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									The Science of Resveratrol

         Mark Lange, Ph. D.
           Market America
      Director of Quality Control
             Important Statement
 This presentation is on the latest research in the areas of
  longevity, cancer, and heart disease.

 Claims are not being made to treat disease or health
  conditions with dietary supplements.

 This research is in its infancy; please refrain from drawing
  conclusions based on preliminary data.
    Berry and Fruit Extracts to be Discussed
 Resveravine® – whole grape extract containing resveratrol

 BioVin® Advanced – grape skin extract containing OPCs,
  anthocyanins, and resveratrol

 Vita Blue® – wild blueberry extract containing
 A natural extract from grape combining the
 synergistic biological effects of trans-resveratrol
 and -viniferin

 A standardized extract with 20% total trans-
 resveratrol and  -viniferin

 The most concentrated source of Resveratrol
               Resveratrol is naturally produced by
               plants as a defense system against
               infection and oxidative stress due to
               external attacks.

   UV       level

           Sources of Resveratrol
 Resveratrol is found in
   Grapes (only in skin)
   Wine
   Grape Juice
   Peanuts
   Blueberries
   Bilberries
   Cranberries
            Benefits of Resveratrol
 Induces apoptosis              Promotes cardiovascular
  (programmed cell death) in      health
  unhealthy cells                  Normal platelet activity
                                   Normal vasorelaxation
 Promotes normal nuclear          Antioxidant protection of
  factor kappa B and                LDL particles
  cyclooxygenase-2 activity
                                 Possibly Fights Obesity and
 Promotes normal activity        Diabetes
  of the SIRT gene (involved
  in calorie restriction, fat
  mobilization, mitochondrial
  function, longevity)

 Apoptosis is programmed cell death. The lifespan of cells
  have genetic limitations. The apoptotic process safely
  disposes of old cells and cell fragments and does not trigger
 Microscope View of Apoptosis
A. Unfertilized embryonic cell receives a biochemical signal to die.
B. Cell starts to shrink as activated enzymes cut up the cytoskeleton and
  DNA in the nucleus.
C. Cell prepares itself to be engulfed by macrophages.
D. Cell fragments into blobs.
         Apoptosis is a Normal Process

 Rapid turnover of white blood cells in the body
 Remodeling of the developing fetus (fingers and toes)
 Formation of connections (synapses) between neurons in
  the brain
 Menstruation – sloughing of the uterine lining
         Apoptosis in Cancer Cells
 Unlike normal cells, cancer cells proliferate rapidly and
  lose the ability to respond to cell death signals and
  apoptosis. Resveratrol has been found to inhibit
  proliferation and induce apoptosis in a number of
  cancer cell lines.

 Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S,
  Takada Y. Role of resveratrol in prevention and therapy of cancer:
  preclinical and clinical studies. Anticancer Res. 2004;24(5A):2783-
         Importance of Apoptosis

 Defective cell cycle regulation may result in
  the propagation of mutations that contribute
  to the development of cancer. Resveratrol has
  been found to induce cell cycle arrest when
  added to cancer cells grown in culture.

 Joe AK, Liu H, Suzui M, Vural ME, Xiao D, Weinstein IB.
  Resveratrol induces growth inhibition, S-phase arrest,
  apoptosis, and changes in biomarker expression in several
  human cancer cell lines. Clin Cancer Res. 2002;8(3):893-
               Resveratrol Research

 Resveratrol caused significant cytotoxicity and increased
  apoptosis in malignant hemorrhagic tumors.

 Resveratrol blocks the multi-step process of carcinogenesis
  at various stages: suppressing tumor initiation, promotion
  and progression.

 Resveratrol shown to delay development and reduce the
  metastasizing capacity of spontaneous mammary tumors
  in mice due to apoptosis.
          NIH Resveratrol Study

 National Institutes of Health is currently
 sponsoring a Phase I Study of Resveratrol in
 Patients With Surgically Removable
 Colorectal Cancer
          Increased frequency of apoptosis in two tumor cell
          lines induced by polyphenolic extracts

                                  Caco-2                    control                              80
Cells death rate (%)

                       50                                                                        60

                                                                          Cells death rate (%)
                       40                                                                        50
                       30                                   resveravine
                       10                                   Poligonum
                                                            cuspidatum                           10
                       0                                    extract                               0
                            0,1   1            3     10
                                      µg/ml                                                           0,1   1            3   10

                                              (Japanese knotweed)
          Nuclear factor-kappa B

 is a protein involved in cellular responses to stress
  (free radicals, UV light, and bacterial or viral
 NF-κB plays a key role in regulating the immune
  response to infection.
 Incorrect regulation of NF-κB has been linked to
  cancer, inflammatory and viral infection.
                 Resveratrol and NF-kB
 Resveratrol was shown to be a potent inhibitor of NF-kB by blocking IkB
  kinase activity
   Cancer Research. 60:3477-3483, 2000.

 This study examined the anti-inflammatory effects of resveratrol on human
  airway epithelial cells, resveratrol inhibited NF-kB
   Am J Physiol Lung Cell Mol Physiol, 2004 .

 Resveratrol has been shown to promote normal NF-kB activity in several
    Cancer Research. 60:3477-3483, 2000.
    Polish Journal of Pharmacology. 53(6):557-69, 2001.
    Resveratrol Inflammation Research
 Cyclooxygenase (COX) – Blocking this enzyme impedes the production
  of the chemical messengers (prostaglandins) that cause pain and swelling from

 Suppression of COX-2 expression by blocking the activation of MAPKs
  and AP-1 may represent possible molecular mechanisms responsible for
  previously reported anti-tumor promoting effects of resveratrol on
  mouse skin carcinogenesis.
   Biofactors. 21(1-4):33-39, 2004.

 Study concluded in addition to other effects on gene expression,
  resveratrol also directly inhibited the activity of COX-2.
   J Biol Chem. 273(34):21875-21882, 1998.
Non-Steroidal Anti-Inflammatory Drugs

 Commonly prescribed for rheumatoid arthritis
 and osteoarthritis.

 Sept. 30, 2004: Vioxx recalled due to sudden
 heart attacks, strokes, and blood clots.
  Resveratrol for Cardiovascular Support
 Healthy Platelet Activity

   Study reported a dose-dependent inhibition of platelet aggregation
    (blood clotting) by resveratrol.
      Clin Chim Acta. 235:207-219, 1995.

   Rodent study demonstrated that resveratrol protects the heart and
    improves heart functions after diminished blood flow, affecting
    developed pressure and arterial flow.
      Journal of Cardiovascular Pharmacology. 35(2):263-268, 2000.

   Shown to inhibit platelet aggregation both in vitro and in vivo
      International Journal of Molecular Medicine. 9:77-9, 2002.
 Resveratrol Inhibits Platelet Aggregation

 Platelet aggregation is one of the first steps in the
  formation of a blood clot that can occlude a coronary or
  cerebral artery, resulting in myocardial infarction or
  stroke. Resveratrol has been found to inhibit platelet
  aggregation in vitro.
 Blood Cells Mol Dis. 2000;26(2):144-150.
 Clin Chim Acta. 1995;235(2):207-219.
     Resveratrol stimulates eNOS
 eNOS is an enzyme that catalyzes the formation of
  nitric oxide (NO) by vascular endothelial cells.
  NO is needed to maintain arterial relaxation
  (vasodilation), and impaired NO-dependent
  vasodilation is associated with increased risk of
  cardiovascular disease. Resveratrol has been
  found to stimulate eNOS activity in cultured
  endothelial cells.

 Circulation. 2002;106(13):1652-1658.
                        A study of mechanisms involved in
                        vasodilation by Resveratrol
       Arterial Relaxation (%)


                        60                                                                          Endothelium
                        40                                                      E-NOS
                                      20                                       (L-NNA)
                                 0             1           5           10                50                 100
                                           1           5   5             50        100
                                                   Red Wine Extract Concentration (μM)

Li etal. A Study of Mechanisms Involved in Vasodilation Induced by Resveratrol in Isolated Porcine Coronary Artery. Physiol. Res. 55:365-72, 2006.
Cardiovascular Support
 Antioxidant protection of LDL particles

   Resveratrol was shown to protect LDL by scavenging free radicals and
    chelating copper
     Fremont L et al. Antioxidant activity of resveratrol and alcohol-free wine polyphenols
      related to LDL oxidation and polyunsaturated fatty acids. 64(26):2511-21, 1999.
     Belguendouz, L., et al. Resveratrol inhibits metal ion-dependent and independent
      peroxidation of porcine low-density lipoproteins. Biochem Pharmacol. 53(9):1347-
      1355, 1997.

                                                                Lipoprotein Particle
 Resveravine protects LDL from oxidation better than
synthetic resveratrol, catechin
and vitamin E

      Tlag (min)
                                           vitamin E


         100                               resveratrol

           0                               resveravine
               Caloric Restriction
 Caloric restriction is reducing caloric intake without

 Proven method for extending life span (30-50%) and
  postponing age-related functional decline and age-related
      Resveratrol Research in Extending
                  Life Span

 Restricting calorie intake extends the life spans of
  organisms ranging from yeast cells to lab animals.
 Sirtuins enhance cell survival during times of stress,
  especially lack of food.
 Sirtuins are regulators of aging in virtually all living
 Resveratrol activates sirtuin activity without the
  extreme difficulty of starving oneself!
         Sirtuins Help Cells Survive

 Sirtuins help rejuvenate old or dying cells by beefing up their
  DNA repair process and stimulating production of protective

 If a cell is at a point of deciding whether to live or die,
  Sirtuins push toward the survival mode by making the cell fix
   Studies Backing Resveratrol’s Activation
                 of Sirtuins
 Tests onNothobranchius furzeri, a short-lived seasonal fish
   Resveratrol extended the maximum life span by 59% and
    extended the median lifespan by 56%
   Study also showed resveratrol supplementation improved
    swimming performance and delayed motor and cognitive
    age-related decline
     Trends in Pharmacological Sciences 26, 2005.
     Current Biology, 2006.
  Obese mice supplemented with resveratrol lived an average of
    15% longer than obese mice not given resveratrol
     Nature, 2006.
Studies Backing Resveratrol’s Activation
              of Sirtuins
   Saccharomyces cerevisiae (yeast), resveratrol mimics calorie
    restriction by stimulating Sir2, increasing DNA stability and
    extending lifespan by 70%.
     Howitz, K. T., et al. Small molecule activators of
      sirtuins extend Saccharomyces cerevisiae lifespan.
      Nature. 2003.
   Drosophila melanogaster, resveratrol identified as being
    beneficial and shown to extend lifespan under normal
    laboratory conditions
     Bauer, J. H., et al. An accelerated assay for the
      identification of lifespan-extending interventions in
      Drosophila melanogaster. Proc Natl Acad Sci U S A.
      101:12980-12985, 2004.
    Resveratrol is a Superior Antioxidant
 Oxidative stress is implicated in numerous disease processes

 A lead resveratrol investigator, Dr. Milos Sovak commented, “There is
  no question that resveratrol is one of the best free-radical scavengers and
  that it has many effects whose ramifications might affect not only
  longevity but also general health.”
       Resveratrol as an Antioxidant
 In vitro studies revealed that red wine
  extract is a potent antioxidant as
  evidenced by its ability to scavenge
  peroxyl radical in vitro.
      Sato M et al. Myocardial protection with red
        wine extract. J Cardiovasc
        Pharmacol.35(2):263-8, 2000.

 Olas et al demonstrated that resveratrol
  inhibits the production of several
  different reactive oxygen species (O2.-,
  H2O2, singlet oxygen and organic radicals
  in pig blood platelets
      Olas B et al. Resveratrol may reduce
        oxidative stress induced by platinum
        compounds in human plasma, blood
        platelets and lymphocytes. Anticancer
        Drugs. 16(6):659-65, 2005.
Protection against oxidative stress
   Peroxidation rate (%)

                           100                                        Resveratrol

                           20                                         cuspidatum
                                 0        5               10
                                     concentration (µg)

              Influence of three related polyphenols on the oxidative stress of
                    lymphocytes infected by the Epstein-Barr virus (EBV)
   Resveratrol Might Fight Obesity

 June 16th. Google: “Martin Wabitsch endo08 webcast”

 Human fat cells exposed to resveratrol or not exposed

 Number of fat cells in control doubled. Number of fat cells
  exposed to resveratrol decreased by 50%.
   Resveratrol Might Fight Obesity

 In addition, exposure to resveratrol also reduced the
  secretion of substances called interleukin 6 and 8, which may
  be linked to the development of diabetes and clogged
  arteries, both thought to be obesity-related problems.
             Safety of Resveratrol
 Data in humans have revealed that resveratrol is safe to
    Aggarwal B et al. Role of resveratrol in prevention and
     therapy of cancer: preclinical and clinical studies.
     Anticancer Res. 24(5A):2783-840, 2004.

 Human trials on Resveravine®
   Single oral doses of 1, 2.5 and 5 grams were given to 29
    volunteers, and no serious adverse events were reported.
   Possible Herb-Drug Interactions

 Resveratrol has been found to inhibit human platelet
  aggregation in vitro. Theoretically, high intakes of
  resveratrol (e.g., from supplements) could increase the
  risk of bleeding when taken with anticoagulant drugs,
  such as warfarin (Coumadin), and antiplatelet drugs,
  such as clopidogrel (Plavix), dipyridamole (Persantine),
  non-steroidal anti-inflamatory drugs (NSAIDs), aspirin
  and others.
As mentioned, Resveravine also provides  -Viniferin,
which is a dimer of Resveratrol :

                    Naturally synthesized by the plant, it is
                    involved in the defense system against
                    various fungi such as Botrytis cinerea .
                    It is naturally present in the grapes and

                     Like Resveratrol,  -Viniferin has also very
                     interesting biological properties:

                            • anti-inflammatory
                            • antioxidant effects
BioVin® Advanced
 BioVin Advanced is a French red wine extract, offering a
 full 5% of pure resveratrol

 Made exclusively from French red wine grapes, naturally
 high in resveratrol

 Contains red wine polyphenols   and trans-resveratrol
 BioVin® Advanced vs. Wine

                 Amount required to be
                  equivalent to 200 mg
  Amount of
                   BioVin® Advanced
Resveratrol in
200mg BioVin®
                   Red Wine    White Wine

                  10 glasses   40 glasses
     10 mg         (1500 ml)    (6000 ml)
 Benefits of BioVin® Advanced
Due to the synergistic blend of OPCs and resveratrol,
BioVin Advanced offers numerous health advantages
   Cardiovascular health
     Improves blood circulation
     Strengthens blood vessels
     Decreases platelet aggregation
   Cellular health (as described earlier for Resveratrol)
     Induces apoptosis, involvement in SIRT-1 activity, involvement in
      nuclear factor-kappa B and cyclooxygenase-2 activity
   Vision health
   Excellent antioxidant capabilities
   Skin health
 VitaBlue™ Wild Blueberry Extract

 Through a unique proprietary process, VitaBlue™ extract has
  concentrated the phytochemicals of the blueberry into an extract of
  unmatched purity, anthocyanin content and antioxidant potency.

 Only the finest, ripest North American wild blueberries qualify to be
  used in this patented extract.

 12.5% Anthocyanins, 40% Polyphenolics, 6500 ORAC units,
  including pterostilbene.
  ORAC of Selected Foods
 2007 U.S. Department of Agriculture

Cranberry 9584
Blueberry 6552
Plum 6259
Blackberry 5347
Raspberry 4882
Strawberry 3577
Cherry 3365
Apple 3082
Pear 2941
    Benefits of Blueberries

       Blueberries have been shown to be beneficial in several

         Provides 30 anthocyanins and pterostilbene
         Powerful antioxidant
         Inhibits cellular proliferation and induces apoptosis
          (programmed cell death in unhealthy cells)
         Promotes cardiovascular health
         Contains COX-2 inhibitors
         Promotes healthy vision
    Blueberries and Cell Health
 The following review summarizes current knowledge on the various molecular
  evidences of cancer chemoprevention by anthocyanins including 1) antioxidant
  activity 2) the molecular mechanisms involved in anti-carcinogenesis 3) the
  molecular mechanisms involved in the induction of apoptosis in tumor cells.

    Hou D et al. Potential mechanisms of cancer chemoprevention by
     anthocyanins. Curr Mol Med. 3(2):149-159, 2003.

 In this study, blueberry exhibited potential anti-carcinogenic activity as
  evaluated by in vitro screening tests.
    Bomser, J., et al. In vitro anticancer activity of fruit extracts from
     Vaccinium species. Planta Medica. 62(3):212-216, 1996.
  Hypoxia-Inducible Factor (HIF) – Why
Antioxidants May Help to Prevent Cancer

 NORMAL                                 OXYGEN

Hypoxia                                 OXYGEN

Nat Rev Cancer. 2003 Oct;3(10):721-32
HIF Helps Cells Survive, But Free Radicals
            Must Be Present

   Hypoxia                    HIF             OXYGEN

                                         FREE RADICALS
  "HIF-1 helps an oxygen- starved cell convert sugar to energy
  without using oxygen and also initiates the construction of new
  blood vessels to bring in a fresh oxygen supply."
  Cancer Cells Consume All The Oxygen
              Around Them

   Hypoxia               OXYGEN

 But HIF Can’t Help the Cancer Cells Survive When
Antioxidants Have Neutralized All The Free Radicals.


 Hypoxia                          OXYGEN

                                       FREE RADICALS

  And the Cancer Cells Die….

Hypoxia            OXYGEN

Grape Extract                                            Resveratrol

                          Cells               Longevity,
          Skin                                Diabetes?


                 Eyes                   Apoptosis,

   Conclusions about Berry Extracts and
   Cell Health

 The active chemicals in selected berries have shown
  promise in maintaining cardiovascular, immune, and visual
  health, as well as lengthening life span and using fat stores
  more efficiently in experimental animal models.
 The active chemicals are more than potent antioxidants –
  they interact with key enzymes and signaling pathways in
 Research is ongoing. More to come….

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