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

Diplomate, American Board of Psychiatry and NeurologyMichael E. Lara, MD

‣ www.DrMikeLara.com ‣ Email: [email protected] ‣ Facebook: www.facebook.com/BrainMD ‣ Twitter: @MichaelLaraMD

!2

$30 Billion Estimated amount of money Americans spent on health supplements in 2012

Nutrients from healthy food sources or from supplements? Which Would You Choose?

!4

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

How The Brain Ages The insidious effects of chronic physical and psychological stress 1

2

3

4

5






2

3

4

5




Strategies to Protect The Aging Brain Caloric Restriction and Exercise


2

3

4

5






2

3

4

5






2

3

4

5

Psychological stress leads to inflammatory, oxidative, and metabolic stress

Chronic Stress Leads to Premature Aging

!10

High-stressed caregivers age prematurely Telomere Length and Telomerase Activity

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.

High-Stressed group had aged the equivalent of 9-17 additional years

Healthy aging, mild cognitive impairment, and Alzheimer’sAge-Related Memory Loss vs MCI

!12

Sleep becomes more fragmented and less restorative as we ageSleep Changes in the Aging Brain

!13

Younger Subject

Older Subject

Nearly 50% of older adults have insomnia, and most do not meet RDA for magnesium intake

Magnesium

‣ 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

Derived from plant Valeriana officinalis, valerian is a common folk treatment for insomnia.

Valerian

‣ 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

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

Mean Difference: 8.48 minutes

PET imaging of β-amyloidAnatomical Changes in the Aging Brain

!18

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.

Characterized by cortical and hippocampal atrophy, and enlargement of ventricles

Pathologic Changes in the Aging Brain

!19

Age-associated reductions in receptor binding and signalingNeurotransmitters and The Aging Brain

!20

Cognitive Function

Serotonin Norepinephrine

Dopamine

‣ Serotonin associated with sleep, appetite, and mood

‣ Norepinephrine regulates attention and concentration

‣ Dopamine associated with pleasure and reward

Neurotransmitters

Changes in neurotransmitter synthesis, release, binding and reuptake with normal aging

The Synapse

!21

The major inhibitory and excitatory neurotransmittersGABA and Glutamate

!22

Glutamate

GABA

‣ Major inhibitory neurotransmitter in CNS

‣ Target of anti-anxiety and anti-convulsant drugs

‣ Regulates sleep-wake cycle

GABA ‣ Major excitatory

neurotransmitter in CNS

‣ Regulates synaptogenesis and neurogenesis

‣ Excitotoxity

Glutamate

Synthesized from L-tryptophan and Vitamin B6

Synthesis of Serotonin

!23

Synthesized from L-Tyrosine

Synthesis of Dopamine and Norepinephrine

!24

A biomarker linked to heart disease, stroke, and cognitive decline

Homocysteine

‣ 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

Accelerated rate of atrophy in elderly with MCI can be slowed by treatment with homocysteine-lowering B vitamins

B-Vitamins Lower Homocysteine

‣ 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

!26

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.

Homocysteine levels are correlated with rate of brain atrophy

B-Vitamin Therapy Reduces Brain Atrophy

!27

Supplementing with B-vitamins

led to 50% reduction in rates of brain atrophy in subjects with MCI

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 anti-oxidant 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

!33

“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






2

3

4

5

Chronic inflammation is associated with cancer, diabetes, heart disease, obesity, depression and dementia

Chronic Inflammation Accelerates Aging

!35

Adipocytes secrete a range of pro-inflammatory hormonesIs Obesity is a Disease of Inflammation?

!36

BMI is inversely correlated with total brain volume in healthy middle-aged adults

As Adiposity Increases, Brain Volume Decreases

!37

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.

Essential fatty acidsOmega-3 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

Correlations between prevalence of major depression and fish consumption

Omega-3 Consumption and Depression

!39Hibbeln, J. R. (1998). Fish consumption and major depression. Lancet, 351(9110), 1213.

Omega-3s reduce inflammation, improve triglyceride levels, and stabilize blood glucose

Omega-3 Fatty Acids and Inflammation

!40

Omega-3sEPA/DHA

PPAR-α PPAR-γ

↓Triglyceride and VLDL secretion ↑ Fatty Acid Oxidation

Improved Blood Lipid Profile

Improved Insulin Sensitivity

↑ Triglyceride Clearance Improved Glucose Control

↓ Risk of CVD

Arachidonic Acid

Pro-inflammatory Prostaglandins

COX-2

Potent anti-inflammatory compounds derived from plant sourcesPolyphenols

!41

Intake of chocolate, red wine and green tea is associated with better cognitive function in healthy adults

Flavonoids Improve Cognitive Function

!42

Chocolate 10 g/day

Red Wine .75 glass/day

Green Tea 4 cups/day

Curcumin

‣ 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

Derived from turmeric, a member of the ginger family, curcurmin has medicinal properties.

An overview of the neuroprotective effects of curcuminCurcumin Inhibits β-amyloid Formation

!44Lee, 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.

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

An anti-inflammatory diet that promotes brain health

The Mediterranean Diet

!46

Meat%%Sweets%

Poultry,%Eggs,%Cheese,%Yogurt%

Fish%and%Seafood%

Fruits,%Vegetables%Grains,%Beans,%Nuts,%Olive%Oil%

Physical%AcCvity;%Enjoy%meals%with%others%

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

Mediterranean Diet and MCI

!47Scarmeas, 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

!48

“Eat food. Not too much. Mostly plants.” !

~Michael Pollan






2

3

4

5

Organelles within cells that extract energy from nutrients to synthesize ATP, the cell’s common energy currency

Mitochondria

!50

Cellular power plants that convert nutrients to ATPStructure of the Mitochondrion

!51

ROS

Reactive oxygen species are by-products of the electron transport chain

Formation of ROS in Mitochondria

!52

Electron Transport Chain

ATP Synthase

ROS

A classs of anti-oxidants that neutralize ROSPolyphenols

!53

Reduces inflammatory, metabolic, and oxidative stressHealth Benefits of Resveratrol

‣ Reduces chronic inflammation via inhibition of COX and NF-κΒ

‣ Reduces oxidative stress via de novo synthesis of anti-oxidant 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 a serving of wine ranges from 0.2 to 2.0 mg/L Supplements contain anywhere from 100-500 mg

Resveratrol Content in Selected Wines

!55

Pinot Noir—California !Beaujoulais—France !Cabernet and Merlot—Chile !Zinfandel—California !Cabernet Savignon—California !!

5.01 mg/L !3.55 mg/L !1.56 mg/L !1.38 mg/L !0.99 mg/L !!

Derived from the seeds of the tree theobroma cacao, “drink of the gods”, cocoa is rich in anti-oxidants

Cocoa

‣ 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

Per Capita Chocolate consumption correlates with number of Nobel Laureates per country

Chocolate Consumption and Nobel Laureates

!57Messerli, F. H., "Chocolate consumption, cognitive function, and Nobel laureates" N Engl J Med 367 (16), 1562 (2012).

Rich in polyphenols, blueberries are potent anti-oxidantsBlueberries

‣ 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

Ubiquinone, an electron carrier in the electron transport chain, is depleted with normal aging

Coenzyme Q10

‣ 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

Carnitine shuttles fatty acids into mitochondriaAcetyl-L-Carnitine

‣ 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

A mitochondrial fatty acid used as cofactor in synthesis of ATP and a potent anti-oxidant

Alpha Lipoic Acid

‣ 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

The combination of alpha-lipoid acid and acetyl-l-carnitine helps restore mitochondrial function

Supplement Stack for Energy

‣ Acetyl-l-carnitine: 500 mg twice daily

‣ Alpha-lipoic acid: 300 mg twice daily

‣ Green tea extract: 200-400 mg twice daily

‣ Co-Enzyme Q10: 150 mg twice daily

‣ B-complex twice daily

!63

ALCAR transports fatty acids into matrix

ALA used as cofactor in synthesis of ATP

ECGC reduces ROS

Co Q10 assists in ETC

Vitamin B Complex (folate, B12) reduce homocysteine and assist in metabolism of proteins, fats, and carbohydrates

~W. Goethe

“A meal without wine is like a day without

sunshine”

!64






2

3

4

5

Dynamic balance between energy intake and energy expenditureEnergy Intake v. Energy Expenditure

!66

Intake

Output

Glycolysis, the Krebs Cycle and the Electron Transport ChainAn Overview of Metabolism

!67

AMP:ATP

Glycolysis

Krebs Cycle β-oxidation

Electron Transport Chain

AMP protein kinase is activated when ratio of AMP:ATP increases, an indication that energy is low

AMPK is a Nutrient and Energy Sensor

!68

AMPK

HypothalamusFood Intake

Skeletal MuscleFA Oxidation

Glucose UptakeExpression of Glut4

Mitochondria

Adipose TissueFatty Acid Synthesis

Lipolysis

PancreasInsulin Secretion

LiverFatty Acid Synthesis

GluconeogenesisCholesterol Synthesis

HeartGlucose Uptake

GlycolysisFatty Acid Oxidation

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

Higher Glucose Levels Associated with Lower Memory and Reduced Hippocampal Volume

!69

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.

A plant alkaloid used in TCM to treat diabetesBerberine

‣ 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

A Systemic Review and Meta-AnalysisBerberine in the Treatment of Type 2 DM

!71

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

Fasting Plasma Glucose

Postprandial Glucose

Hemoglobin A1c

A methylxanthine, coffee is rich in anti-oxidant and neuroprotective compounds

Coffee

‣ 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 4-fold slower rate of cognitive decline in study of elderly men over a 10-year period

‣ Black coffee or espresso are best choices

!72

High plasma caffeine levels over a 2-4 year observation period were associated with lack of progression of MCI to dementia

High Blood Caffeine Levels in MCI Linked to Lack of Progression to Dementia

!73

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.

Cinnamoman Cassia (Ceylon Cinnamon) stabilizes blood sugar and reduces lipids

Cinnamon

‣ 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

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

Cinnamon Use in Type 2 Diabetes

!75Allen, R. W., Schwartzman, E., Baker, W. L., Coleman, C. I., & Phung, O. J. (2013). Cinnamon use in type 2 diabetes: an updated systematic review and meta-analysis. The Annals of Family Medicine, 11(5), 452-459.

Saturated fatty acids containing 6-12 carbon atomsMedium-Chain Triglycerides

‣ 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

Improvements in cognition correlate with levels of the ketone body β-hydroxybutyrate

Ketosis in Alzheimer’s Disease

!77Henderson, S. T. (2008). Ketone bodies as a therapeutic for Alzheimer's disease. Neurotherapeutics, 5(3), 470-480.

Smart Coffee

‣ 1 cup of caffeinated black coffee

‣ 1/2 tablespoon coconut oil

‣ 1/4 teaspoon of cinnamon

!78






2

3

4

5

Decrease of 30% to 60% of ad libitum feeding without malnutrition

Caloric Restriction

‣ 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

20% increase in verbal memory after only 3 months of CRCaloric Restriction Improves Memory

!81

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.

n=50

An alternative to daily CRIntermittent Fasting

‣ 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

Easter Island, located in Southeaster Pacific OceanRapa Nui

!83

Highly-conserved metabolic switches

mTOR and AMPK

‣ mTOR: anabolism ‣ AMPK: catabolism

!84

Glycolysis

Krebs

!85

Carbohydrate metabolism

Lipid metabolism

Protein metabolism

Cell Growth and Apoptosis

Aging

AMPKmTOR

Aerobic Exercise and Nutraceuticals Mimic The Cellular Effects of CR/IF

!86

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

Resistance training protects against sarcopenia and endurance training increases mitochondrial biogenesis

Benefits of Resistance and Endurance Training

!87

Regular physical activity builds a better brainBenefits of Aerobic Exercise

‣ 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.

Resistance training improves physical and cognitive functionBenefits of Resistance Training

‣ 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 age-

related muscle loss ‣ 75-85% 1 RM weight, 10-15 total reps, once/week

!90

Leisurely Walks in Nature

Intermittent Fasting

Omega-3 Fatty Acids

Interval Training

Nutrition and Exercise Strategy for Protecting The Aging Brain

!91

Resistance Training

Leisurely outdoor activities 5 days/week

4 grams of EPA+DHA daily

Fast for 12-18 hours 3x/week

2 sessions/week; 20 seconds work; 20 minutes total

Resistance Training, once/week

~Ayurvedic Proverb

“When diet is wrong, medicine is of no use; When diet is correct, medicine is of no need”

!92

Health & Medicine

Evidence-Based Nutritional Strategies for the Aging Brain