A compilation of growing evidence supports the conclusion that …

Resveratrol Moderates Alzheimer’s Severity
And helps with daily activities
By Will Block

Arandomized, placebo-controlled, double-blind, multicenter study has discovered that high doses of resveratrol may be beneficial for fighting Alzheimer’s disease (AD).1 Resveratrol is a member of the stilbene family, which acts as an antifungal molecule in a variety of plant species in response to pathogen attack or under stress conditions such as UV radiation and exposure to heavy metal ions. Over the years, resveratrol has been touted as a possible antidote to Alzheimer’s disease, cancer, diabetes and many other conditions.

In the new report, the first study of resveratrol in people with AD, researchers reported that a purified form of resveratrol—what “purified” means wasn’t clarified*—helped stabilize amyloid-beta40 (Aβ40) levels in the blood and cerebrospinal fluid of those who consumed resveratrol, compared to the placebo group, which saw their Aβ40 levels declined. Deposition of Aβ in the brain is a pathological hallmark of AD. There are two major isoforms of Aβ: Aβ42 and Aβ40. A decrease in Aβ40 is seen in the blood and cerebrospinal fluid as dementia worsens and Alzheimer’s disease progresses. Stabilization is good.

* An “investigational new drug” application was required by the U.S. Food and Drug Administration to test the pure synthetic (pharmaceutical-grade) resveratrol in the study. It is not available commercially in this form. See Georgetown University Medical Center. Resveratrol Impacts Alzheimer’s Disease Biomarker. Sept. 11, 2015. Available at http://gumc.georgetown.edu/news/Resveratrol-Impacts-Alzheimers-Disease-Biomarker. Accessed September 16, 2015.

From Blood to Brain

This decline is thought to be a sign that Aβ40 was being taken from their blood and deposited in Alzheimer’s patients’ brains. Those taking resveratrol, however, showed little or no change in Aβ40 levels in their blood.

The study included 119 patients randomly assigned to either high doses of resveratrol (n = 64) or placebo (n = 55). Ranging from age 50 to 90, the mean age for the resveratrol group was 70; the mean age for the placebo group was 73.

A decrease in Aβ40 is seen in
the blood and cerebrospinal fluid as
dementia worsens and Alzheimer’s
disease progresses. Resveratrol
stabilizes blood and cerebral levels.

The resveratrol used in the study was introduced at a dose of 500 mg a day and was increased every 3 months by 500 mg, so that by the end of the 1-year study, subjects were taking 2000 mg a day. The researchers looked at several biomarkers of Alzheimer’s and found that people who took up to 2,000 mg a day during the last quarter year had higher levels of Aβ40 in their spinal fluid than those who took a placebo.

Although accumulation of Aβ40 in the brain is a marker for AD, these same individuals have lower levels of Aβ40 outside of the brain. Thus, the study’s finding suggests that resveratrol could help change the balance from Aβ40 buildup in the brain to circulating protein in the body, where it is less reflective of neurodegeneration.

At the highest dose given in the study (2,000 mg resveratrol per day), you’d have to drink at least 400 bottles of red wine per day to obtain that much resveratrol—but in the study, that amount was represented by four 500 mg capsules per day. Parenthetically, by using a non-natural form of resveratrol, the researchers were granting superior status to extracts or synthetic forms.

The finding suggests that resveratrol
could change the balance from Aβ40
buildup in the brain to circulating
protein in the body, where it is less
reflective of neurodegeneration.

The current study was the largest nationwide clinical trial to study high-dose resveratrol long-term in people with mild to moderate AD.

However, this is not the first time that resveratrol has been connected to AD. In fact, the earliest research goes back to 1998, and includes 200 scientific papers involving AD and resveratrol.

During this time there have been many hypotheses, many of which have been tested again and again.

See the sidebar, “Studies Associating Resveratrol with Alzheimer’s,” below. Read it now or after you’ve finished the main article.

Studies Associating Resveratrol with Alzheimer’s

Dampening Aβ-Induced Inflammation with Resveratrol

In a 1998 cell study, resveratrol was found to protect cells from both the activation of NF-κB/DNA binding activity—nuclear factor kappa-light-chain-enhancer of activated B cells is the master regulator of inflammation and induces senescence2—and apoptotic cell death.3 According to the study’s conclusions, resveratrol may be beneficial as a neuroprotectant stemming from its ability to deal with oxidative stress in the central nervous system by preventing the oxidation of lipoproteins. Once oxidized, lipoproteins can activate NF-κB binding and apoptosis in brain cells (see Fig. 1). Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aβ-introduced inflammation, cutting it off at the pass is desirable, as a more recent report has shown.4 This successor study showed that oxidized lipoproteins may serve as an oxidative mediator and may activate apoptosis through a nuclear signaling pathway contributing to the pathology in AD.

Resveratrol Helps Prevent Induced-Cognitive Deficits

Then in 2002, a rat study found that resveratrol is effective in preventing induced-cognitive deficits as well as the oxidative stress, and that resveratrol has potential in the treatment of neurodegenerative diseases such as AD.5 The next year, researchers found that resveratrol maintains cell viability and exerts an anti-oxidative action by enhancing the intracellular free-radical scavenger glutathione.6 Since a moderate wine intake correlates with a lower risk for AD, an additional neuroprotective effect has been postulated for resveratrol.

The Forkhead on the Road to Longevity

Then, in 2005, a paper was published finding that forkhead/winged helix box gene, group O (FOXO) protein transcription factors can accelerate aging when suppressed.7 Such suppression can increase generation of reactive oxygen species (ROS), which are pivotal for the onset of various aging diseases, including hypertension, atherosclerosis, type 2 diabetes, cancer and AD. Each of these conditions can shorten lifespan (see Fig 1). However, just like caloric restriction, lifespan can be increased in various species by plant-derived polyphenols, such as resveratrol, via activation of sirtuins in cells. Sirtuins, such as SIRT1 in mammals, utilize FOXO and other pathways to achieve their beneficial effects on health and lifespan.

Degradation of Aβ Via Proteasome Mechanism

Figure 1. The pro-growth survival pathways Insulin/IGF-1 and mTOR are known to stimulate NF-κB. These pathways employ two mechanisms, AKT and mTOR signaling, to activate NF-κB. However, through AKT, Insulin/IGF-1 signaling also interacts with known longevity processes by inhibiting FOXO. As with the other known longevity factors and signaling components, SIRT1 and caloric restriction, FOXO inhibits NF-κB signaling. Also, stress/damage pathways known to promote age-associated changes including genotoxic stress, reactive oxygen species (ROS), and inflammation also activate NF-κB. Secondary to activation of NF-κB by pro-aging pathways, NF-κB then acts to promote aging-related changes by contributing to cellular senescence, apoptotoic signals, and inflammatory responses.
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The same year, researchers reported that resveratrol does not inhibit production, because it has no effect on the -producing enzymes beta- and gamma-secretases.8 Instead, however, resveratrol promotes intracellular degradation of via a mechanism that involves the proteasome. Located in the nucleus and the cytoplasm, the main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds.

In 2006, a paper was published showing that sirtuins upregulated by resveratrol may protect neurons in those with neurodegenerative diseases such as AD.9

Antioxidants May Help Prevent Alzheimer’s

In a progression of papers right up the present, the antioxidant properties of resveratrol have been shown to be beneficial for fighting AD.

Red wine possesses antioxidant activities that favor protection against cardiovascular disease—the so-called. “French paradox”— and possibly, central nervous system disorders such as AD.10

Another study demonstrated the effectiveness of trans resveratrol in preventing induced-cognitive deficits as well as the oxidative stress in rats and it’s potential in the treatment of neurodegenerative diseases such as AD.11

Collectively, the results indicate that
modulation of NF-kappaB activity is
involved in the neuroprotective
action of resveratrol against -
induced toxicity.

Resveratrol is an Anti-Inflammatory

A Chinese study showed that resveratrol possesses the capacity to modulate the function of G protein-coupled chemoattractant receptors, which play important roles in inflammation and immune responses.12

Resveratrol also reduces phosphorylation of extracellular signal-regulated kinase (ERK1/2) along with the activation of NF-κB induced by formylpeptide receptor agonists (see Fig. 2). These results suggest that the inhibition of the function of chemoattractant receptors may contribute to the anti-inflammatory properties of resveratrol. Thus, resveratrol may be promising for diseases in which activation of formylpeptide receptors contributes to the pathogenic processes.

Inhibition of NO Production and iNOS Expression

Figure 2. Molecular Targets of Resveratrol: As a pharmacological agent, resveratrol has wide spectrum of targets. [See Mukherjee S, Dudley JI, Das DK. Dose-dependency of resveratrol in providing health benefits. Dose Response. 2010 Mar 18;8(4):478-500.]
(click on thumbnail for full sized image)

In another study, resveratrol protected cultured rat brain cells from the growth inhibition induced by treatment, which led to increased nitric oxide (NO) synthesis and inducible nitric oxide synthase (iNOS) expression.13 However, cells pretreated with resveratrol showed a dose-dependent inhibition of NO production and iNOS expression following treatment.

Reducing Inflammatory Prostaglandin Release and COX-2 Expression

Resveratrol also reduced -induced prostaglandin E2 (PGE2) release, which was associated with the inhibition of cyclooxygenase (COX)-2 expression (see Fig. 2). Furthermore, treatment induced nuclear translocation of NF-kappaB, which was suppressed by resveratrol pretreatment. Collectively, the results indicate that modulation of NF-kappaB activity is involved in the neuroprotective action of resveratrol against -induced toxicity.

Trans-Resveratrol-loaded lipid-core
nanocapsules increased the
concentration of trans-resveratrol in
the brain tissue.

Wine’s Mechanisms that Act on AD

Studies conducted through 2006 on red wine bioactive compounds suggest that resveratrol modulates multiple mechanisms of AD pathology.14 Emerging literature indicates that mechanisms of aging and AD are intricately linked and that these mechanisms can be modulated both by caloric restriction regimens and caloric restriction mimetics, the prime mediator of which is the SIRT1 protein, the activity of which is directly increased by resveratrol.

Resveratrol Increases Cognitive Ability in Mice

In a Chinese study, resveratrol was found to improve the cognitive ability of AD mice, by contributing to resveratrol’s antioxidation and antiapoptosis mechanisms, along with modulating the enzyme acetylcholinesterase.15

Brief Resveratrol Treatment Protects Against Cerebral Ischemia

A 2008 paper demonstrated that brief resveratrol pretreatment bestowed neuroprotection against cerebral ischemia via SIRT1 activation.16 Inhibition of SIRT1 abolished ischemic preconditioning-induced neuroprotection in the hippocampus. Since resveratrol and ischemic preconditioning-induced neuroprotection require activation of SIRT1, this signaling pathway may provide targeted therapeutic treatment modalities as it relates to stroke and other brain pathologies.

Resveratrol Protects Astrocytes

In a rat study, a significant activation of ERK1/2 by hydrogen peroxide was completely prevented by resveratrol.17 Impairments of astrocyte activities induced by hydrogen peroxide confirmed the importance of these cells as targets for therapeutic strategy in brain disorders involving oxidative stress. This study reinforced the protective role of resveratrol and indicates some possible molecular sites of activity of this compound on glial cells in the acute damage of brain tissue during oxidative stress.

Altogether, studies suggest that
resveratrol is an effective
therapeutic agent in inflammatory
neurodegenerative diseases.

Reduces Plaque Throughout the Brain in Mice

Dietary supplementation with resveratrol reduced plaque pathology in a mice model of AD.18 Resveratrol diminished plaque formation in a region-specific manner. The largest reductions in the percent area occupied by plaques were observed in medial cortex (-48%), striatum (-89%) and hypothalamus (-90%). This study supports the concept that onset of neurodegenerative disease may be delayed or mitigated with dietary chemo-preventive agents—such as resveratrol—that protect against beta-amyloid plaque formation and oxidative stress.

Rat Study Demonstrates Neuroprotective Properties of Resveratrol

In vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases.19 Moreover, recent work in cell cultures and animal models has shed light on the molecular mechanisms potentially involved in the beneficial effects of resveratrol intake against the neurodegenerative process in AD.

Resveratrol Inactivates ERK1/2 Pathway in the Rat Hippocampus

In a tissue study using a rat hippocampal culture, data reveal an anti-inflammatory mechanism of resveratrol involving the inactivation of the ERK1/2 pathway in the hippocampus, which is linked principally to AD-associated cognitive dysfunction.20

The data confirm the potential of
resveratrol in treating AD and also
offer an effective way to improve
the efficiency of resveratrol through
nanodrug delivery systems.

Resveratrol Activates AMPK

In a mouse study, orally administered resveratrol was detected in the brain where it activated AMPK and reduced cerebral levels and deposition in the cortex.21 5’ AMP-activated protein kinase or AMPK or 5’ adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against AD (see Fig. 3).

Activation of SIRT1 and Vitagenes Prevent Oxidative Damage

Excess production of ROS in the brain has been implicated as a common underlying risk factor for the pathogenesis of a number of neurodegenerative disorders, including AD. Recent studies (this review was published in 2010) show that the beneficial effects of resveratrol are not only limited to its antioxidant and anti-inflammatory action, but also include activation of SIRT1 and vitagenes, which can prevent the deleterious effects triggered by oxidative stress.22 Vitagenes are a group of genes involved in preserving homeostasis during stressful conditions.

In fact, SIRT1 activation by resveratrol is gaining importance in the development of innovative treatment strategies for stroke and other neurodegenerative disorders. The goals of this review were deemed to provide a better understanding of the mode of action of resveratrol and its possible use as a potential therapeutic agent to ameliorate stroke damage as well as other age-related neurodegenerative disorders.

Resveratrol Remodels Misfolded Protein into Non-Toxic Aggregated Species

Another study found that resveratrol selectively remodels three so-called conformers (also known as misfolded proteins) into an alternative aggregated species that is non-toxic, high molecular weight, and unstructured.23 Surprisingly, resveratrol does not remodel non-toxic oligomers or accelerate Aβ monomer aggregation despite that both conformers possess random coil secondary structures indistinguishable from soluble oligomers and significantly different from their beta-sheet rich, fibrillar counterparts. The researchers expected that resveratrol and other small molecules with similar conformational specificity will aid in shedding light on the conformational epitopes (the part of an antigen that is recognized by the immune system) responsible for -mediated toxicity.

Hormesis Varies Effects of Resveratrol

Hormetic effects were reported in animal models for the use of resveratrol in AD, in which there are often protective effects at low doses, but adverse effects at higher doses, exacerbating the disease process/incidence.24 This analysis indicates that many effects induced by resveratrol are dependent on dose, and that opposite effects occur at low and high doses, being indicative of a hormetic dose response.

The Benefit of Nano-Encapsulated Resveratrol

Noting that there is great interest to stabilize resveratrol in order to preserve its biological activities and to improve its bioavailability in the brain, researchers loaded resveratrol into lipid-core nanocapsules and analyzed for particle size, polydispersity, and zeta potential.25 The nanocapsule distribution in brain tissue was evaluated by intraperitoneal and gavage routes in healthy rats.

Figure 3. During aging, the autophagic capacity declines and increased ROS production and aggregated proteins activate inflammasomes which provoke a low-grade inflammation in several tissues and in that way inhibit autophagy and accelerate the aging process. There are several activators of autophagy, which can delay the aging process. It is known that mTOR inhibitors and AMPK activators can extend lifespan in certain conditions. [See http://www.impactaging.com/papers/v4/n3/full/100444.html]
(click on thumbnail for full sized image)

Lipid-core nanocapsules showed high entrapment of resveratrol, and displayed a higher resveratrol concentration in the brain, the liver and the kidney after daily administration than that observed for free resveratrol. Because trans-resveratrol is a potent COX-1 inhibitor, gastrointestinal damage was evaluated. Animals that were administered with resveratrol-loaded lipid-core nanocapsules showed significantly less damage when compared to those administered with free resveratrol.

In summary, lipid-core nanocapsules exhibited great trans-resveratrol encapsulation efficiency. Trans-Resveratrol-loaded lipid-core nanocapsules increased the concentration of trans-resveratrol in the brain tissue. Gastrointestinal safety was improved when compared with free trans-resveratrol. Thus, trans-resveratrol-loaded lipid-core nanocapsules may be used as an alternative potential therapeutic for several diseases including AD.

Another Anti-inflammation Route for Resveratrol

Figure 4. Resveratrol in AD pathogenesis. 1) APP is cleaved by β- and γ-secretases and the production of Aβ aggregates together. 2) Resveratrol promotes the intracellular clearance of Aβ without influencing the generation of Aβ, by activating AMPK independently of SIRT1. 3)The phosphorylation of PKC, mainly PKC-δ, is induced by resveratrol and consequently plays a major role in the neuroprotective properties against Aβ-induced toxicity. 4) Resveratrol reduces the generations of Aβ-Fe, Aβ-Cu, and Aβ-Zn and thus reduces their toxicity. 5) ROS is produced by damaged mitochondria during oxidative stress, mainly iNOS and COX-2, and plays an important role in apoptosis. Resveratrol reduces iNOS and COX-2 levels and increases the production ofHO-1 to attenuate oxidative damage. 6) Resveratrol decreases the expression of the ROS-producing enzymeNox4 but increases the expression of ROS-inactivating enzymes, SOD1 and GPx1. 7) Resveratrol influences the Aβ-induced apoptotic signaling pathway, including restoring the decrease of Bcl-XL expression, inhibiting the expression of Bax, blocking the activation of JNK, and suppressing the increase of NF-κB DNA binding. 8) Resveratrol can inhibit PGE2 formation by activated microglial cells. 9) Aβ aggregation is responsible for the activation of astrocytes and microglia, which excrete cytokines, such as IL-1β, IL-6, and TNF-α, which all were transcriptionally controlled by NF-κB. Resveratrol inhibits the increase of STAT1, STAT3, and IκBα phosphorylation.
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Recent evidence in mouse models indicates that microglia are required for the neurodegenerative process of AD. Aβ peptides, the core components of the amyloid plaques, can trigger microglial activation by interacting with several Toll-like receptors including TLR4.26

In the study declaring this, researchers show that resveratrol, a natural polyphenol associated with anti-inflammatory effects and currently in clinical trials for AD, prevented the activation of mouse macrophages and microglial BV-2 cells treated with the TLR4 ligand, lipopolysaccharide (LPS). Further studies in cell culture systems showed that resveratrol acted via a mechanism involving the TLR4/NF-κB/STAT signaling cascade.

Resveratrol Improves Spatial Memory in Rats

In a rat study, researchers found that the injection of Aβ could result in a significant impairment in spatial memory, a marked increase in the cellular level of iNOS and lipid peroxidation, and an apparent decrease in the expression of heme oxygenase-1 (HO-1).27

Resveratrol was able to confer a significant improvement in spatial memory, and protect animals from Aβ-induced neurotoxicity. These neurological protection effects of resveratrol were associated with a reduction in the cellular levels of iNOS and lipid peroxidation and an increase in the production of HO-1.

Resveratrol Activates Autophagy

Resveratrol initiates neuroprotective effects via the activation of autophagy, which protects organelles, cells, and organisms against misfolded protein-disorders, including AD via regulation of mitochondrial homeostasis. A recent paper indicates that treatment with resveratrol appears to protect against neurotoxicity caused by prion protein peptides, and the neuroprotection is induced by resveratrol-mediated autophagy signals.28Autophagy is a normal physiological process in the body that cleans up cellular garbage in the body. It maintains homeostasis or normal functioning by protein degradation and turnover of the destroyed cell organelles for new cell formation.

Besides its documented free radical
scavenging and anti-inflammatory
properties, resveratrol has been
shown to increase the clearance of
Aβ, a key feature of AD.

Resveratrol Is Therapeutic in Neurodegenerative Diseases Caused by Inflammatory Processes

In another recent study,29 resveratrol-LPS-inhibited lipopolysaccharide-induced production of nitric oxide (NO); the cytokines tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), and IL-6; and the chemokine monocyte chemotactic protein-1 (MCP-1), which play critical roles in innate immunity, by astrocytes.

Resveratrol also suppressed astrocyte production of IL-12p40 and IL-23, which are known to alter the phenotype of T cells involved in adaptive immunity.

Finally, resveratrol inhibited astrocyte production of C-reactive protein (CRP), which plays an instigational role in a variety of chronic inflammatory disorders. Collectively, these studies suggest that resveratrol may be an effective therapeutic agent in neurodegenerative diseases initiated or maintained by inflammatory processes.

Resveratrol-Loaded Lipid-Core Nanocapsules Are Neuroprotective

Another research report compared the neuroprotective effects of free resveratrol treatment with those of resveratrol-loaded lipid-core nanocapsule treatment against intracerebroventricular injection of Aβ1-42 in rats.30

The animals were administered either free resveratrol or resveratrol-loaded lipid-core nanocapsules for 14 days. Aβ1-42-infused animals showed a significant impairment on learning memory ability, which was paralleled by a significant decrease in hippocampal synaptophysin levels.

The results clearly show that by using lipid-core nanocapsules, resveratrol was able to rescue the deleterious effects of Aβ1-42 while treatment with resveratrol presented only partial beneficial effects. These findings might be explained by the robust increase of resveratrol concentration in the brain tissue achieved by lipid-core nanocapsules. The data not only confirm the potential of resveratrol in treating AD but also offer an effective way to improve the efficiency of resveratrol through the use of nanodrug delivery systems.

Resveratrol Promotes Brain-Derived Neurotrophic Factors Synthesis

In a mouse study, researchers found that after intraventricular injection of resveratrol for one week in 8-9 month-old mice, the long-term memory formation and the LTP induction from hippocampus CA1 were improved.31

By increasing the NEP level in brain,
Aβ deposition is decreased and its
degradation is increased.

The resveratrol enhancement effects were blocked in SIRT1 mutant mice. Additional experiments suggest that resveratrol effects are likely to be mediated through reduced expressions of miR-134 and miR-124, which may in turn up-regulate CREB levels to subsequently promote brain-derived neurotrophic factors (BDNF) synthesis. These findings demonstrate a role for resveratrol in cognition and a microRNA-CREB-BDNF mechanism by which resveratrol regulates these processes, demonstrating its value as a potential therapeutic target against central nervous system disorders in aging.

Resveratrol Increase Clearance of

Besides its well documented free radical scavenging and anti-inflammatory properties, resveratrol has been shown to increase the clearance of Aβ, a key feature of AD, and to modulate intracellular effectors associated with oxidative stress, neuronal energy homeostasis, kinase, programmed cell death, and longevity.32 This new study summarizes the most recent findings on mechanisms of action involved in the protective effects of this multi-target polyphenol, and discusses its possible roles in the prevention of various age-related neurological disorders (see Fig. 4).

Resveratrol Reverses Memory Decline through Estradiol

Resveratrol, one of the most important plant-derived estrogens, is considered to be useful as estrogen plays an important role in AD.33 In a study investigating the role of resveratrol, after 7 days mice in one of four groups, one given resveratrol were subjected to different behavioral tests using Y-maze, object recognition test, and open field tests.

Estradiol and neprilysin (NEP) (an important Aβ-degrading protease) levels were measured. Results showed resveratrol was able to reverse the decline in different types of memory (working, nonspatial, and locomotor functions) caused by LPS induction in mice. Moreover, resveratrol was able to significantly increase both the estradiol level and NEP level and that may have a great role to decrease Aβ deposition as it has been confirmed that there is a link between NEP and estradiol level. The upregulation of estradiol level leads to an increase in the level of NEP level. By increasing the NEP level in brain, Aβ deposition is decreased and its degradation is increased.

“Somehow, resveratrol is affecting
cerebrospinal amyloid levels. … We
don’t quite fully understand why or
how, but [we] think it may be related
to sirtuins. The biggest risk factor for
developing AD is aging.”

Returning to the Current Resveratrol-Alzheimer’s Study

Said Dr. R. Scott Turner, MD, PhD, lead author of the study and director of the Memory Disorders Program at Georgetown University Medical Center, “Somehow, resveratrol is affecting cerebrospinal amyloid levels,”34

He also stated, “We don’t quite fully understand why or how, but [we] think it may be related to sirtuins.” Sirtuins are proteins that are activated by caloric restriction, as well as by resveratrol. The biggest risk factor for developing AD is aging. Previous animal studies have found that long-term caloric restriction—eating two-thirds one’s normal caloric intake—prevents or delays most age-related diseases, including cancer, diabetes, heart disease, and once again AD.

Able to Penetrate the Blood Brain Barrier

Continuing, “It does appear that resveratrol was able to penetrate the blood brain barrier, which is an important observation.” Also, “Somehow, resveratrol is affecting cerebrospinal amyloid levels,”34

“It does appear that resveratrol
was able to penetrate the
blood brain barrier, which is an
important observation.”

Turner also related that the study found that resveratrol was safe and well tolerated. The most common side effects experienced by participants were gastrointestinal-related, including nausea and diarrhea. Also, patients taking resveratrol experienced weight loss while those on placebo gained weight (see “Fewer Cancers and Weight Loss with Resveratrol”).

One outcome in particular was confounding. The researchers obtained brain MRI scans on participants before and after the study, and found that resveratrol-treated patients lost more brain volume than the placebo-treated group.

“We’re not sure how to interpret this finding. A similar decrease in brain volume was found with some anti-amyloid immunotherapy trials,” Turner added. This may result from resveratrol’s ability to reduce inflammation (or brain swelling) found with AD.

Ongoing Studies

The study, funded by the National Institute on Aging, and conducted with the Alzheimer’s Disease Cooperative Study, began in 2012 and ended in 2014. Georgetown University Medical Center was one of 21 participating medical centers across the U.S. Further studies, including analysis of frozen blood and cerebrospinal fluid taken from patients, are underway to test possible drug mechanisms.

Turner also related that the study
found that resveratrol was safe and
well tolerated.

“Given safety and positive trends toward effectiveness in this phase 2 study, a larger phase 3 study is warranted to test whether resveratrol is effective for individuals with Alzheimer’s—or at risk for Alzheimer’s,” Turner said.

As well, resveratrol and similar compounds are being tested in many age-related disorders including cancer, diabetes, neurodegenerative disorders, and AD. To restate an important point, the study Turner led, however, is the largest, longest and highest dose trial of resveratrol in humans to date, and more are on the way. According to ClinicalTrials.gov there are 102 trials that are recruiting, not yet recruiting, underway, or completed with unknown status. Only some of the completed items have been published.

“[The study] is showing us a new mechanism, or a new pathway, towards Alzheimer’s treatments,” Turner commented.35 “This is targeting amyloid in an indirect way,” he said. Researchers think that resveratrol activates proteins called sirtuins, which are also activated by calorie restriction, and may have anti-aging effects.

Researchers think that
resveratrol activates proteins called
sirtuins, which are also activated by
calorie restriction, and may have
anti-aging effects.

Daily Activities Benefit with Resveratrol

Nonetheless, the new study did not include enough people to definitively determine whether resveratrol had an effect on symptoms of AD. But participants did take five cognitive tests, and most showed that there was no difference in thinking abilities between the group that took resveratrol and the group that took placebo. But one test showed that people who took resveratrol showed less decline in daily activities such as cooking, getting dressed, using a telephone, tasks of everyday life, compared with the placebo group.

The real gold standard for testing
treatment claims that delay aging
diseases is controlled trials with
rodents, usually mice.

Fewer Cancers, and Weight Loss with Resveratrol

Of interest, in addition to the difference in Aβ40 levels, the multicenter researchers also observed that, compared to the placebo group, the resveratrol-treated group had fewer cancers and lost weight.

Average weight loss amounted to about 2 lbs. over the course of the year, whereas patients in the placebo group gain was about 1 lb. Weight loss is not something that is desirable in AD patients because patients tend to lose weight anyway with the disease (the opposite was shown in the study). So if resveratrol ends up being used in patients, they may need to take supplements to prevent weight loss, Turner pronounced.

James Hendrix, director of global science initiatives at the Alzheimer’s Association, said the findings were “encouraging,” because the stabilization of Aβ40 means that patients who took resveratrol may not be declining as quickly.35

According to a Georgetown University Medical Center press release, the main goal of the current study was to find out whether high doses of resveratrol could be safe.36 And that was found to be true.

Anecdotally, patients who took
resveratrol told the researchers that
they felt like they were maintaining
their mental ability.

The Real Gold Standard in Aging Disease Tests

Even for the relatively small number of participants in the study (compared to the “gold standard” for drug studies), the researchers did see indications that resveratrol could improve cognition.

In truth, because aging disease tests (including those for AD) with human subjects require decades, and are impossible to control, the real gold standard for testing treatment claims that delay aging diseases is controlled trials with rodents, usually mice.

Every gold standard treatment is applied to about 50 mice for their life span (2-3 year), and an equal number of controls is housed in identical circumstances. The total cost for a single experiment is usually little more than $200,000, and what is obtained for this is two full mortality curves, with and without treatment.

Finally, to repeat, subjects who took resveratrol in the current study had slight improvements in their ability to carry out daily tasks, such as remembering to brush their teeth. And anecdotally, patients who took resveratrol told the researchers that they felt like they were maintaining their mental ability.


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

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