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Evidence-Based Nutritional

Strategies For The Aging Brain

Michael Lara, MD

Diplomate, American Board of Psychiatry and Neurology


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Diplomate, American Board of Psychiatry and Neurology

Michael E. Lara, MD

! www.DrMikeLara.com

! Email: [email protected]

! Facebook: www.facebook.com/BrainMD

!

Twitter: @MichaelLaraMD

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$30 BillionEstimated amount of money Americans spenton health supplements in 2012


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Nutrients from healthy food sources or from supplements?

Which Would You Choose?

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Immune Stress and Anti-Inflammatory NutrientsAdiposity, brain volume, and chronic inflammation

Oxidative Stress and Anti-OxidantsMitochondria, reactive oxygen species and polyphenols

Metabolic Stress and Nutrients that Support MetabolismNutrient sensors, elevated blood sugar, and type 3 diabetes

Strategies to Protect The Aging BrainCaloric Restriction and exercise

How The Brain Ages

The insidious effects of chronic physical and psychological stress


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How The Brain Ages



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Strategies to Protect The Aging BrainCaloric Restriction and Exercise

How The Brain Ages



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How The Brain Ages



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How The Brain Ages



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Psychological stress leads to inflammatory, oxidative, and

metabolic stress

Chronic Stress Leads to Premature Aging

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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-Stressedgroup had aged the

equivalent of 9-17

additional years


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Healthy aging, mild cognitive impairment, and Alzheimers

Age-Related Memory Loss vs MCI

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Sleep becomes more fragmented and less restorative as we age

Sleep Changes in the Aging Brain

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Younger Subject

Older Subject


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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 GABAagonist.

! For mild insomnia: 400-800 mg/night of magnesium

aspartate, citrate, lactate or chloride

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Derived from plant Valeriana officinalis, valerian is a common folk

treatment for insomnia.

Valerian

! A GABA agonist, valerian may improve sleep qualityand latency, but a 2010 meta-analysis showed only

subjective improvements in insomnia

! 450 mg of valerian extract (0.8% valerenic acid) onehour before bedtime.

!

Doses larger than 450 mg may cause vivid dreamsand morning grogginess

! Long-term use may cause withdrawal symptoms onabru t cessation

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Melatonin

! Results of 2013 meta-analysis: May reduce

sleep latency, sleep quality, and improveoverall sleep quality but effects are

modest! Strongest evidence is for insomnia

associated with circadian rhythm

disorders (shift work sleep disorder andjet lag)

! Dose range: between 0.3 mg and 3 mg 30minutes before bedtime

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Efficacy of Melatonin in Increasing Total sleep Time

Ferracioli-Oda E, Qawasmi A, Bloch MH (2013) Meta-Analysis: Melatonin for the Treatment of Primary SleepDisorders. PLoS ONE 8(5): e63773. doi:10.1371/journal.pone.0063773http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063773

Mean Difference: 8.48 minutes


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PET imaging of !-amyloid

Anatomical Changes in the Aging Brain

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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.


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Characterized by cortical and hippocampal atrophy, andenlargement of ventricles

Pathologic Changes in the Aging Brain

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Age-associated reductions in receptor binding and signaling

Neurotransmitters and The Aging Brain

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CognitiveFunction

Serotonin Norepinephrine

Dopamine

! Serotonin associated

with sleep, appetite, andmood

! Norepinephrineregulates attention andconcentration

! Dopamine associatedwith pleasure and reward

Neurotransmitters


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Changes in neurotransmitter synthesis, release, binding andreuptake with normal aging

The Synapse

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The major inhibitory and excitatory neurotransmitters

GABA and Glutamate

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Glutamate

GABA

! Major inhibitoryneurotransmitter inCNS

! Target of anti-anxiety and anti-convulsant drugs

! Regulates sleep-wake cycle

GABA

! Major excitatoryneurotransmitter in

CNS

! Regulatessynaptogenesis andneurogenesis

! Excitotoxity

Glutamate


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Synthesized from L-tryptophan and Vitamin B6

Synthesis of

Serotonin

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Synthesized from L-Tyrosine

Synthesis of Dopamine

and Norepinephrine

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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 toAD by reducing homocysteine levels

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Accelerated rate of atrophy in elderly with MCI can be slowed bytreatment 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 24months

! 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

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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: arandomized controlled trial. PloS one, 5(9), e12244.


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Homocysteine levels are correlated with rate of brain atrophy

B-Vitamin Therapy Reduces Brain Atrophy

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Supplementing

with B-vitamins

led to 50%reduction in rates

of brain atrophy insubjects with MCI


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Cerefolin NAC

! Medical food product for thedietary management of MCI or

early AD

! 5.6 grams L-methlyfolate

800 mcg folic acid

! 2 mg methylcobalamin

! 600 mg N-acetylcysteine

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Bacopa

! Brahmi, an ayurvedic herbused to promote learningand memory

! Promotes release ofacetylcholine in prefrontalcortex and increases anti-

oxidant enzymes

! 300-450 mg/day of extractcontaining 55% bacosides

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Ginko Biloba

! Believed to promote learningand memory

!

In some studies GB improvesattention in healthy adults

! 2012 meta-analysis found NOimprovements in attention,

memory or problem solving inhealthy and memory-impaired

populations

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Huperzine-A

! Alkaloid from fir moss

Huperzia serrata

! In some studies, huperzine

is as effective as

prescription medications

used to treat Alzheimers

! Enhances memory inhealthy young adults

! Dose range: 50-200 mcg/

day31


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Supplement Stack for Memory/Learning

! Huperzine-A: 50 mcg

! Vitamin B12: 500 mg/day

! Folic Acid: 800 mcg/day

! N-acetylcysteine: 600 mg/day

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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


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Metabolic Stress and Nutrients that Support Metabolism

Nutrient sensors, elevated blood sugar, and type 3 diabetes


How The Brain Ages



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

Chronic Inflammation Accelerates Aging

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Adipocytes secrete a range of pro-inflammatory hormones

Is Obesity is a Disease of Inflammation?

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

As Adiposity Increases, Brain Volume Decreases

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Interleukin-6

C-Reactive ProteinLeptin

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.


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Essential fatty acids

Omega-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 Westerndiets ratio is closer to 16:1

! For general brain health: 2-4 grams of pharmaceuticalgrade fish oil/day

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Correlations between prevalence of major depression and fishconsumption

Omega-3 Consumption and Depression

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


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

Omega-3 Fatty Acids and Inflammation

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Omega-3s

EPA/DHA

PPAR-! PPAR-"

!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


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Potent anti-inflammatory compounds derived from plant sources

Polyphenols

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

Flavonoids Improve Cognitive Function

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Chocolate

10 g/day

Red Wine

.75 glass/day

Green Tea

4 cups/day


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Curcumin

! Anti-inflammatory via inhibition of cytokineproduction

! Anti-cancer effects via induction of apoptosis

! Anti-depressant effects via MAO inhibition

! Inhibits formation of !-amyloid

! For inflammatory disorders, 2-8 grams curcumin/day

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


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An overview of the neuroprotective effects of curcumin

Curcumin Inhibits !-amyloid Formation

44

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.


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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

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Th M dit Di t


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An anti-inflammatory diet that promotes brain health

The Mediterranean Diet

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!"#$

&'""$(

)*+,$-./ 011(/

23""("/ 4*1+-$

56(3 #78 &"#9**8

5-+6$(/ :"1"$#;,"(


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Higher adherence to the MeDi is associated with a trend for reduced risk ofdeveloping MCI and with reduced risk of MCI conversion to AD

Mediterranean Diet and MCI

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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


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Eat food. Not too much. Mostly plants.

~Michael Pollan


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How The Brain AgesThe insidious effects of chronic physical and psychological stress

Mi h d i


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Organelles within cells that extract energy from nutrients tosynthesize ATP, the cells common energy currency

Mitochondria

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St t f th Mit h d i


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Cellular power plants that convert nutrients to ATP

Structure of the Mitochondrion

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ROS

F ti f ROS i Mit h d i


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Reactive oxygen species are by-products of the electrontransport chain

Formation of ROS in Mitochondria

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Electron Transport Chain

ATP Synthase

ROS

P l h l


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A classs of anti-oxidants that neutralize ROS

Polyphenols

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H lth B fit f R t l


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Reduces inflammatory, metabolic, and oxidative stress

Health Benefits of Resveratrol

! Reduces chronic inflammation via inhibition of COX and

NF-"#

! 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

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R t l C t t i S l t d Wi


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Resveratrol content in a serving of wine ranges from 0.2 to 2.0 mg/LSupplements contain anywhere from 100-500 mg

Resveratrol Content in Selected Wines

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Pinot NoirCalifornia

BeaujoulaisFrance

Cabernet and MerlotChile

ZinfandelCalifornia

Cabernet SavignonCalifornia

5.01 mg/L

3.55 mg/L

1.56 mg/L

1.38 mg/L

0.99 mg/L

Cocoa


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Derived from the seeds of the tree theobroma cacao, drink ofthe 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

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Ch l t C ti d N b l L t


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Per Capita Chocolate consumption correlates with numberof 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).

Bl b i


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Rich in polyphenols, blueberries are potent anti-oxidants

Blueberries

! 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

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Blueberry Smart

Frappe

! 1 cup ice

! 1/2 cup blueberries

! 1/2 cup blueberry juice

! 2 tablespoons psylliumhusk

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Coen me Q10


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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

!-amyloid

! Statin drugs may deplete

levels of CoQ10

! Doses range from

100-300 mg daily

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Acetyl L Carnitine


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Carnitine shuttles fatty acids into mitochondria

Acetyl-L-Carnitine

! Protects endothelium from oxidative damage

! Enhances blood flow

! May slow progression of MCI and Alzheimers

! Dose: 1.5 to 3.0 grams/day

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Alpha Lipoic Acid


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

Alpha Lipoic Acid

! Improves symptoms of diabetic neuropathy

! Improves insulin sensitivity

! Acts synergistically with acetyl-L-carnitine asantioxidant

! May slow progression of Alzheimers

! Dietary sources: Spinach, broccoli

! Supplemental doses: 300-900 mg/day

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Supplement Stack for Energy


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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

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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 andassist in metabolism of proteins, fats, and carbohydrates


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~W. Goethe

A meal without wine is

like a day without

sunshine

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Energy Intake v Energy Expenditure


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Dynamic balance between energy intake and energy expenditure

Energy Intake v. Energy Expenditure

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Intake

Output

An Overview of Metabolism


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Glycolysis, the Krebs Cycle and the Electron Transport Chain

An Overview of Metabolism

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AMP:ATP

Glycolysis

Krebs

Cycle !-oxidation

Electron Transport Chain

AMPK is a Nutrient and Energy Sensor


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

AMPK is a Nutrient and Energy Sensor

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AMPK

Hypothalamus

Food Intake

Skeletal Muscle

FA OxidationGlucose Uptake

Expression of Glut4Mitochondria

Adipose Tissue

Fatty Acid SynthesisLipolysis

Pancreas

Insulin Secretion

LiverFatty Acid Synthesis

GluconeogenesisCholesterol Synthesis

Heart

Glucose UptakeGlycolysis

Fatty Acid Oxidation

Higher Glucose Levels Associated with Lower


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Even in the absence of manifest type 2 diabetes mellitus or impaired glucosetolerance, chronically higher blood glucose levels exert a negative influence oncognition

Higher Glucose Levels Associated with Lower

Memory and Reduced Hippocampal Volume

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Kerti, L., Witte, A. V., Winkler, A., Grittner, U., Rujescu, D., & Flel, A. (2013). Higher glucose levels associated with lower

memory and reduced hippocampal microstructure. Neurology, 81(20), 1746-1752.

Berberine


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A plant alkaloid used in TCM to treat diabetes

Berberine

! Stabilizes blood glucose, and reduces triglyceride and

LDL-cholesterol levels

! Mechanism of action: activates AMPK, therebystimulating glycolysis and !-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

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Berberine in the Treatment of Type 2 DM


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A Systemic Review and Meta-Analysis

Berberine in the Treatment of Type 2 DM

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Dong, H., Wang, N., Zhao, L., & Lu, F. (2012). Berberine in the treatment of type 2 diabetes mellitus: a systemic review andmeta-analysis. Evidence-Based Complementary and Alternative Medicine, 2012

Fasting Plasma Glucose

Postprandial Glucose

Hemoglobin A1c

Coffee


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A methylxanthine, coffee is rich in anti-oxidant andneuroprotective compounds

Coffee

! Enhances cognitive function and reduces

formation of !-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 ofelderly men over a 10-year period

! Black coffee or espresso are best choices

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High Blood Caffeine Levels in MCI Linked


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

High Blood Caffeine Levels in MCI Linked

to Lack of Progression to Dementia

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Cao, C., Loewenstein, D. A., Lin, X., Zhang, C., Wang, L., Duara, R., ... & Arendash, G. W. (2012). High blood caffeine levels inMCI linked to lack of progression to dementia. Journal of Alzheimer's Disease, 30(3), 559-572.

Cinnamon


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Cinnamoman Cassia(Ceylon Cinnamon) stabilizes blood sugar andreduces lipids

Cinnamon

! Meta-analyses demonstrate that cinnamon lowers fastingplasma glucose, triglycerides, and LDL cholesterol in

patients with type 2 diabetes

! Anti-inflammatory and anti-cancer effects have beendemonstrated in vitro

! Reduces formation of !-amyloid in animal models ofAlzheimers disease

! Supplemental doses: 1-6 grams/day

! Contains coumarin, which may cause drug-drug

interactions74

Cinnamon Use in Type 2 Diabetes


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In a meta-analysis of 10 RCTs (n = 543 patients), cinnamon doses of120 mg/d to 6 g/d for 4 to 18 weeks reduced fasting blood glucose

Cinnamon Use in Type 2 Diabetes

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Allen, 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.

Medium-Chain Triglycerides


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Saturated fatty acids containing 6-12 carbon atoms

Medium-Chain Triglycerides

! Coconut oil is composed of ~65% MCTs

! MCTs are metabolized to ketone bodies, which

improve cognition in patients with mild memoryimpairment

! Axona, a medical food product containing MCTs,

improves cognitive function in patients with MCIor AD

! Dose of MCTs: 5-40 grams/day

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Ketosis in Alzheimers Disease


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Improvements in cognition correlate with levels of the ketonebody !-hydroxybutyrate

Ketosis in Alzheimer s Disease

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


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Smart Coffee

! 1 cup of caffeinatedblack coffee

! 1/2 tablespoon

coconut oil

!

1/4 teaspoon ofcinnamon

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Caloric Restriction


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Decrease of 30% to 60% of ad libitum feeding withoutmalnutrition

Caloric Restriction

! Increases lifespan across a range of animal

species

! CR improves memory, cognitive function andoverall health in humans

! Little or no evidence that CR extends life in

humans

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Caloric Restriction Improves Memory


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20% increase in verbal memory after only 3 months of CR

Caloric Restriction Improves Memory

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Witte, A. V., Fobker, M., Gellner, R., Knecht, S., & Flel, A. (2009). Caloric restriction improves memory in

elderly humans. Proceedings of the National Academy of Sciences, 106(4), 1255-1260.

n=50

Intermittent Fasting


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An alternative to daily CR

Intermittent Fasting

! Nutrient strategy that alternatives brief periods (


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Easter Island, located in Southeaster Pacific Ocean

Rapa Nui

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mTOR and AMPK


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Highly-conservedmetabolic switches

mTOR and AMPK

! mTOR: anabolism

! AMPK: catabolism

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Glycolysis

Krebs


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Carbohydrate metabolism

Lipid metabolism

Proteinmetabolism

Cell Growth andApoptosis

Aging

AMPKmTOR

Aerobic Exercise and Nutraceuticals


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Aerobic Exercise and Nutraceuticals

Mimic The Cellular Effects of CR/IF

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Mercken, E. M., Carboneau, B. A., Krzysik-Walker, S. M., & de Cabo, R. (2012). Of mice and men: the benefits ofcaloric restriction, exercise, and mimetics. Ageing research reviews, 11(3), 390-398

Benefits of Resistance and Endurance Training


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Resistance training protects against sarcopenia and endurancetraining increases mitochondrial biogenesis

Benefits of Resistance and Endurance Training

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Benefits of Aerobic Exercise


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Regular physical activity builds a better brain

Benefits 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

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Aerobic Exercise Training Increases


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Aerobic Exercise Training IncreasesBrain Volume In Aging Adults

Blue regions: Gray matter volume was increased for aerobic exercisersYellow 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):11661170.

Benefits of Resistance Training


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Resistance training improves physical and cognitive function

Benefits 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

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Nutrition and Exercise Strategy for Protecting The


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Leisurely Walks in Nature

Intermittent

Fasting

Omega-3 Fatty

Acids

Interval

Training

Aging Brain

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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


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~Ayurvedic Proverb

When diet is wrong, medicine is of no use;

When diet is correct, medicine is of no need

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