The Science of
Mark Lange, Ph. D.
Director of Quality Control
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
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 -
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
Sources of Resveratrol
Resveratrol is found in
Grapes (only in skin)
Benefits of Resveratrol
Induces apoptosis Promotes cardiovascular
(programmed cell death) in health
unhealthy cells Normal platelet activity
Promotes normal nuclear Antioxidant protection of LDL
factor kappa B and particles
Possibly Fights Obesity and
Promotes normal activity of Diabetes
the SIRT-1 gene (involved in
calorie restriction, fat
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 inflammation.
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
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):2783-2840.
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):893-903.
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
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
Increased frequency of apoptosis in two tumor cell
lines induced by polyphenolic extracts
Caco-2 control 80
Cells death rate (%)
Cells death rate (%)
0 extract 0
0,1 1 3 10
µg/ml 0,1 1 3 10
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
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 inflammation.
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
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
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.
A study of mechanisms involved in
vasodilation by Resveratrol
Arterial Relaxation (%)
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.
Antioxidant protection of LDL particles
Resveratrol was shown to protect LDL by scavenging free radicals and
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,
Resveravine protects LDL from oxidation better
than synthetic resveratrol, catechin
and vitamin E
Caloric restriction is reducing caloric intake
Proven method for extending life span (30-
50%) and postponing age-related functional
decline and age-related disease.
Resveratrol Research in Extending
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 itself.
Studies Backing Resveratrol’s
Activation of Sirtuins
Tests on Nothobranchius 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
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
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
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.
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
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 (%)
0 5 10
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
Human fat cells exposed to resveratrol or not
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
Safety of Resveratrol
Data in humans have revealed that resveratrol is safe to ingest.
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:
• antioxidant effects
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
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
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
Excellent antioxidant capabilities
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,
ORAC of Selected Foods
2007 U.S. Department of Agriculture
Benefits of Blueberries
Blueberries have been shown to be beneficial in several
Provides 30 anthocyanins and pterostilbene
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
Nat Rev Cancer. 2003 Oct;3(10):721-32
HIF Helps Cells Survive, But Free
Radicals Must Be Present
Hypoxia HIF OXYGEN
"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
But HIF Can’t Help the Cancer Cells Survive When
Antioxidants Have Neutralized All The Free Radicals.
And the Cancer Cells Die….
Grape Extract Resveratrol
Conclusions about Berry Extracts and
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 cells.
Research is ongoing. More to come….