Evidence-Based Nutritional Strategies for the Aging Brain

Evidence-Based Nutritional Strategies for the Aging Brain
Evidence-Based Nutritional Strategies For The Aging Brain Michael Lara, MD Diplomate, American Board of Psychiatry and Neurology
Michael E. Lara, MD Diplomate, American Board of Psychiatry and Neurology ‣ www.DrMikeLara.com ‣ Email: mlaramd@gmail.com ‣ Facebook: www.facebook.com/BrainMD ‣ Twitter: @MichaelLaraMD !2
$30 Billion Estimated amount of money Americans spent on health supplements in 2012
Which Would You Choose? Nutrients from healthy food sources or from supplements? !4
How The Brain Ages The insidious effects of chronic physical and psychological stress Immune Stress and Anti-Inflammatory Nutrients Adiposity, brain volume, and chronic inflammation Oxidative Stress and Anti-Oxidants Mitochondria, reactive oxygen species and polyphenols Metabolic Stress and Nutrients that Support Metabolism Nutrient sensors, elevated blood sugar, and type 3 diabetes Strategies to Protect The Aging Brain Caloric Restriction and exercise 1 2 3 4 5
How The Brain Ages The insidious effects of chronic physical and psychological stress Immune Stress and Anti-Inflammatory Nutrients Adiposity, brain volume, and chronic inflammation Oxidative Stress and Anti-Oxidants Mitochondria, reactive oxygen species and polyphenols Metabolic Stress and Nutrients that Support Metabolism Nutrient sensors, elevated blood sugar, and type 3 diabetes Strategies to Protect The Aging Brain Caloric Restriction and Exercise 1 2 3 4 5
Chronic Stress Leads to Premature Aging Psychological stress leads to inflammatory, oxidative, and metabolic stress !10
Telomere Length and Telomerase Activity High-stressed caregivers age prematurely High-Stressed group had aged the equivalent of 9-17 additional years Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D., & Cawthon, R. M. (2004). Accelerated telomere shortening in response to life stress. Proceedings of the National Academy of Sciences of the United States of America, 101(49), 17312-17315.
Age-Related Memory Loss vs MCI Healthy aging, mild cognitive impairment, and Alzheimer’s !12
Sleep Changes in the Aging Brain Sleep becomes more fragmented and less restorative as we age Younger Subject Older Subject !13
Magnesium Nearly 50% of older adults have insomnia, and most do not meet RDA for magnesium intake ‣ Supplemental magnesium decreases sleep latency, improves sleep efficiency, and increases total sleep time in elderly. ‣ Magnesium is a glutamate (NMDA) antagonist and GABA agonist. ‣ For mild insomnia: 400-800 mg/night of magnesium aspartate, citrate, lactate or chloride !14
Valerian Derived from plant Valeriana officinalis, valerian is a common folk treatment for insomnia. ‣ A GABA agonist, valerian may improve sleep quality and latency, but a 2010 meta-analysis showed only subjective improvements in insomnia ‣ 450 mg of valerian extract (0.8% valerenic acid) one hour before bedtime. ‣ Doses larger than 450 mg may cause vivid dreams and morning grogginess ‣ Long-term use may cause withdrawal symptoms on abrupt cessation !15
Melatonin ‣ Results of 2013 meta-analysis: May reduce sleep latency, sleep quality, and improve overall sleep quality but effects are modest ‣ Strongest evidence is for insomnia associated with circadian rhythm disorders (shift work sleep disorder and jet lag) ‣ Dose range: between 0.3 mg and 3 mg 30 minutes before bedtime !16
Efficacy of Melatonin in Increasing Total sleep Time Mean Difference: 8.48 minutes Ferracioli-Oda E, Qawasmi A, Bloch MH (2013) Meta-Analysis: Melatonin for the Treatment of Primary Sleep Disorders. PLoS ONE 8(5): e63773. doi:10.1371/journal.pone.0063773 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063773
Anatomical Changes in the Aging Brain PET imaging of β-amyloid AD MCI Control Small, G. W., Kepe, V., Ercoli, L. M., Siddarth, P., Bookheimer, S. Y., Miller, K. J., ... & Barrio, J. R. (2006). PET of brain amyloid and tau in mild cognitive impairment. New England Journal of Medicine, 355(25), 2652-2663. !18
Pathologic Changes in the Aging Brain Characterized by cortical and hippocampal atrophy, and enlargement of ventricles !19
Neurotransmitters and The Aging Brain Age-associated reductions in receptor binding and signaling Neurotransmitters Serotonin Norepinephrine Cognitive Function ‣ Serotonin associated with sleep, appetite, and mood ‣ Norepinephrine regulates attention and concentration ‣ Dopamine associated with pleasure and reward Dopamine !20
The Synapse Changes in neurotransmitter synthesis, release, binding and reuptake with normal aging !21
GABA and Glutamate The major inhibitory and excitatory neurotransmitters GABA Glutamate ‣ Major inhibitory neurotransmitter in CNS Regulates synaptogenesis and neurogenesis ‣ Target of antianxiety and anticonvulsant drugs Excitotoxity ‣ Regulates sleepwake cycle ‣ Major excitatory neurotransmitter in CNS ‣ ‣ Glutamate GABA !22
Synthesis of Serotonin Synthesized from Ltryptophan and Vitamin B6 !23
Synthesis of Dopamine and Norepinephrine Synthesized from L-Tyrosine !24
Homocysteine A biomarker linked to heart disease, stroke, and cognitive decline ‣ Elevated homocysteine levels are a risk factor for brain atrophy, cognitive impairment, and dementia. ‣ B-vitamins serve as co-factors for enzymes that convert homocysteine into methionine ‣ B-vitamin therapy may slow progression of MCI to AD by reducing homocysteine levels !25
B-Vitamins Lower Homocysteine Accelerated rate of atrophy in elderly with MCI can be slowed by treatment with homocysteine-lowering B vitamins ‣ Randomized, double-blind trial of high dose folic acid, vitamins B6 and B12 in 271 individuals with MCI ‣ Treatment group received folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d), and vitamin B6 (20 mg/day) for 24 months ‣ Outcome measure: rate of whole brain atrophy assessed by MRI scans ‣ Results: Mean rate of brain atrophy was 0.76% in treatment group and 1.08% in placebo group Smith, A. D., Smith, S. M., de Jager, C. A., Whitbread, P., Johnston, C., Agacinski, G., ... & Refsum, H. (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PloS one, 5(9), e12244. !26
B-Vitamin Therapy Reduces Brain Atrophy Homocysteine levels are correlated with rate of brain atrophy Supplementing with B-vitamins led to 50% reduction in rates of brain atrophy in subjects with MCI !27
Cerefolin NAC ‣ Medical food product for the dietary management of MCI or early AD ‣ 5.6 grams L-methlyfolate • 800 mcg folic acid ‣ 2 mg methylcobalamin ‣ 600 mg N-acetylcysteine !28
Bacopa ‣ Brahmi, an ayurvedic herb used to promote learning and memory ‣ Promotes release of acetylcholine in prefrontal cortex and increases antioxidant enzymes ‣ 300-450 mg/day of extract containing 55% bacosides !29
Ginko Biloba ‣ Believed to promote learning and memory ‣ In some studies GB improves attention in healthy adults ‣ 2012 meta-analysis found NO improvements in attention, memory or problem solving in healthy and memory-impaired populations !30
Huperzine-A ‣ Alkaloid from fir moss Huperzia serrata ‣ In some studies, huperzine is as effective as prescription medications used to treat Alzheimer’s ‣ Enhances memory in healthy young adults ‣ Dose range: 50-200 mcg/ day !31
Supplement Stack for Memory/Learning ‣ Huperzine-A: 50 mcg ‣ Vitamin B12: 500 mg/day ‣ Folic Acid: 800 mcg/day ‣ N-acetylcysteine: 600 mg/day !32
“To love a person is to learn the song that is in their heart and to sing it to them when they have forgotten” ! ~Thomas Chandler!33
Chronic Inflammation Accelerates Aging Chronic inflammation is associated with cancer, diabetes, heart disease, obesity, depression and dementia !35
Is Obesity is a Disease of Inflammation? Adipocytes secrete a range of pro-inflammatory hormones !36
As Adiposity Increases, Brain Volume Decreases BMI is inversely correlated with total brain volume in healthy middleaged adults Interleukin-6 C-Reactive Protein Leptin Debette, S., Beiser, A., Hoffmann, U., DeCarli, C., O'Donnell, C. J., Massaro, J. M., ... & Seshadri, S. (2010). Visceral fat is associated with lower brain volume in healthy middle‐aged adults. Annals of neurology, 68(2), 136-144. !37
Omega-3 Fatty Acids Essential fatty acids ‣ Essential fatty acids required for normal metabolism ‣ EPA, DHA, and ALA ‣ Sources: Wild fish, seaweed, algae ‣ Ideal ratio of omega-6:omega-3 is 1:1, but in Western diets ratio is closer to 16:1 ‣ For general brain health: 2-4 grams of pharmaceutical grade fish oil/day !38
Omega-3 Consumption and Depression Correlations between prevalence of major depression and fish consumption Hibbeln, J. R. (1998). Fish consumption and major depression. Lancet, 351(9110), 1213. !39
Omega-3 Fatty Acids and Inflammation Omega-3s reduce inflammation, improve triglyceride levels, and stabilize blood glucose Arachidonic Acid COX-2 Omega-3s EPA/DHA PPAR-α ↓Triglyceride and VLDL secretion Improved Blood Lipid Profile PPAR-γ ↑ Fatty Acid Oxidation ↑ Triglyceride Clearance Pro-inflammatory Prostaglandins Improved Insulin Sensitivity Improved Glucose Control ↓ Risk of CVD !40
Polyphenols Potent anti-inflammatory compounds derived from plant sources !41
Flavonoids Improve Cognitive Function Intake of chocolate, red wine and green tea is associated with better cognitive function in healthy adults Chocolate 10 g/day Red Wine .75 glass/day Green Tea 4 cups/day !42
Curcumin Derived from turmeric, a member of the ginger family, curcurmin has medicinal properties. ‣ Anti-inflammatory via inhibition of cytokine production ‣ Anti-cancer effects via induction of apoptosis ‣ Anti-depressant effects via MAO inhibition ‣ Inhibits formation of β-amyloid ‣ For inflammatory disorders, 2-8 grams curcumin/day !43
Curcumin Inhibits β-amyloid Formation An overview of the neuroprotective effects of curcumin Lee, W. H., Loo, C. Y., Bebawy, M., Luk, F., Mason, R. S., & Rohanizadeh, R. (2013). Curcumin and its Derivatives: Their Application in Neuropharmacology and Neuroscience in the 21st Century. Current neuropharmacology, 11(4), 338. !44
Anti-Inflammatory Stack ‣ 800 mg curcumin twice daily ‣ 2 mg pharmaceutical grade fish oil twice daily ‣ 2 pinches of black pepper mixed in 1 tablespoon of Greek yogurt (to enhance absorption of curcumin) ‣ 200 mg CoEnzyme Q10 twice daily !45
The Mediterranean Diet An anti-inflammatory diet that promotes brain health Meat% %Sweets% Poultry,%Eggs,% Cheese,%Yogurt% Fish%and%Seafood% Fruits,%Vegetables%Grains,%Beans,%Nuts,% Olive%Oil% Physical%AcCvity;%Enjoy%meals%with%others% !46
Mediterranean Diet and MCI Higher adherence to the MeDi is associated with a trend for reduced risk of developing MCI and with reduced risk of MCI conversion to AD Scarmeas, N., Stern, Y., Mayeux, R., Manly, J. J., Schupf, N., & Luchsinger, J. A. (2009). Mediterranean diet and mild cognitive impairment. Archives of neurology, 66(2), 216 !47
“Eat food. Not too much. Mostly plants.” ! ~Michael Pollan !48
Mitochondria Organelles within cells that extract energy from nutrients to synthesize ATP, the cell’s common energy currency !50
Structure of the Mitochondrion Cellular power plants that convert nutrients to ATP ROS !51
Formation of ROS in Mitochondria Reactive oxygen species are by-products of the electron transport chain Electron Transport Chain ATP Synthase ROS !52
Polyphenols A classs of anti-oxidants that neutralize ROS !53
Health Benefits of Resveratrol Reduces inflammatory, metabolic, and oxidative stress ‣ Reduces chronic inflammation via inhibition of COX and NF-κΒ ‣ Reduces oxidative stress via de novo synthesis of antioxidant enzymes, SOD and catalase ‣ Reduces metabolic stress by increasing mitochondrial biogenesis and fat oxidation ‣ Resveratrol may prolong life in some animal models but so far no evidence of life extension in humans !54
Resveratrol Content in Selected Wines Resveratrol content in a serving of wine ranges from 0.2 to 2.0 mg/L Supplements contain anywhere from 100-500 mg Pinot Noir—California 5.01 mg/L ! ! Beaujoulais—France 3.55 mg/L ! ! Cabernet and Merlot—Chile 1.56 mg/L ! ! Zinfandel—California 1.38 mg/L ! ! Cabernet Savignon—California 0.99 mg/L ! ! ! ! !55
Cocoa Derived from the seeds of the tree theobroma cacao, “drink of the gods”, cocoa is rich in anti-oxidants ‣ Improves cardiovascular health by reducing blood pressure, inhibiting platelet aggregation, and reducing insulin resistance ‣ Contains range of bioactive compounds, including theobromine (similar to caffeine) and phenylethylamine (a psychostimulant) ‣ Dark, unsweetened 70% cacao ‣ Optimal dose 10 g/day !56
Chocolate Consumption and Nobel Laureates Per Capita Chocolate consumption correlates with number of Nobel Laureates per country Messerli, F. H., "Chocolate consumption, cognitive function, and Nobel laureates" N Engl J Med 367 (16), 1562 (2012). !57
Blueberries Rich in polyphenols, blueberries are potent anti-oxidants ‣ Blueberries contain anthocyanins, a class of polyphenols that neutralize free radicals (ROS) ‣ Inhibit AChE, the enzyme that degrades acetylcholine ‣ Blueberries stimulate neurogenesis and enhance neuronal plasticity in the hippocampus ‣ Improve insulin sensitivity in obese subjects !58
Blueberry Smart Frappe ‣ 1 cup ice ‣ 1/2 cup blueberries ‣ 1/2 cup blueberry juice ‣ 2 tablespoons psyllium husk !59
Coenzyme Q10 Ubiquinone, an electron carrier in the electron transport chain, is depleted with normal aging ‣ Lack of CoQ10 depletes cellular energy stores ‣ May reduce formation of β-amyloid ‣ Statin drugs may deplete levels of CoQ10 ‣ Doses range from 100-300 mg daily !60
Acetyl-L-Carnitine Carnitine shuttles fatty acids into mitochondria ‣ Protects endothelium from oxidative damage ‣ Enhances blood flow ‣ May slow progression of MCI and Alzheimer’s ‣ Dose: 1.5 to 3.0 grams/day !61
Alpha Lipoic Acid A mitochondrial fatty acid used as cofactor in synthesis of ATP and a potent anti-oxidant ‣ Improves symptoms of diabetic neuropathy ‣ Improves insulin sensitivity ‣ Acts synergistically with acetyl-L-carnitine as antioxidant ‣ May slow progression of Alzheimer’s ‣ Dietary sources: Spinach, broccoli ‣ Supplemental doses: 300-900 mg/day !62
Supplement Stack for Energy The combination of alpha-lipoid acid and acetyl-l-carnitine helps restore mitochondrial function ‣ Acetyl-l-carnitine: 500 mg twice daily ALCAR transports fatty acids into matrix ALA used as cofactor in synthesis of ATP ‣ Alpha-lipoic acid: 300 mg twice daily ECGC reduces ROS ‣ Green tea extract: 200-400 mg twice daily ‣ Co-Enzyme Q10: 150 mg twice daily Co Q10 assists in ETC ‣ B-complex twice daily Vitamin B Complex (folate, B12) reduce homocysteine and assist in metabolism of proteins, fats, and carbohydrates !63
“A meal without wine is like a day without sunshine” ~W. Goethe !64
Energy Intake v. Energy Expenditure Dynamic balance between energy intake and energy expenditure Output Intake !66
An Overview of Metabolism Glycolysis, the Krebs Cycle and the Electron Transport Chain Glycolysis Krebs Cycle β-oxidation AMP:ATP Electron Transport Chain !67
AMPK is a Nutrient and Energy Sensor AMP protein kinase is activated when ratio of AMP:ATP increases, an indication that energy is low Hypothalamus Food Intake Skeletal Muscle FA Oxidation Glucose Uptake Expression of Glut4 Mitochondria Heart Glucose Uptake Glycolysis Fatty Acid Oxidation AMPK Liver Fatty Acid Synthesis Gluconeogenesis Cholesterol Synthesis Pancreas Insulin Secretion Adipose Tissue Fatty Acid Synthesis Lipolysis !68
Higher Glucose Levels Associated with Lower Memory and Reduced Hippocampal Volume Even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition Kerti, L., Witte, A. V., Winkler, A., Grittner, U., Rujescu, D., & Flöel, A. (2013). Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology, 81(20), 1746-1752. !69
Berberine A plant alkaloid used in TCM to treat diabetes ‣ Stabilizes blood glucose, and reduces triglyceride and LDL-cholesterol levels ‣ Mechanism of action: activates AMPK, thereby stimulating glycolysis and β-oxidation ‣ As effective as metformin in the treatment of type 2 diabetes; potential as a lipid-lowering agent ‣ Dosage: 300-400 mg 3-4x/day !70
Berberine in the Treatment of Type 2 DM A Systemic Review and Meta-Analysis Fasting Plasma Glucose Postprandial Glucose Hemoglobin A1c Dong, H., Wang, N., Zhao, L., & Lu, F. (2012). Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evidence-Based Complementary and Alternative Medicine, 2012 !71
Coffee A methylxanthine, coffee is rich in anti-oxidant and neuroprotective compounds ‣ Enhances cognitive function and reduces formation of β-amyloid ‣ Decaffeinated coffee does NOT provide same level of neuroprotection as caffeinated coffee ‣ Drinking 3 cups coffee/day associated with 4fold slower rate of cognitive decline in study of elderly men over a 10-year period ‣ Black coffee or espresso are best choices !72
High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia High plasma caffeine levels over a 2-4 year observation period were associated with lack of progression of MCI to dementia Cao, C., Loewenstein, D. A., Lin, X., Zhang, C., Wang, L., Duara, R., ... & Arendash, G. W. (2012). High blood caffeine levels in MCI linked to lack of progression to dementia. Journal of Alzheimer's Disease, 30(3), 559-572. !73
Cinnamon Cinnamoman Cassia (Ceylon Cinnamon) stabilizes blood sugar and reduces lipids ‣ Meta-analyses demonstrate that cinnamon lowers fasting plasma glucose, triglycerides, and LDL cholesterol in patients with type 2 diabetes ‣ Anti-inflammatory and anti-cancer effects have been demonstrated in vitro ‣ Reduces formation of β-amyloid in animal models of Alzheimer’s disease ‣ Supplemental doses: 1-6 grams/day ‣ Contains coumarin, which may cause drug-drug interactions !74
Cinnamon Use in Type 2 Diabetes In a meta-analysis of 10 RCTs (n = 543 patients), cinnamon doses of 120 mg/d to 6 g/d for 4 to 18 weeks reduced fasting blood glucose Allen, R. W., Schwartzman, E., Baker, W. L., Coleman, C. I., & Phung, O. J. (2013). Cinnamon use in type 2 diabetes: an updated systematic !75 review and meta-analysis. The Annals of Family Medicine, 11(5), 452-459.
Medium-Chain Triglycerides Saturated fatty acids containing 6-12 carbon atoms ‣ Coconut oil is composed of ~65% MCTs ‣ MCTs are metabolized to ketone bodies, which improve cognition in patients with mild memory impairment ‣ Axona, a medical food product containing MCTs, improves cognitive function in patients with MCI or AD ‣ Dose of MCTs: 5-40 grams/day !76
Ketosis in Alzheimer’s Disease Improvements in cognition correlate with levels of the ketone body β-hydroxybutyrate Henderson, S. T. (2008). Ketone bodies as a therapeutic for Alzheimer's disease. Neurotherapeutics, 5(3), 470-480. !77
Smart Coffee ‣ 1 cup of caffeinated black coffee ‣ 1/2 tablespoon coconut oil ‣ 1/4 teaspoon of cinnamon !78
Caloric Restriction Decrease of 30% to 60% of ad libitum feeding without malnutrition ‣ Increases lifespan across a range of animal species ‣ CR improves memory, cognitive function and overall health in humans ‣ Little or no evidence that CR extends life in humans !80
Caloric Restriction Improves Memory 20% increase in verbal memory after only 3 months of CR n=50 Witte, A. V., Fobker, M., Gellner, R., Knecht, S., & Flöel, A. (2009). Caloric restriction improves memory in elderly humans. Proceedings of the National Academy of Sciences, 106(4), 1255-1260. !81
Intermittent Fasting An alternative to daily CR ‣ Nutrient strategy that alternatives brief periods (<24 hours) of fasting with non-fasting ‣ Improves blood glucose, lipid profiles and cognitive function ‣ CF and IF reduce inflammation, increase BDNF, improve insulin signaling, and inhibit mTOR ‣ These physiologic changes are similar to those seen with aerobic exercise !82
Rapa Nui Easter Island, located in Southeaster Pacific Ocean !83
mTOR and AMPK Highly-conserved metabolic switches Glycolysis ‣ mTOR: anabolism ‣ AMPK: catabolism Krebs !84
mTOR AMPK Protein metabolism Cell Growth and Apoptosis Carbohydrate metabolism Aging Lipid metabolism !85
Aerobic Exercise and Nutraceuticals Mimic The Cellular Effects of CR/IF Mercken, E. M., Carboneau, B. A., Krzysik-Walker, S. M., & de Cabo, R. (2012). Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing research reviews, 11(3), 390-398 !86
Benefits of Resistance and Endurance Training Resistance training protects against sarcopenia and endurance training increases mitochondrial biogenesis !87
Benefits of Aerobic Exercise Regular physical activity builds a better brain ‣ Increases Brain-Derived Neurotrophic Factor ‣ Increases neurogenesis and synaptogenesis ‣ Increases brain volume in older adults ‣ Improves cognitive function ‣ Inoculates the brain against depression ‣ 75% MHR for 30 minutes, 5x/week !88
Aerobic Exercise Training Increases Brain Volume In Aging Adults Blue regions: Gray matter volume was increased for aerobic exercisers Yellow regions: White matter was increased for aerobic exercisers Colcombe SJ, Erickson KI, Scalf PE, et al. Aerobic exercise training increases brain volume in aging humans. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2006;61(11):1166–1170.
Benefits of Resistance Training Resistance training improves physical and cognitive function ‣ RT improves short-term memory in older adults ‣ RT improves insulin sensitivity and protects against the development of type 2 DM ‣ RT is the ONLY intervention that protects against agerelated muscle loss ‣ 75-85% 1 RM weight, 10-15 total reps, once/week !90
Nutrition and Exercise Strategy for Protecting The Aging Brain Resistance Training Resistance Training, once/week Interval Training 2 sessions/week; 20 seconds work; 20 minutes total Intermittent Fasting Fast for 12-18 hours 3x/week Omega-3 Fatty Acids Leisurely Walks in Nature 4 grams of EPA+DHA daily Leisurely outdoor activities 5 days/ week !91
“When diet is wrong, medicine is of no use; When diet is correct, medicine is of no need” ~Ayurvedic Proverb !92

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