ILSI Europe Satellite Workshop on: Nutrition for the Ageing Brain: Towards Evidence for an Optimal Diet

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1 ILSI Europe Satellite Workshop on: Nutrition for the Ageing Brain: Towards Evidence for an Optimal Diet July 2014, Milan, Italy Organized by The ILSI Europe Nutrition and Mental Performance Task Force

2 Oxidative stress in ageing brain: Potential protective effects of antioxidant micronutrients and polyphenols A.M. Roussel, Emeritus Professor Joseph Fourier University, Grenoble - France

3 Introduction: antioxidant nutrients and the brain There is an age-associated increase in brain oxidative damages This increase, reported in specific crucial brain areas, might render the brain more susceptible to degeneration and cognitive decline. Which possible targets for nutritional interventions? Interest for nutrients that can cross the blood-brain barrier and decrease oxidative damages? 3

4 Oxidative stress and brain ageing: a delicate balance 1 Physiological level of oxidative stress 2 High level of oxidative stress moderate oxyradicals production by mitochondria oxidative stress inflammation mitochondrial biogenesis program inactivation of mitochondrial functions activation of transcriptional factors up-regulation of antioxidant capacity (cells and mitochondria) oxidative cell damages altered cell signalling pathways changes in gene expression brain protection brain ageing 4

5 Environmental factors of brain oxidative damages

Diet and life style are key environmental factors in

brain disorders Stress 0besity Metabolic syndrome

nutritional density Low antioxidant defenses Chronic

6 Diet and life style are key environmental factors in delaying or halting oxidative stress and age-related brain disorders Stress 0besity Metabolic syndrome Insulin resistance Overeating, junk food Poor nutritional density Low antioxidant defenses Chronic inflammation cytokines and radical species Oxidative stress Brain aggression 6

7 Oxidative stress in the metabolic syndrome Plasma isoprostanes are 4-fold higher in patients with the metabolic syndrome Hansen et al. J Clin Endocrinol Metab. 2004;89(10): Correlation between the plasma levels of 8-epi-PGF2a and BMI Plasma levels of 8-epi-PGF2a 17 men BMI < 25 (no metabolic syndrome) 14 men BMI > 25 (metabolic syndrome) Furakawa H et al. J Clin Endocrinol Metab Oct;88(10):

8 Insulin resistance is a leading cause of oxidative stress Correlation between the plasma levels of 8-epi-PGF2a and GIR (glucose infusion rate) Furakawa H and coll. J Clin Endocrinol Metab Oct;88(10):

9 Oxidative stress and brain insulin signalling Alzheimer s disease is proposed as "insulin resistant brain state". brain insulin signalling altered cerebral insulin signalling glucose utilization decreased oxidative stress increased neuronal survival promotion of learning and memory glucotoxicity oxidative stress advanced glycosylated end products changes in brain vasculature altered amyloid metabolism brain neurodegeneration cognitive impairment 9

10 Iron accumulation in ageing brain Age-related iron retention is associated with cognitive decline and neurodegenerative pathologies. Fenton Reaction O2 - + H2O2 OH + OH - + O2 Alzheimer s Disease astrocytes Fe ++ DNA Damage Cancers Proteins HbA1C Diabetes Lipids TBAR's MCV Iron accumulation in brain results in an oxidative burst: Fenton chemistry, oxidized lipids as ceramides, sphingolipids, synaptic dysfunction. Hare D et al. Front Aging Neurosci. 2013; 5:34. 10

11 In summary: Environmental factors, neuronal resilience or vulnerability Stranahan AM et Mattson JP. Neurobiol Learn Mem 2011; 96(4):

12 Antioxidant nutrients and brain protection?? Vitamins C, E, Carotenoids, Zinc, Selenium

13 Vitamin E intakes and neuroprotection High vitamin E intakes are associated with: reduced Alzheimer's disease incidence. The Chicago Health and Aging Project (Morris et al. Am J Clin Nutr 2005; 81:508-14). reduced dementia incidence. The Rotterdam Study (Devore et al. Arch Neurol 2010; 67:819-25). BUT. 13

14 Vitamin E intakes for brain: Supplements vs foods? 1 - No effects of vitamin E supplements on the risk of Alzheimer's disease: no replication of vitamin E forms found in foods provide only a tocopherols, reduces serum concentrations of g and d tocopherols. 2 - g tocopherols in brain (115 deceased patients) were associated with lower amyloid load. - High a tocopherols in brain were associated with higher amyloid load ONLY when g tocopherols were low. The Rush Memory and Aging Project. Morris et al. Alzheimer Dement, 2014 Feb. 3 Potential toxicity of high vitamin E doses: mortality (Bjelakovic et al. JAMA hemorragic stroke (Schüerks et al. BJM 2010). 14

15 Vitamin E intakes and neuroprotection Vitamin E should come from foods rather than supplements. R.D.A. for vitamin E: 15 mg/d. International Conference on Nutrition and the Brain. Washington DC; July 19-20, 2013 in Neurobiology of Ageing, 2014 RRR-a-tocophérol and the 7 stereo-isomeres. 15

16 Ascorbic acid, cognitive functions and Alzheimer's disease high concentrations in the brain, human brain is totally dependant on dietary sources Large prospective studies of dietary intakes and supplementation: mostly negatives Relationship AA status and cognition: mostly positives controversial debate, interest of combined antioxidant supplementation vs single Bowman GL et al. Biofactors. 2012; 38(2):

Vitamin C recommended intakes and status Intakes Healthy Subject (RDA) 110 mg/d 150 mg/d (smoker) Status Plasma : 60 90 µmol/l Plasma : Acute Deficiciency : < 10 µmol/l

17 Vitamin C recommended intakes and status Intakes Healthy Subject (RDA) 110 mg/d 150 mg/d (smoker) Status Plasma : µmol/l Plasma : Acute Deficiciency : < 10 µmol/l Mild Deficiency: < 60 µmol/l Plasma level if stress or inflammation. Clinical signs of vitamin C deficiency : fatigue, infections, arthralgia, petechia delayed healing 17

18 Carotenoid rich intakes may help to prevent brain ageing Fruit and vegetable are major sources of carotenoids: lutein, zeaxanthin, b cryptoxanthin as xantophyles, a, b carotenes and lycopene as carotenes. A carotenoid rich dietary pattern results in better cognitive performance: 2983 adults from Suvimax 1 Carotenoid rich Dietary Pattern higher cognitive score 13 yrs later Kesse-Guyot et al. Br J Nutr. 2014, 111(5):

19 A high carotenoid status may help to prevent brain ageing Nurse's health Study: highest quartile of plasma carotenoids better performance Georgia Centenarian Study: lutein, zeaxanthin, b carotenes concentrations and tocopherols in brain and plasma better cognitive performance. Johnson et al. J Aging Res

20 Selenium, essential trace element for the brain Antioxidant and anti-inflammatory (GPx, selenoprotein P thioredoxin reductase) immunostimulating (glutathione cycle in lymphocytes) Detoxifying (heavy metals and xenobiotics) Cognitive functions Thyroid hormones (T4/T3) 20

21 Selenium and the brain: a special relationship... Brain saves and stores selenium through a specific regulation of the selenoproteins P (SeP) synthesis When selenium deficiency appears, SeP is up regulated in the brain. This tissular hierarchy suggests a major neuroprotecting effect of selenium. - A low level of plasma Se is a risk factor of cognitive decline (3 points lost in 4 yrs, assessed by MMSE). Berr et al, JAGS, 2000,48(10): The greater is the decrease in plasma selenium, the higher is the probability of cognitive decline subjects yrs 4 yrs follow-up Akbaraly et al., Epidemiology, 2007, 18(1):52-8. plasma Se (0.96 µm/l) 21

22 Selenium recommended intakes and sources Recommended dietary intakes : GPx optimal activity : 75 µg/d 100 µg/d Low intakes in European and Middle East countries (< 50 µg/d) Very low intakes in China (< 20 µg/d) Important risks of subdeficiency Sources : Brazil nuts ++ (600 µg/100g) Oysters and seafood (50 µg/100g) Meat, fish (20 µg/100g) Total cereals ( 6 to 10 µg/100g) 22

23 Zinc and the brain Zinc concentration is higher in brain than in the rest of the body: Zinc is present in hippocampus synapsis. Zn metalloproteins are part of glial cells and neurons Zn is a neuromodulator for synaptic and axonal transmission. Pivotal role of zinc in neurotransmission: enzymatic activities, gene regulation, stabilization of proteins. Sanstead et al, J Nutr, 2000,130 (2S suppl) : 496S-502S 23

24 The Zincage study: Zinc status impacts brain functioning Italy, Greece, Germany, France, Poland Zinc intakes and status Minimum State Examination (MMSE), Geriatric Depression Scale (GDS), Perceived Stress Scale (PSS). Strong correlation between plasma zinc when < 11 µmol/l and cognitive decline Strong correlation between low intakes (< 10 mg/d) and cognitive decline. Marcellini et al, Biogerontology, Oct

25 Zinc intakes and supplementation in aging brain: where are we? 1. Zinc deficiency (status and intakes) is frequent in the aged population. 2. Zinc deficiency could be an aggravating factor of cognitive decline. 3. Zinc could act positively in: reducing inflammation and oxidative stress. improving insulin sensitivity. But, so far, inconsistent data for zinc supplementation. Recommended intakes: 15 to 20 mg Zinc / day as organic form. McCord and Aizenman Frontiers in Neurosciences Lai et al. J Affect Disord

26 Sources Oysters, fish, meat, nuts and almonds, tea, (oysters 20 mg/100 g) Total cereals Very low concentrations in fruit and vegetables. 1 to 10 yrs: 10 mg/d Adults: 12 to 10 mg/d Nutritional negative interactions Phytates Calcium Fibers Polyphenols, tannins Copper Cadmium Iron Folates Dietary sources and RDA 26

Caution!! Zinc dyshomeostasis in Alzheimer's disease Alterations in cellular and systemic zinc distribution in Alzheimer's disease. Zinc accumulation in brain is neurotoxic: 1.

27 Caution!! Zinc dyshomeostasis in Alzheimer's disease Alterations in cellular and systemic zinc distribution in Alzheimer's disease. Zinc accumulation in brain is neurotoxic: 1. Zinc release induces senile plaques. 2. Zinc inhibits App and increases iron accumulation. 3. Zinc activates Tau phosphorylation. Potential role of excess zinc in Alzheimer's disease pathology. Zinc is released from synaptic vesicles in response to neuronal activity. Three mechanisms : 1. Zn can accumulate bound to Ab at zinc secreting synapses, Zn can inhibit the iron export ferroxidase activity of App Zn stimulates kinases and inhibits protein phosphatase... Nuttall J and Oteiza P Genes Nutr; 9:

28 Polyphenols, friends of the brain fruits, vegetables,wine, cocoa, cinnamon Stocket JC et al. Annales Pharmaceutiques Françaises 2011; 69:78-90.

29 2 9 Polyphenols, friends of the brain.. PAQUID study, France, West South subjects > 65 yrs, 5yrs follow up. Dementia incidence : Flavonoïdes < 11 mg/j RR = 1 Flavonoïdes > 11 mg/j RR = 0.55 Commenges et al, Eur J Epidemiol, 2000,16: Suvimax 2 Study : 2135 subjects, 13 years after Suvimax : Suvimax 1 middle-aged volunteers became "seniors" Total and specific polyphenols intakes in middle-life are associated with cognitive function measured 12 yrs later Kesse-Guyot et al, J Nutr 2012,142(1):76-83

30 Cinnamon polyphenols, oxidative stress and insulin resistance Decrease dietary-induced insulin resistance (Qin B, Panikar KS, Anderson RA J Diabetes Sci Technol; 4: ). Act as antioxidant (Roussel AM et al, JACN,2009) Decrease brain glucotoxicity (Panickar K and Anderson RA. Neuroscience 2012; 87-98). RA Anderson s Group, BHNRC,USA 30

31 mrna levels (fold) mrna levels (fold) Cinnamon effects* on Akt1 and Sirt Akt1-hippocampus/diet a a a b Sirt1-hippocampus/diet ab ab a b 0 C C+CN HF/HF HF/HF+CN 0 C C+CN HF/HF HF/HF+CN Cinnamon increases Akt1 following HF/HF. Key control step for insulin. Activation of AKt1 has been implicated as a major contributor to neuronal survival after an ischemic insult. Anderson RA, Qin B, Canini F, Roussel AM Plos One 2014 Silent information regulator t1:sirt1 HF/HF trend to decrease and cinnamon increases Sirt1. Sirt 1 is increased by calorie restriction, blocks formation of beta amyoid neuropathology. *Dietary-induced insulin resistance in rats (High Fat/High Fructose diet) plus Cinnamon powder 10g/Kg diet 31

32 mrna levels (fold) mrna levels (fold) Cinnamon* effects on App and Tau App-hippocampus/diet a a b ab Tau-hippocampus/diet a a b ab C C+CN HF/HF HF/HF+CN 0 C C+CN HF/HF HF/HF+CN Amyloid precursor protein (App) - associated with Alzheimers: HF/HF increases App, cinnamon decreases. Anderson RA, Qin B, Canini F, Roussel AM Plos One 2014 Tau is associated with Alzheimers, Cinnamon decreases Tau phosphorylation & breaks up Tau filaments. HF/HF increases Tau. *Dietary-induced insulin resistance in rats (High Fat/High Fructose diet) plus Cinnamon powder 10g/Kg diet 32

Cinnamon reverses Tau aggregation and breaks

33 Cinnamon reverses Tau aggregation and breaks up Tau filaments A) Heparin induced Tau187 filaments after 24 h. B) After 48 h; C) A + 24 h incubation with Cinnamon: 0.1 mg/ml. A : 24 hours B : 48 hours C : 24 h + Cinn Peterson et al, J Alzheimers Dis 17:585-97,

34 Up-regulation of neuroprotectives genes by polyphenols Vauzour D. Oxidative Med Cell Longevity. 2012; ID

35 Polyphenols and neuroprotection: more than antioxidants... Polyphenols Polyphenols Aging Polyphenols STOP STOP STOP neuro inflammation NO production TNFa, CRP.. neurotoxicity oxidative stress DNA damages protein aggregation neurotoxins glucotoxicity altered insulin signalling DNA damages altered amyloid metabolism Neuronal dysfunction STOP Polyphenols cognitive decline Alzheimer's disease Parkinson's disease adapted from Vaujour in Oxidative Med Cell Longevity

36 In summary how to prevent or delay age-induced oxidative damages in brain??

37 Nutrition, brain aging and cognitive decline: an early implication of oxidative stress to take in consideration Hypothetical framework for nutrition and brain aging research. Bowman GL Biofactors; 38(2):

38 Potential nutritional targets for preventing brain oxidative damages antioxidant defenses brain insulin signalling Neuroprotective genes life style environmental factors iron metabolism Antioxidant micronutrients Zn, Se, Cr, Vit E, vit C carotenoids Polyphenols tea, cocoa Cinnamon Exercise Moderate caloric intakes No stress No iron excess Thank you! 38

Reviewing novel dietary strategies to delay or prevent Alzheimer s disease. Dr David Vauzour

Reviewing novel dietary strategies to delay or prevent Alzheimer s disease Dr David Vauzour Populations are getting older x 2.5 United Nations 2012 Ageing and dementia Global impact of dementia World Alzheimer