1. 1 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 Nutrition Moscow November 16-17, 2011

2. 2 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

3. 3 Traditional Heart Health Risk Factors Elevated LDL cholesterol Hypertension Hyperglycemia Sedentary Lifestyle Obesity Family history

4. 4 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

5. 5 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

6. 6 GroupN (M/F)Age (y) 2 BMI (kg/m 2 )WHR Control100 (27/73)49.7 ± 6.227.5 ± 5.00.85 ± 0.12 CVD100 (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

7. 7 Oxidative & Inflammatory Stress Markers Group 8-oxo-dG 1 (  M/ml) MDA 2 (nmol/ml) hsCRP 1 (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. 1 median (Q25%-Q75%). 2 mean ± SD. *p < 0.05 vs Control

8. 8 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

9. 9 Time (hours - days) Inflammation Differences In IL-1 Genotype Are The Basis For Quantitative Variations In The Robustness Of The Inflammatory Response Environmental Challenges Hyper-responsive IL-1 Genotype Non-hyper-responsive IL-1 Genotype

10. 10 Exaggerated Inflammation (Hyper- responsive IL-1 Genotype) Across Years May Increase Risk To Heart Health Poor Health Good Health years

11. 11 IL-1 Genotype Are At Increased Risk For A First Heart Attack 1987-89 Age 45-64 Total Cholesterol <200 N= 955 Relative risk = 4.03 (1.58-10.24); p= 0.003 non Hyper-Responsive Hyper-Responsive 11 Years

12. 12 Open Innovation & Partnership >15 years experience w Clinical Genetic research, gene testing, counseling 75 years experience w Nutrition research, Dietary supplement development, & manufacture

13. 13 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

14. 14 Rose Hips Formulation Marker Dose mg/day Rose Hips Extract dehydro- ascorbate 1,200 Blackberry Powder chlorogenic acid165 Blueberry Powderanthocyanins330 Grape Vine Extract all-trans- resveratrol 40

15. 15 Clinical Trial Design Blood 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 0 week Placebo Rose Hips Formulation 124 Intervention 8

16. 16 Rose Hips Formulation Reduced Inflammatory Mediators vs Placebo

17. 17 Rose Hips Formulation Preferentially Reduced IL-1 in At-Risk Subjects At Risk Genotype Non Risk Genotype

18. 18

19. 19 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.

20. 20 Acknowledgments Institute 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