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Stress Markers and Effects of Minor Bioactive Compounds on Heart Health Risk Factors

R. Keith Randolph PhD, Nutrilite Health Institute

Victor A. Tutelyan, Prof, MD, PhD, Russian Institute of NutritionMoscow November 16-17, 2011

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Objectives

• Overview of selected stress marker outcomes from a recent assessment study conducted in collaboration with the Russian Institute Of Nutrition

• Overview of research focused on the development of a botanical nutraceutical designed to moderate inflammation driven by IL-1 overexpression

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Traditional Heart Health Risk Factors• Elevated LDL cholesterol• Hypertension• Hyperglycemia• Sedentary Lifestyle• Obesity• Family history

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Aging Stress Responses—“Wellness” Markers for Heart Health?

Unmitigated AGING stresses are associated with age-related health decline and heart health risks

Inflammation Metabolic stress Oxidative stress DNA Damage Mitochondrial Dysfuntion

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ION Assessment Study Design

• Study population Patients (40-70 yr old) admitted to the Russian

Institute of Nutrition (Moscow):• 100 individuals with no cardiovascular disease history

(Control group)• 100 individuals with cardiovascular disease history

(CVD group)

• Anthropometric measures, blood chemistries, inflammation & oxidative stress markers

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Group N (M/F) Age (y) BMI (kg/m2) WHR

Control 100 (27/73)

49.7 ± 6.2 27.5 ± 5.0 0.85 ±

0.12

CVD 100 (29/71)

53.8 ± 7.6*

34.2 ± 9.4*

0.96 ± 0.15*

mean ± SD

* p < 0.05 vs Control

Subject General Characteristics Summary

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Oxidative & Inflammatory Stress Markers

Group 8-oxo-dG1

(mM/ml)MDA2

(nmol/ml)hsCRP1

(ng/mL)

Control 0.013(0.008 – 0.015) 1.86 ± 0.82 1311.0

(484 – 3,042)

CVD 0.018(0.016 – 0.019)* 2.12 ± 0.81* 3493.0*

(1,685 – 7,087)

• No difference was found between groups in antioxidant activity determined by SOD and GSHPx blood level.

1median (Q25%-Q75%).

2mean ± SD.

*p < 0.05 vs Control

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Conclusions

• There is clear evidence of metabolic, oxidative and inflammatory stress in overweight Russian adults with and without CVD

• Individuals presenting with CVD exhibit heightened signs of stress

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Time (hours - days)

Infl

am

mati

on

Differences In IL-1 Genotype Are The Basis For Quantitative Variations In The Robustness Of The Inflammatory Response

EnvironmentalChallenges

Hyper-responsiveIL-1 Genotype

Non-hyper-responsiveIL-1 Genotype

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Exaggerated Inflammation (Hyper-responsive IL-1 Genotype) Across Years May Increase Risk To Heart Health

Poor

Health

Good

Health

years

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IL-1 Genotype Are At Increased Risk For A First Heart Attack

1987-89

Age 45-64

Total Cholesterol <200

N= 955Relative risk = 4.03

(1.58-10.24); p= 0.003

non Hyper-Responsive

Hyper-Responsive

11 Years

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Open Innovation & Partnership

>15 years experience w

Clinical Genetic research,

gene testing, counseling

75 years experience w

Nutrition research, Dietary

supplement development, & manufacture

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Research Strategy

(1) Genotype clinical research volunteers (IL-1)

(2) In vitro screening for IL-1 inhibition (gene expression & production)

(3) Clinical evaluation of individual lead botanicals

(4) Development of multi-component botanical formulation

(5) Clinical evaluation of prototype formulas for IL-1 and CRP

Inhibition

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Rose Hips Formulation

MarkerDose

mg/day

Rose Hips Extract

dehydro-ascorbate

1,200

Blackberry Powder

chlorogenic acid 165

Blueberry Powder anthocyanins 330

Grape Vine Extract

all-trans-resveratrol 40

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Clinical Trial DesignBlood draws for IL-1 gene expression,

ex vivo IL-1 production, and CRP

n= 50 IL-1 genotyped

volunteers/arm,

CRP= 2-10 mg/L

0week

Placebo

Rose Hips Formulation

12

4

Intervention

8

16

Rose Hips Formulation Reduced Inflammatory Mediators vs Placebo

CRP

>10% >20% >30%0

10

20

30

40

50

60

Placebo

RH B GV

*

**P=0.02* P=0.03

**

**

% o

f G

eno

1 S

ub

ject

sw

AV

G C

RP

Lo

wer

ing

@

12

Wee

ks

IL-1 Production

0

25

50

75

100

125

PlaceboRH B GV

*

*P<0.0001

IL-1

Pro

du

cti

on

% o

f B

as

eli

ne

IL-1 Gene Expression

0

50

100

150

200

RH B GV Placebo

*

*P<0.0001

IL-1

Ge

ne

Ex

pre

ss

ion

% o

f B

as

eli

ne

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Rose Hips Formulation Preferentially Reduced IL-1 in At-Risk Subjects

CRP

>10% >20% >30%0

25

50

75

100

Genotype 1Genotype 0

#P=0.088*P=0.03#

*

% o

f S

ub

ject

sw

AV

G C

RP

Lo

wer

ing

@ 1

2 W

eeks

IL-1 Production

>20% >50% >70%0

25

50

75

100

Genotype 1Genotype 0

% o

f S

ub

ject

sw

AV

G IL

-1 P

rod

uct

ion

Lo

wer

ing

@ 1

2 W

eeks

*

*P=0.05

IL-1 Gene Expression

>20% >50% >70%0

25

50

75

100

Genotype 1

Genotype 0

*P=0.02#P=0.1*

#

% o

f S

ub

ject

sw

AV

G IL

-1 G

E L

ow

erin

g @

12

Wee

ks

At Risk Genotype

Non Risk Genotype

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IL-1 Nutrigenetic Research Conclusions

• Nutritional interventions that moderate inflammatory stress are feasible.

• Inflammation driven by overexpression of IL-1 can be moderated via nutritional interventions.

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AcknowledgmentsInstitute of Nutrition

V.A. Tutelyan

B.S. Kagonov

V.A. Isakov

G.A. Silvestrova

A.A. Golubeva

Nutrilite Health Institute/Amway

K. Grann

A. Davies

D. Krempin

K. Gellenbeck

H. Roh-Schmidt

D. Pusateri

Y. Lin

Interleukin Genetics

K. Kornman

K. Martha

J. Rogus