfusion (blood shortage)29

  • Inhibits memory impairment in the vascular dementia rat model, by reducing expression levels of Bax (which promotes cell death), cleaved caspase-3 [plays essential roles in apoptosis (programmed cell death), necrosis, and inflammation] and cleaved PARP (inactivation of DNA damage repair). “Coinciding with population aging and improved survival from cardiovascular diseases and stroke, vascular dementia is more frequent and is likely to affect an increasing number of patients in the future.”30

  • Significantly prevents memory loss as measured by the object recognition test in mice31

  • Improves cognition and reduces oxidative stress in rats with vascular dementia32

  • Reverses the decline in different types of memory (working, nonspatial, and locomotor functions) caused by lipopolysaccharide AD induction in mice33

  • Significantly attenuates the deficits in emotional learning and spatial memory seen in chronically stressed rats34

Moving Memory Upwards

There are lots of reasons to take resveratrol, along with the flavonoid quercetin, which is also found in red wine, as a co-compound polyphenol. Quercetin has been found to enhance resveratrol bioavailability.35

As we move further into age-related function decline, and fall less prey to cardiovascular diseases and stroke, vascular dementia is likely to become more of a Maginot-type defense line. Even when thinking about the issues and problems of aging. So that is where we should point our nutritional fortifications and weapons in order to reap more memory benefits.


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  13. Sharma M, Gupta YK. Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats. Life Sci. 2002 Oct 11;71(21):2489 – 98.
  14. Schmatz R, Mazzanti CM, Spanevello R, et al. Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2009 May 21;610(1 – 3):42 – 8.
  15. Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem. 2005 Nov 11;280(45):37377 – 82.
  16. Kumar A, Naidu PS, Seghal N, Padi SS. Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology. 2007;79(1):17 – 26.
  17. Sönmez U, Sönmez A, Erbil G, Tekmen I, Baykara B. Neuroprotective effects of resveratrol against traumatic brain injury in immature rats. Neurosci Lett. 2007 Jun 13;420(2):133 – 7.
  18. Kim D, Nguyen MD, Dobbin MM, et al. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J. 2007 Jul 11;26(13):3169 – 79.
  19. Ranney A, Petro MS. Resveratrol protects spatial learning in middle-aged C57BL/6 mice from effects of ethanol. Behav Pharmacol. 2009 Jul;20(4):330 – 6.
  20. Abraham J, Johnson RW. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation Res. 2009 Dec;12(6):445 – 53.
  21. Dal-Pan A, Pifferi F, Marchal J, Picq JL, Aujard F; RESTRIKAL Consortium. Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. PLoS One. 2011 Jan 31;6(1):e16581. doi: 10.1371/journal.pone.0016581.
  22. Tiwari V, Chopra K. Resveratrol prevents alcohol-induced cognitive deficits and brain damage by blocking inflammatory signaling and cell death cascade in neonatal rat brain. J Neurochem. 2011 May;117(4):678 – 90.
  23. Girbovan C, Morin L, Plamondon H. Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia. Behav Pharmacol. 2012 Feb;23(1):1 – 13.
  24. Huang TC, Lu KT, Wo YY, Wu YJ, Yang YL. Resveratrol protects rats from Aβ-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoS One. 2011;6(12):e29102. doi: 10.1371/journal.pone.0029102. Epub 2011 Dec 29.
  25. Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS. Resveratrol attenuates obesity-associated peripheral and central inflammation and improves memory deficit in mice fed a high-fat diet. Diabetes. 2012 Jun;61(6):1444 – 54.
  26. Liu GS, Zhang ZS, Yang B, He W. Resveratrol attenuates oxidative damage and ameliorates cognitive impairment in the brain of senescence-accelerated mice. Life Sci. 2012 Oct 29;91(17 – 18):872 – 7.
  27. Koz ST, Etem EO, Baydas G, Yuce H, Ozercan HI, Kulog˘lu T, Koz S, Etem A, Demir N. Effects of resveratrol on blood homocysteine level, on homocysteine induced oxidative stress, apoptosis and cognitive dysfunctions in rats. Brain Res. 2012 Nov 12;1484:29 – 38.
  28. Zhao YN, Li WF, Li F, Zhang Z, Dai YD, Xu AL, Qi C, Gao JM, Gao J. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. Biochem Biophys Res Commun. 2013 Jun 14;435(4):597 – 602.
  29. Anastácio JR, Netto CA, Castro CC, Sanches EF, Ferreira DC, Noschang C, Krolow R, Dalmaz C, Pagnussat A. Resveratrol treatment has neuroprotective effects and prevents cognitive impairment after chronic cerebral hypoperfusion. Neurol Res. 2014 Jul;36(7):627 – 33.
  30. Sun ZK, Ma XR, Jia YJ, Liu YR, Zhang JW, Zhang BA. Effects of resveratrol on apoptosis in a rat model of vascular dementia. Exp Ther Med. 2014 Apr;7(4):843 – 848.
  31. Porquet D, Griñán-Ferré C, Ferrer I, Camins A, Sanfeliu C, Del Valle J, Pallàs M. Neuroprotective role of trans-resveratrol in a murine model of familial Alzheimer’s disease. J Alzheimers Dis. 2014;42(4):1209 – 20.
  32. Ma X, Sun Z, Liu Y, Jia Y, Zhang B, Zhang J. Resveratrol improves cognition and reduces oxidative stress in rats with vascular dementia. Neural Regen Res. 2013 Aug 5;8(22):2050 – 9.
  33. El-Sayed NS, Bayan Y. Possible role of resveratrol targeting estradiol and neprilysin pathways in lipopolysaccharide model of Alzheimer disease. Adv Exp Med Biol. 2015;822:107 – 18.
  34. Yazir Y, Utkan T, Gacar N, Aricioglu F. Resveratrol exerts anti-inflammatory and neuroprotective effects to prevent memory deficits in rats exposed to chronic unpredictable mild stress. Physiol Behav. 2015 Jan;138:297 – 304.
  35. De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum. Xenobiotica. 2000 Jun;30(6):609 – 17.

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

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