For a surprising wide range of ages, in men and women …

Resveratrol Improves Brain Power
Specially important in women,
who are more prone to dementia than men.

By Will Block

It was only a decade ago that substantial evidence began to accumulate that resveratrol is good for memory and probably beneficial for Alzheimer’s disease (AD), too. In 2005, an article appeared touting the anti-AD effects of the antioxidant compounds with potential neuroprotective activities found in wine, including resveratrol.1 Citing several epidemiological studies, the researchers went on to indicate that moderate consumption of wine is associated with a lower incidence of AD.

Lowers the Levels of Amyloid-Beta Peptides

Nonetheless, at that time, the exact molecular mechanisms involved in the beneficial effects of wine intake on the neurodegenerative process in AD brain remained to be more clearly defined. Resveratrol (trans-3,4’,5-trihydroxystilbene), a naturally occurring polyphenol mainly found naturally in the skin of red grapes and red wine—as well as in blueberries, peanuts, and the Japanese knotweed—evidently lowers the levels of secreted and intracellular ­amyloid-beta peptides produced from different cell lines. Amyloid beta is comprised of peptides that are crucially involved in AD as the principal component of the amyloid plaques found in the brains of those with AD.


These findings demonstrate a
proteasome-dependent
anti-amyloidogenic activity of
resveratrol and suggest that this
natural compound has a
therapeutic potential in AD.


Intracellular Degradation of Amyloid-Beta

Yet, while resveratrol does not inhibit amyloid-beta production—because it has no effect on the amyloid-beta-producing enzymes beta- and gamma-secretases—it promotes intracellular degradation of amyloid-beta via a mechanism that involves the proteasome. A proteasome is a protein complex found in the nucleus and the cytoplasm of our cells. Its main function is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds.

Actually, the resveratrol-induced decrease of amyloid-beta could be prevented by several selective proteasome inhibitors and by siRNA-directed silencing of the proteasome subunit beta type-5.* These findings demonstrate a proteasome-dependent anti-amyloidogenic activity of resveratrol and suggest that this natural compound has a therapeutic potential in AD.


* Proteasome subunit beta type-5 is a protein encoded by a specific gene, PSMB5. One of the 17 essential subunits, Beta5 contributes to the complete assembly of the 20S proteasome complex. In particular, proteasome Beta5 contains “chymotrypsin-like” activity and is capable of cleaving large hydrophobic residues of peptide.


Preventing Neurodegenerative Disorders with Resveratrol

As a SIRT1 activator, resveratrol when given for 52 weeks was found to help subjects with mild-moderate AD (N = 119).1 Although the amount of the dose was high (up to 1 g by mouth twice daily), plant-derived resveratrol improved progressive declines in cerebrospinal fluid (CSF) Aβ40 levels and activities of daily living (ADL) scores.

For this retrospective study, the researchers examined banked CSF and plasma samples from a subset of AD subjects with CSF Aβ42 < 600 ng/ml at baseline (19 of which were resveratrol-treated and another 19 who were placebo-treated). The researchers used multiplex Xmap technology to measure markers of neurodegenerative disease and metalloproteinases (MMPs).


Resveratrol treatment lessened
declines in mini-mental status
examination (MMSE) scores,
change in ADL (ADCS-ADL) scores,
and CSF Aβ42 levels during
the 52-week trial.


Compared to the placebo-treated group, at 52 weeks, resveratrol markedly reduced CSF MMP and increased macrophage-derived chemokine (MDC), interleukin (IL)-4, and fibroblast growth factor (FGF)-2.

Compared to baseline, resveratrol increased plasma MMP10 and decreased IL-12P40, IL12P70, and RANTES. In this subset analysis, resveratrol treatment lessened declines in mini-mental status examination (MMSE) scores, change in ADL (ADCS-ADL) scores, and CSF Aβ42 levels during the 52-week trial.


Resveratrol decreases CSF MMP,
modulates neuro-inflammation, and
induces adaptive immunity.


Collectively, these data suggest that resveratrol decreases CSF MMP, modulates neuro-inflammation, and induces adaptive immunity. SIRT1 activation may be a practical target for treatment or prevention of neurodegenerative disorders.

Reference

  1. Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer's disease. J Neuroinflammation. 2017 Jan 3;14(1):1.


Resveratrol led to significant
increases in hippocampal FC,
decreases in glycated hemoglobin
(HbA1c) and body fat, and increases
in leptin compared with placebo.


Success with Resveratrol Taken for 26 Weeks

A double-blind placebo-controlled 2014 study noted that while resveratrol increases memory performance in primates, interventional studies in older humans were lacking.2 Twenty-three healthy overweight individuals 50–75 years old were treated with resveratrol 200 mg/day, and were age-matched against 23 controls, who received an identical-appearing placebo, for 26 weeks.

Before and after the intervention period, 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 evaluated.


Dementia is predicted to be the top
health crisis of this century.


Retention of Words and Reduction of Body Fat

The researchers observed a significant effect of resveratrol on retention of words over 30 minutes compared with placebo. 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. Increases in FC between the left posterior hippocampus and the medial prefrontal cortex correlated with increases in retention scores and with decreases in HbA1c.

Resveratrol Improves Memory Performance

This study provided initial 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 novel strategies to maintain brain health during aging.


Resveratrol supplementation was
associated with 17% increases in
cerebrovascular responsiveness to
cognitive stimuli.


Memory Improvements in Women Up to 85 Years of Age

A new report published in the January 3, 2017 issue of the journal Nutrients has found a connection between resveratrol and improvements in cerebrovascular responsiveness and cognitive performance among postmenopausal women between 45 and 85 years of age.3

Dementia disproportionately affects older women (47% by the age of 85 years, compared with 31% in men).

Dementia not only destroys cognitive capabilities but also deprives individuals of their independence and places emotional and financial burdens on families, caregivers and society. Shockingly, dementia is predicted to be the top health crisis of this century, outpacing heart disease and cancer in terms of years lost due to disability, and there is currently no cure nor means of slowing its progression.

Substantial Gap Between First Notice and Advent of Care

Additionally, there tends to be a substantial gap between the noticeable symptoms of cognitive decline and when medical advice is sought, and a further delay before dementia is diagnosed. In Australia, it takes an average of three years from presentation of first symptoms to diagnosis. Consequently, the quality of life in the later years is apt to be sub-optimal due to impaired cognition.

Cognitive impairment may also contribute to decline in physical functioning, such as activities of daily living, and is associated with increased risk of falls in the elderly. Early intervention to maintain high-level cognitive function and well-being may help prolong independent living in older adults. Consequently, it is important to identify feasible lifestyle strategies to counteract cognitive decline in aging women.


Consequently, it is important to
identify feasible lifestyle strategies to
counteract cognitive decline in
aging women.


Just 150 MG of Resveratrol per Day

Researchers at the University of Newcastle in New South Wales, Australia, randomized 80 postmenopausal women to receive a placebo or 75 milligrams resveratrol twice daily (150 mg per day) for 14 weeks. Tests to evaluate cognition, followed by questionnaires to assess mood and depressive symptoms, were administered at the beginning and end of the study. Transcranial Doppler ultrasound assessment of the middle cerebral arteries measured cerebrovascular response (indicated by changes in blood flow velocity to cognitive stimuli and high levels of carbon dioxide, which is a regulator of cerebral blood flow).


Mood also tended to improve and
anxiety was significantly reduced in
women who received resveratrol.


17% Increase in Cognitive Response and Enhanced Mood

Resveratrol supplementation was associated with 17% increases in cerebrovascular responsiveness to cognitive stimuli and elevated carbon dioxide levels (hypercapnia) in comparison with the placebo. Overall cognitive performance, as well as semantic and verbal memory improved to a significantly greater extent among those who received resveratrol compared to the placebo group. Differences in cerebrovascular responsiveness to the cognitive tests were correlated with differences in overall cognitive performance. Mood also tended to improve and anxiety was significantly reduced in women who received resveratrol.


“We hypothesize that resveratrol
elicits its benefits on cognition and
also mood through its ability to
modulate cerebral perfusion during
times of demand.”


While women enjoy longer life expectancy, longer life may not be the only reason for the higher risk of dementia in elderly women. Growing evidence has shown that loss of estrogen after menopause may lead to accelerated deficits in brain function, which may lead to higher risk of dementia.

In the Australian study, the risk of cognitive decline and dementia, was thought to be at least partly due to loss of beneficial effects of estrogen on the cerebrovasculature. The researcher’s hypothesis was that resveratrol, a ­phyto­estrogen, might counteract this risk by enhancing cerebro­vascular function and improving regional blood flow in response to cognitive demands. The results of the study appear to bear this out.


“Findings of these studies are an
important step forward in
preventative strategies to delay
accelerated cognitive decline in our
aging population.”


First Study to Demonstrate Benefits

“This is the first study to demonstrate benefits of chronic resveratrol supplementation on cognitive performance and cerebrovascular responsiveness to hypercapnia and cognitive stimuli,” authors Hamish M. Evans and colleagues announced. “We hypothesize that resveratrol elicits its benefits on cognition and also mood through its ability to modulate cerebral perfusion during times of demand.”

“While the exact mechanisms are still to be confirmed, we have demonstrated that daily resveratrol supplementation for 14 weeks was not only tolerable, but was able to enhance measures of mood and cognitive performance and the latter may be at least partially mediated through improvements in the responsiveness of cerebral vessels to dilate during cognitive demands,” they conclude. “Findings of these studies are an important step forward in preventative strategies to delay accelerated cognitive decline in our aging population.”

References

  1. 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.
  2. 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.
  3. Evans HM, Howe PR, Wong RH. Effects of Resveratrol on Cognitive Performance, Mood and Cerebrovascular Function in Post-Menopausal Women; A 14-Week Randomised Placebo-Controlled Intervention Trial. Nutrients. 2017 Jan 3;9(1).


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

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