Joe: My doctor told me to give up drinking, smoking, and fatty foods.

Sam: What will you do?

Joe: I think I’ll give up my doctor.

I try not to get too excited about memory benefits of supplements, because too often the claims are not substantiated by studies that are well controlled and peer reviewed. I now think resveratrol may be one of the few supplements that benefits brain function.

When I wrote my first blog on research on resveratrol benefits for brain function and memory, there were over 2,000 scientific papers.[1]Don't worry; I am only going to tell you about a few studies.

Resveratrol is an active ingredient in red wine. This compound has been credited for explaining why red-wine drinkers in France, who drink more wine than most people, are healthier than would be predicted by their lifestyle of little exercise and eating lots of cheese. The problem is most studies suggest you would have to drink a 100 or more glasses of red wine a day to get much resveratrol effect (and that effect would obviously be negated by a toxic dose of alcohol). An obviously more healthful choice is the highly concentrated pill forms of resveratrol that are now on the market.

Most of the protective biological actions associated with resveratrol have been associated with its scavenger properties for free radicals and the protective effects that it confers on the heart and diabetes. 

One important study comes from a diabetes research group in Brazil recently who reported a beneficial effect of resveratrol on diabetic rats.[2]Resveratrol (in a modest rat dose of 10 and 20 mg per kilogram per day for 30 days) prevented the impairment of memory induced by diabetes. Resveratrol may be protecting neuron terminals that diabetes can damage. An earlier study by another group showed resveratrol improved glucose metabolism and promoted longevity in diabetic mice.

Another benefit of resveratrol is the anti-oxidant property. The brain produces more free-radical damage than other organs, because it burns so much oxygen. Compared with other organs, the brain has especially low levels of antioxidant defense enzymes. 

One recent study has revealed resveratrol had protective effects against brain damage caused by a chemical that kills acetylcholine neurons. Injection of this toxin into the brain of rats impaired their memory performance in two kinds of maze tasks. The impairment was significantly reduced by repeated injection of resveratrol (10 and 20 mg/kg) per day for 25 days, beginning four days before the toxin injection.[3]

Another recent study examined effects on working memory in mice fed a resveratrol-supplemented diet for four weeks before being injected with a cytokine to induce inflammation and accelerate aging. Resveratrol significantly reduced memory impairment in the aged group, but not in the young adults[4]. The lack of benefit in young adults was a little misleading, in that there was a "ceiling effect" in that the young adults were not impaired by the cytokine injection.

 The practical issue for us is whether resveratrol will help cognitive function in humans, especially healthy humans. It seems likely because other substances that have strong anti-oxidant properties seem to improve memory capability. Because animal studies have shown promise for resveratrol in preventing or treatment several different conditions associated with aging, several human clinical trials have been initiated.[5]

 An impressive new study of older humans, male and female, has just been reported.[6]Twenty-three healthy, but overweight people completed 6 months of daily resveratrol intake (200 mg ― the commercial brand I take has 300 mg/capsule). A paired control group got placebo pills. A double-blind design assured that neither the subjects nor the experimenters knew which individuals were in each group during data processing. Memory tests of word recall revealed significant improvement in the resveratrol group. Resveratrol also increased brain-scan measures of functional connectivity, which identified linked neural activity between the hippocampus and several areas of cerebral cortex.

Because others had shown that resveratrol increased insulin sensitivity in humans, these authors examine several markers important to diabetes. Resveratrol decreased the standing levels of sugar-bound hemoglobin, a standard marker for glucose control.  

What foods besides red grapes have resveratrol? The most likely other sources you would eat or drink are blueberries, cranberries, and peanuts. It is not likely that you could drink or eat enough of such substances to get enough resveratrol to do much good. Because of the scientifically documented benefits of resveratrol, highly concentrated supplements are now on the market (I have been taking it for a couple of years). I haven't given up my two glasses of red wine each day, but I have started taking one of the supplements. I haven't seen any reports that high doses of resveratrol are toxic.

---

[1] http://thankyoubrain.blogspot.com/2010/04/resveratrol-red-wine-magic-chemical.htmlApril 4, 2010.

[2] Schmatz R, et al. (2009). 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. Epub 2009 Mar 19.

[3] Kumar, A. et al. 2007. Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology.79 (1): 17-26. DOI: 10.1159/000097511

[4] Abraham, J., and Johnson, R. W. 2009. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation research. 12 (6): 445-453.  DOI: 10.1089/rej.2009.0888

[5]Smoliga, J. M. et al. (2011). Resveratrol and health – a comprehensive review of human clinical trials.  Mol. Nutrition Food Res. 55: 1129-1141

[6] Witte, A. V., et al. (2014) Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J. Neuroscience. 34 23): 7862-7870.

"Memory Medic's latest book is for seniors (Improve Your Memory for a Healthy Brain. Memory Is the Canary in Your Brain's Coal Mine," available in inexpensive e-book format at https://www.smashwords.com/books/view/496252.  See also his recent book, "Mental Biology. The New Science of How the Brain and Mind Relate" (Prometheus).

Joe: My doctor told me to give up drinking, smoking, and fatty foods.

Sam: What will you do?

Joe: I think I’ll give up my doctor.

I try not to get too excited about memory benefits of supplements, because too often the claims are not substantiated by studies that are well controlled and peer reviewed. I now think resveratrol may be one of the few supplements that benefits brain function.

When I wrote my first blog on research on resveratrol benefits for brain function and memory, there were over 2,000 scientific papers.[1]Don't worry; I am only going to tell you about a few studies.

Resveratrol is an active ingredient in red wine. This compound has been credited for explaining why red-wine drinkers in France, who drink more wine than most people, are healthier than would be predicted by their lifestyle of little exercise and eating lots of cheese. The problem is most studies suggest you would have to drink a 100 or more glasses of red wine a day to get much resveratrol effect (and that effect would obviously be negated by a toxic dose of alcohol). An obviously more healthful choice is the highly concentrated pill forms of resveratrol that are now on the market.

Most of the protective biological actions associated with resveratrol have been associated with its scavenger properties for free radicals and the protective effects that it confers on the heart and diabetes. 

One important study comes from a diabetes research group in Brazil recently who reported a beneficial effect of resveratrol on diabetic rats.[2]Resveratrol (in a modest rat dose of 10 and 20 mg per kilogram per day for 30 days) prevented the impairment of memory induced by diabetes. An earlier study by another group showed resveratrol improved glucose metabolism and promoted longevity in diabetic mice.

Another benefit of resveratrol is the anti-oxidant property. The brain produces more free-radical damage than other organs, and compared with other organs the brain has especially low levels of antioxidant defense enzymes. 

One recent study has revealed resveratrol had protective effects against brain damage caused by a chemical that kills acetylcholine neurons. Injection of this toxin into the brain of rats impaired their memory performance in two kinds of maze tasks. The impairment was significantly reduced by repeated injection of resveratrol (10 and 20 mg/kg) per day for 25 days, beginning four days before the toxin injection.[3]

Another recent study examined effects on working memory in mice fed a resveratrol-supplemented diet for four weeks before being injected with a cytokine to induce inflammation and accelerate aging. Resveratrol significantly reduced memory impairment in the aged group, but not in the young adults[4]. The lack of benefit in young adults was a little misleading, in that there was a "ceiling effect" in that the young adults were not impaired by the cytokine injection.

 The practical issue for us is whether resveratrol will help cognitive function in humans, especially healthy humans. It seems likely because other substances that have strong anti-oxidant properties seem to improve memory capability. Because animal studies have shown promise for resveratrol in preventing or treatment several different conditions associated with aging, several human clinical trials have been initiated.[5]

 An impressive new study of older humans, male and female, has just been reported.[6]Twenty-three healthy, but overweight people completed 6 months of daily resveratrol intake (200 mg ― the commercial brand I take has 300 mg/capsule). A paired control group got placebo pills. A double-blind design assured that neither the subjects nor the experimenters knew which individuals were in each group during data processing.

Memory tests of word recall revealed significant improvement in the resveratrol group. Resveratrol also increased brain-scan measures of functional connectivity, which identified  linked neural activity between the hippocampus and several areas of cerebral cortex.

Because others had shown that resveratrol increased insulin sensitivity in humans, these authors examine several markers important to diabetes. Resveratrol decreased the standing levels of sugar-bound hemoglobin, a standard marker for glucose control.  

What foods besides red grapes have resveratrol? The most likely other sources you would eat or drink are blueberries, cranberries, and peanuts. It is not likely that you could drink or eat enough of such substances to get enough resveratrol to do much good. Because of the scientifically documented benefits of resveratrol, highly concentrated supplements are now on the market (I have been taking it for a couple of years) I haven't given up my two glasses of red wine each day, but I have started taking one of the supplements. I haven't seen any reports that high doses of resveratrol are toxic.

---

[1] http://thankyoubrain.blogspot.com/2010/04/resveratrol-red-wine-magic-chemical.htmlApril 4, 2010.

[2] Schmatz R, et al. (2009). 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. Epub 2009 Mar 19.

[3] Kumar, A. et al. 2007. Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology.79 (1): 17-26. DOI: 10.1159/000097511

[4] Abraham, J., and Johnson, R. W. 2009. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation research. 12 (6): 445-453.  DOI: 10.1089/rej.2009.0888

[5]Smoliga, J. M. et al. (2011). Resveratrol and health – a comprehensive review of human clinical trials. Mol. Nutrition Food Res. 55: 1129-1141

[6] Witte, A. V., et al. (2014) Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J. Neuroscience. 34 23): 7862-7870.

People are constantly exposed to stressful situations. These may be physical (like participating in marathons, being exposed to radiation, and, perhaps surprisingly, exposed to sedatives or anesthetics). But stress can also be mental, wherein we become anxious and worried over certain events, existing or anticipated. Whether physical or mental, stress activates a brain network involving most directly the hypothalamus, the pituitary gland, and the adrenal cortex to release stress hormones. Such hormones include several cortisone-like compounds called glucocorticoids, and the most prominent one in humans is cortisol.

Glucocorticoids have profound effects on both body and brain. Regulation of glucocorticoids is accomplished by the brain, and learning experiences have profound effects on this control system. Most of what was initially known about glucocorticoids was their effect on the body. I had the great thrill of visiting the pioneer in this field, Hans Selye, in his laboratory complex at the University of Montreal. He had a whole room full of medals, awards, and honorary doctorate diplomas. He won practically every research accolade there was, except the Nobel Prize, one of several grievous slights by the Nobel committee. Dr. Selye wrote an autobiography for my book, Discovery Processes in Modern Biology.

Effects on the Body

Selye’s research led him to formulate the widely accepted concept of the glucocorticoid system as accounting for a “General Adaptation Syndrome,” which basically explained how the brain and body respond to stress. He discovered that glucocorticoids are “Goldilocks” compounds. That is, a little doesn’t do much, a lot is damaging, and intermediate levels are “just right.”

A moderate amount of cortisol is what is normally released every morning before you awaken. By the way, this is the reason surgeons want to operate early in the morning. This release helps prepare the body for the day’s activities by mobilizing blood glucose, typically by breaking down fat and, if needed, protein stores. Glucose is especially important for the brain, which has huge demands for energy, and which can only burn glucose for energy. Neurons are energized and memory ability is enhanced. Another useful thing cortisol does is to reduce the release of cellular chemicals that cause inflammation.

However, the hormone also inhibits systems that channel resources for growth and reproduction, impairs bone formation, and inhibits the immune system. Basically, the idea is that glucocorticoids help brain and body to respond to temporary emergencies by assigning lower priority to other physiological needs.

The rub comes when stress is prolonged. Selye discovered that the beneficial adaptation to temporary stress cannot be sustained in chronic stress. The system becomes exhausted and control breaks down.[1]Under chronic stress, body muscle mass decreases because the system has been breaking down proteins in order to generate energy. Inflammation bathes cells in toxic chemicals. Infections increase because the immune system has been compromised. In obese people, glucocorticoid levels cumulatively increase in fat cells, increase fat deposits still further, and increase the likelihood of type 2 diabetes and cardiovascular disease.[2]

Effects on the Brain

In the case of brain, persistent high levels of glucocorticoid often causes depression. Memory ability is impaired. Brain degeneration and cognitive decline accelerate. Many neurons are actually killed. What I want to stress here is that chronic high levels of cortisone change the neural circuitry that regulates its release. In other words, the brain learns a new way of functioning if constantly bathed in high levels of cortisone.

Effects of Learning

Few people make the connection between glucocorticoid control and learning. The neuronal circuits that control hormone secretion learn from stressful experience, just as all neurons learn from whatever they experience. What neurons in the cortisol control circuit learn in chronic stress is that the usual controls can’t work any more.

A typical response to a repeated stress of a certain type (for example, constant quarrels with a spouse or repeated job failures) can be habituation. It’s like “tuning out.” Repeated exposure to the same stress teaches the neurons to stop responding as much as usual. Thus, there is less of the benefits that glucocorticoids provide.

At the same time, the hormone control system becomes hypersensitive to other stresses, especially unpredictable or especially severe stresses. The control system learns to over-react to everything other than the stress to which it has habituated. Now, the damaging effect of too much glucocorticoid becomes pervasive, both for body and brain.

Whether the brain learns stress-coping strategies depends on conscious over-ride of hyper-active responses to stress, because the neural system (the limbic system) that operates our emotions also regulates the glucocorticoid control system. We can not only reduce excessive glucocorticoid but also teach our brain better ways to deal with stress by doing the following:

·         Simplify and organize our life,

·         Do one thing at a time and finish it,

·         Find pleasure in the little things,

·         Learn to have a more positive attitude,

·         Laugh and be happy,

·         Suppress anxiety,

·         Be more rational and less emotional,

·         Develop supportive social relations,

·         Reduce exposure to stressors. 

For more on learning and memory in general, see Dr. Klemm’s new book, Memory Power 101, Skyhorsepublishing.com.

Photos courtesy of FreeDigitalPhotos.net, by Artur  84 and Ambro

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[1] Herman, James P. 2013. Neural control of chronic stress adaptation. Frontiers in Behavioral Neuroscience. August 8. Doi: 10.3389/fnbeh.2013.00061

[2] Vogelzangs N. et al. 2009. Late-life depression, cortisol, and the metabolic syndrome. Am J Geriatr Psychiatry. 2009 Aug;17(8):716-21. doi: 10.1097/JGP.0b013e3181aad5d7.