Age and Nutrition-induced changes in Immune and Inflammatory Response: Implications for Disease Prevention Simin Nikbin Meydani, DVM, PhD

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Meydani, DVM, PhD Tufts University, Jean Mayer United States

1 Age and Nutrition-induced changes in Immune and Inflammatory Response: Implications for Disease Prevention Simin Nikbin Meydani, DVM, PhD Tufts University, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging

2 Aging is associated with dysregulated immune and inflammatory responses: -- Increased Inflammation -- Decreased T cell-mediated function Inflammation T cell function Aging

3 Age-associated changes in inflammatory markers Old mice have a higher production of inflammatory markers than young mice Dr. Zhihong Ren Young Old Ren etal., J Nutr., 2010

4 Age-associated changes in inflammatory markers Inflammation is linked to: heart disease diabetes II Cancer Alzheimer s disease arthritis pulmonary disease autoimmune disease neurological disease

5 Age-associated changes in T cell-mediated function Decline in T cell-mediated function with age is linked to increase in : --Cancer --Infections --Autoimmune diseases DTH Vaccine efficacy Th1/Th2 Decrease naïve cells CTL activity proliferation IL-2

6 Infections Are Among the Leading Causes of Morbidity and Mortality in Elderly with Significant Impact on Health Care Cost Pneumonia Tuberculosis G.I. infections HIV/AIDS Urinary tract $4.4 billion the costs associated with hospitalization due to community acquired pneumonia in 2002 infections Herpes zoster

7 Changing inflammation and cell mediated immunity with nutrition: Micronutrients [Vitamin E, PLP (vitamin B6)] Wolfberry Fish Oil Prebiotics

8 Changing Inflammation- Micronutrients (Vitamin E) Vitamin E and PGE 2 Production PGE 2 (pg/μg protein) Wu, et al., AJP 1998;275:C661

9 Changing Inflammation- Micronutrients (Vitamin E) mmol/l Plasma Vitamin E * ln pmol/l mmol/l PBMC PGE2 Plasma lipid Peroxides * *

10 Optimal Vitamin E Dose for Improving the Immune Response in Elderly Group Change in antibody response to hepatitis B (U/ml) %Change in DTH diameter of induration Placebo Vitamin E (60 IU) Vitamin E (200 IU) Vitamin E (800 IU) Meydani et al. JAMA.

11 Experimental Design Design: Duration: Treatment: Subject: Double-Blind, Placebo- Controlled Randomized 1 year 200 IU/Day Vitamin E or Placebo 617 Male and Female, Nursing Home Residents >65 years old Main Outcome: Upper and Lower Respiratory Infections

12 Vitamin E reduces the risk of acquiring respiratory infections Meydani et al. JAMA, 292: , 2004.

Changing Inflammation- Micronutrients (Vitamin E) The effect of E on TNF-α production depends on TNF-α -308G>A Vitamin E Placebo Interaction: vitamin E and TNF-α-308G>A p=0.

14 Changing Inflammation- Micronutrients (Vitamin E) The effect of E on TNF-α production depends on TNF-α -308G>A Vitamin E Placebo Interaction: vitamin E and TNF-α-308G>A p=0.039* TNF-a Production (pg/ml) *Adjusted for baseline TNF-α production G/G A/G and A/A Placebo n=56 (G/G =46; A/G and A/A =10); Vitamin E group n=39 (G/G=22; A/G and A/A =17) Sarah Belisle * Belisle et al. J. Nutr., 2009

Changing Inflammation- Micronutrients (Vitamin E) Conclusions These observations suggest that individual inflammatory responses to vitamin E supplementation are in part mediated by genetic factors.

15 Changing Inflammation- Micronutrients (Vitamin E) Conclusions These observations suggest that individual inflammatory responses to vitamin E supplementation are in part mediated by genetic factors. Because A allele at TNFα is associated with higher TNFα levels, our observation suggest that the anti-inflammatory effect of vitamin E is specific to those genetically predispose to higher inflammation.

16 Changing Inflammation- Micronutrients PLP (vitamin B6) Significant percent of older population is at risk for low B6 consumption Low B6 has been shown to be associated with higher incidence of CVD, RA, IBD, Diabetes,& Cancer.

Changing Inflammation- Micronutrients PLP (vitamin B6) Inflammatory Biomarkers Framingham Heart Study Adiponectin, plasma CD40 ligand, plasma C reactive protein (CRP), serum Fibrinogen, plasma

17 Changing Inflammation- Micronutrients PLP (vitamin B6) Inflammatory Biomarkers Framingham Heart Study Adiponectin, plasma CD40 ligand, plasma C reactive protein (CRP), serum Fibrinogen, plasma Intercellular adhesion molecule 1 (ICAM 1), serum Interleukin 6 (IL 6), serum Isoprostanes, urinary indexed to urinary creatinine (8 epi PGF2 /urinary creatinine) Lipoprotein associated phospholipase A 2 (Lp PLA2) mass, plasma Lipoprotein associated phospholipase A 2 (Lp PLA2) activity, plasma Monocyte chemoattractant protein 1 (MCP 1), serum Myeloperoxidase (MPO), serum Osteoprotegerin (OPG), plasma P selectin, plasma Resistin, plasma Tumor necrosis factor (TNF) α, plasma Tumor necrosis factor receptor II (TNFRII), plasma

18 Changing Inflammation- Micronutrients PLP (vitamin B6) Low plasma PLP is associated with higher inflammatory score Plasma PLP <20mol/mL, p-trend< 0.03 % with low plasma PLP Inflammation Score Sakakeeny et al. Nutrition, 2010

19 B 6 Status and Immune Function Study Protocol Duration (Days) Food Diary 3 Baseline 5 Total Intake Male Female B 6 Depletion * 17 to B 6 Repletion * I II III * Protein intake/day: 1.2 g/kg body wt.

20 Vitamin B 6 Status and Lymphocyte Proliferation

21 Vitamin B 6 Status and Lymphocyte Proliferation

22 anging Neutrophil and Lymphocyte Ratio- Micronutrients PLP (vitamin B6)

Changing Immune and Inflammatory Response -- Wolfberry What is Wolfberry? Wolfberry (Goji Berry), contains vitamin C and carotenoids, has long been used in China as a folklore medicine.

23 Changing Immune and Inflammatory Response -- Wolfberry What is Wolfberry? Wolfberry (Goji Berry), contains vitamin C and carotenoids, has long been used in China as a folklore medicine. A milk-based wolfberry preparation, called Lacto-Wolfberry (LWB) was recently reported to enhance the immune response in mice. However, it is not known whether the enhancement of immune response induced by LWB has a clinical relevance, e.g., increasing the host resistance to viral infection.

24 Changing Inflammation- Micronutrients -- Wolfberry Objective To examine the effect of dietary supplementation with LWB on the host immune and inflammatory responses and resistance to viral infection using a mouse influenza infection model.

25 Changing Inflammation- Micronutrients -- Wolfberry Materials and methods Dr. Zhihong Ren 5% LWB diet 4 wk Infected with P/R 8/34 virus (H1N1) C57BL/6 male mice (4 mo) Control diet Killed mice at day 0, 2, 6, 9 postinfection and collected lung, spleen, liver and serum

26 Changing Inflammation- Micronutrients -- Wolfberry Body Weight Loss in Mice Fed With or Without LWB After Influenza Infection * Days postinfection Mean+ SEM, n=11, * p<0.05 by ANOVA Ren et al. J. Nutr.,142: 1596, 2012

27 Changing Inflammation- Micronutrients -- Wolfberry LWB Decreased Lung Pathology in Mice Following Influenza Infection * * Mean ± SEM, n= 6 or 10, * p<0.05 Days Post-infection Ren et al. J. Nutr.,142: 1596, 2012

28 Changing Inflammation- Micronutrients Wolfberry Effect of LWB on Pro-inflammatory Cytokine Production in Lung Diet Day 0 Day 2 Day 6 Day 9 TNF-α Control 13 ± 5 25 ± ± ± 23 (pg/ml) LWB 14 ± 6 24 ± ± 44 # 61 ± 19 IL-6 Control 14 ± 6 12 ± ± ± 130 (pg/ml) LWB 15 ± 7 12 ± ± 494 # 197 ± 153 IL-1 β Control 46 ± ± ± ± 24 (pg/ml) LWB 41 ± ± ± ± 22 # p< 0.05 Ren et al. J. Nutr.,142: 1596, 2012

Changing Inflammation- Micronutrients Wolfberry Correlation Between Symptom Markers and Lung Cytokines R value P value Weight loss * Titer 0.897 0.

29 Changing Inflammation- Micronutrients Wolfberry Correlation Between Symptom Markers and Lung Cytokines R value P value Weight loss * Titer Weight loss * Pathology score Pathology score * Titer Weight loss * TNF-α Weight loss * IL-1β Weight loss * IL Ren et al. J. Nutr.,142: 1596, 2012

30 Dr Xiaogang Du Experimental Design 20 Months C57BL/6 Control or wolfberry diets I.P/5 g flu Vaccine 30 days Day 31 Day 52 Challenge/APR8 Outcomes Day 73

31 Impact of LWB on Antibody Titer of Old mice Control Control+Vaccine Vaccine+Wolfberry Wolfberry b b a a a a a Contro Control+Vaccine Vaccine+Wolfberry Wolfberry 0 a HAI titer Antibody titer

32 Effect of Wolfberry on Weight Loss After Flu Challenge

33 Effect of Wolfberry on Survival of Old Mice Following Flu Challenge

Changing Inflammation- N-3 PUFA (fish oil) Fish oil is known to reduce inflammation and to improve clinical symptoms in several diseases in which inflammation

34 Changing Inflammation- N-3 PUFA (fish oil) Fish oil is known to reduce inflammation and to improve clinical symptoms in several diseases in which inflammation plays a role: Cardiovascular diseases Rheumatoid arthritis Psoriasis Multiple sclerosis Systemic lupus erythematosus Atopic dermatitis Ulcerative colitis Cancer

35 Changing Inflammation- N-3 PUFA (fish oil) Modulatory Effect of EPA on Eicosanoid Synthesis Diet AA membrane phospholipids PLA 2 EPA AA LOX COX LOX COX LTB 5 PGE 3 LTB 4 PGE 2 Less inflammatory Inflammatory

36 Changing Inflammation- N-3 PUFA (fish oil) Experimental Design Ave. American NCEP-2 Low or High Fish weeks In vitro testing In vitro testing DTH DTH

37 Changing Inflammation- N-3 PUFA (fish oil) Effect of Low-fat Diets High and Low in Fish on Ex-vivo Cytokine and PGE 2 Production IL-1 TNF IL-6 PGE2-63* Low fat, low fat, high fish fish low -40* -35* -34* % change # 62* # Compared to their own baseline Meydani et al., JCI;

38 Effect of Diets High and Low in Fish on DTH Induration diameter (mm) Before * After 25 Induration diameter (mm) Before After * Significantly different from before

39 Study Design Double-blind Thirty free-living subjects (65y or above) Continued their usual dietary habits and activity level Provided 2 and 3-day dietary records Randomly assigned to 1 of 3 groups

40 Groups All groups received 5 capsules/d of Omega-500TM (providing 1.5 g EPA, 1 g DHA, and 5 IU vitamin E/d) Each group received a capsule for 100, 200, or 400 IU/d dl- -tocopherol, respectively, for 3 months.

41 Vitamin E Supplementation Increases DTH in Subjects Supplemented with Fish Oil 48 h induration (mm) * Vit E 100 Vit E 200 Vit E 400 Supplementation groups Mean ± SE, n=8 to 10/group *p<0.05 compared to the baseline * Baseline 3-mo

42 Conclusion: Nutrient/nutrient interaction may influence the efficacy of fish oil in helping promote optimal Immune and inflammatory responses.

43 Changes in Gut Microflora With Age A limited number of studies have indicated that structural changes occur in the ecosystem in the elderly people. Species such as bifdobacteria, which are regarded as being protective, are thought to decline in numbers and diversity, whereas clostridia and enterobacterial populations, which are viewed as being detrimental to health, increase. Hopkins and Macfarlane. J. Med. Microbiol. 5: , 2002

44 Changing Immune and Inflammatory Responses- Prebiotics Study Design Double blind, placebo controlled, crossover study 44 healthy elderly subjects Over 60 years of age BMI range Placebo (Maltodextrin), treatment prebiotic galactooligosachrides (GOS) mixture (B-GOS; Bi²muno) both provided in powder form in 5.5g. Volunteers consumed products for 10wks, followed by 4wk wash out period, then switching to the other treatment for the final 10wk.

45 Changing Immune and Inflammatory Responses- Prebiotics Consumption of Prebiotics modifies gut microbiota Increased in numbers compared to baseline and placebo treatment Bifidobacterium spp. Lactobacillus-Enterococcus spp. Decreased in numbers compared to baseline and placebo treatment Bacteroides spp. Clostridium histolyticum group Escherichia coli Desulfovibrio spp.

46 Changing Inflammation- Prebiotics The Change in the Production of IL-10, IL-1, TNF-, and IL-6 at 10 wk of Placebo and B- GOS Treatments from Baseline Concentration (pg/ml) Vulevic et al. AJCN, 2008

47 Changing NK cell activity- Prebiotics Effect of B-GOS on NK activity of older adults Baseline Week 10 % tumor cell killing Placebo B-GOS * *Significantly different from change in Placebo Vulevic et al. AJCN, 2008

48 Summary Inflammation increases with age and has been identified as a key contributor to chronic diseases of aging. T cell-mediated function declines with age and contributes to increased risk for infectious, autoimmune and neoplastic diseases. Several food components have been shown to reduce inflammation and enhance cellmediated immunity.

49 Summary Efficacy may depend on: Dose Age Nutrient/nutrient interaction Gene/nutrient interaction Nutrient/microbiome interaction

50 Acknowledgements Nutritional Immunology Lab: Dayong Wu Basil Fine Zhihong Ren Lixin Na Yanmei Xu Mitra Rozati Junpeng Wang Jianguo Xu Changhao Sun HNRCA Colleagues: Jerry Dallal Alice Lichtenstein Ernst Schaefer Other Institutes: David Hamer (Boston Univ.) Gary Brandies (Boston Univ.) Karine Vidal (Nestle Research Center)

51 Funding Sources United States Department of Agriculture National Institute of Aging Office of Dietary Supplement Hoffmann-LaRoche Inc. (supplements) DSM (student s support) Ellison Medical Foundation (postdoc. support) Nestle

52 Questions?

Nutrition and Age-Associated Inflammation :Role of Nutritional Intervention Simin Nikbin Meydani, DVM, PhD.

Nutrition and Age-Associated Inflammation :Role of Nutritional Intervention Simin Nikbin Meydani, DVM, PhD simin.meydani@tufts.edu Outline 1) Role of immune and inflammatory responses in age-related diseases