The Secrets of High-Dose Polyphenols

Polyphenols

• Provide plants with color

• Little known before 1995

• 8,000 known polyphenols

Classes of Polyphenols

• Flavanoids (green tea)

• Isoflavones (genistein)

• Phenolic acids (curcumin)

• Stilbenoids (resveratrol)

• Tryosol esters (olive oil)

• Proanthocyanins (chocolate)

• Anthocyanins (blueberries)

Maqui

(Aristotelia chilensis)

Delphinidin

Low bioavailability

Good bioavailability

Polyphenols

Gut Health

• Microbial “gardeners”

– How plants fight off microbial invaders

• Prebiotics

– Stimulate friendly bacterial growth

Other Mechanisms of Action

• Anti-oxidants

– Activation of Nrf2

• Anti-inflammatory

– Inhibition of NF-κB

• Aging-aging

– Activation of AMP kinase

Major Pathways Activated By Polyphenols

Polyphenols Are Super-Antioxidants

• Gene transcription factor for expression of SOD and GPX

• Activation by polyphenols

Scapagnini et al Mol Neurobiol 44:192 (2011)

heme oxygenase 1

ferritin

thioredoxin

GSH transferases

UDP-glucoronosyltransferases

NAD(P)H:quinone oxidoreductase 1

-glutamylcysteine synthetase

GSH-reductase

catalase

biliverdin/bilirubin

CO

Fe

GSH synthesis

regeneration of ubiquinol and tocopherol

regeneration of GSH and dehydroascorbate

multifunctional roles

regeneration of oxidized thioredoxinand dehydroascorbate

AN

TIO

XID

AN

T A

ND

CY

TOP

RO

TEC

TIV

E A

CTI

ON

Phase 2 Response Phase 2 ResponseNrf2/keap1/ARE CytoprotectionPhase 2 Response

AN

TIO

XID

AN

T R

ESP

ON

SIV

E EL

EMEN

T (A

RE)

O

OR2

HO

OH

OH

R1

HO

Keap1

Nrf2

antioxidant

Anti-inflammatory Actions

• Activation of PPAR-γ

• PPAR-γ inhibits NF-κB

Anti-Aging Actions

• Activation of AMP-kinase

www.zonediet.com

AMP Kinase: The Enzyme of Life

AMP Kinase

Calorie RestrictionPolyphenols

SIRT1

Actions of AMP kinase

How Many Polyphenols Do You Need?

Reduce oxidation 0.5 g/day

Reduce cellular inflammation 1 g/day

Reduce the rate of aging 1.5 g/day

Potential Sources of Polyphenols

• Vegetables: 0.1% of weight

• Fruits: 0.2% of weight

• Spices : 1% of weight

• Cocoa: 3% of weight

• Refined polyphenol extracts: Up to 40% of weight

www.zonediet.com

Typical Sources Providing 1 gram of Polyphenols

• 1 kg of vegetables

• 500 g of berries

• 500 ml of extra virgin olive oil

• 12 glasses of red wine or 120 glasses of white wine or 1200 glasses of vodka

Is There A “Best of the Best” Among Polyphenols?

Polyphenol Purification

• Whole plant

• Juice

• Powder

• Alcoholic extract

• Chromatographic extract

Maqui Extracty Toxicity Studies

• Acute (rats and rabbits)

– 84 mg/kg I.P for 10 days

– 1g/kg oral for 7 days

• No toxicity

• Sub-chronic (Pigs)

– 1.4 g/kg per day for 42 days

• No histology changes

Domestication Of Wild Maqui Berries is a Dirty

Business

Indiana Jones Without His Bullwhip in Patagonia

Polyphenols Have To Be Absorbed To Increase Longevity

Zamora-Ros et al J Nutr 143: 1445 (2013)

Absorption Depends on Water Solubility

0

20

40

60

80

100

0

20

40

60

80

100

(Nrf

2 D

.U.)

(Nrf

2 D

.U.)

Rev 25µM Maq 25µM

0 1h 3h 6h 12h 0 1h 3h 6h 12h

Maq 25 µM

Activation of Nrf2

**

0.00

TN

F-α

(pg/m

l)

50.00

100.00

150.00

**

*

*

IL-6

(pg/m

l)

**

0.00

50.00

100.00

150.00

200.00

250.00

**

IL-1β

(pg/m

l)

**

0.00

25.00

50.00

75.00

100.00

125.00

LPS

LPS + Res

LPS + Maq

LPS + Rev

Control

Effects On Cytokines.

Polyphenol Pharmacokinetics

Thinking Faster with Purified Cocoa Polyphenol Extracts

• 25% increase in cognitive speed in 3 months

– Mastroiacovo D et al. AJCN 101: 538 (2015)

• Increased activity in hippocampus and improved cognitiion in 3 months

– Brickman et al. Nature Neurosci 17: 1798 (2014)

Refined Is Sometimes Better Than Natural With Cocoa

Cadmium Contamination

• Single serving violates CA Prop 65 for cadmium intake per day

• New EFSA standards for cocoa and chocolate products in 2019

CocoaRx: Coming Soon

• 50 times lower cadmium levels than natural cocoa powder

• 4 times higher polyphenol levels than natural cocoa powder

• Bars, shakes, and desserts as ideal delivery systems for cocoa polyphenol extracts