Cures in the Cupboard: Foods that Fight Disease

Sources of Vitamin A

Carrots SweetpotatoesPumpkin Tomatoes

Red Sweet Pepper SpinachCollards Turnip Greens

Kale BeetGreen Leaf Lettuce Romaine Lettuce

Cantaloupe MangoRed & Pink Grapefruit Apricots

Sources of Vitamin C

Citrus Fruits Kiwi FruitStrawberries Guava

Papaya CantaloupeBroccoli PeppersTomatoes Spinach

Brussels Sprouts PotatoesLeafy Greens Turnip Greens

Cabbage

Sources of Potassium

Baked White or Sweetpotatoes Cooked GreensWinter (orange) Squash Bananas

Plantains Dried FruitsOranges & Orange Juice Cantaloupe

Tomatoes SpinachHoneydew Melons Cooked Dry Beans

Soybeans Tomato ProductsBeet Greens

Avg. Fruit & Vegetable ConsumptionNationwide, 1996 vs. 2002

5+ times a day3 or 4 times a day

1 or 2 times a dayNever or <1 a day

50

40

30

20

10

0

Percent (Median)

19962002

Garlic: Health Benefits• Antibiotic/antifungal effects

• Antiseptic properties useful in fighting infections and dysentery-causing amoebas

• Antioxidant effects, protecting cells from free-radical damage and cancer

• Cholesterol reduction, lowering LDL and increasing HDL

• Natural anticoagulant properties, preventing blood clots and strokes

• Anti-hypertensive effects, reducing blood pressure.

Powerful Antioxidants

Orange JuiceGreen Tea

Cranberry Juice CocktailBlueberry Juice

Red WinePomegranate Juice

7

6

5

4

3

2

1

0

Polyphenols (mM)

Free Radicals Neutralized

Green TeaOrange Juice

Cranberry Juice CocktailBlueberry Juice

Red WinePomegranate Juice

80

60

40

20

0

Percent

Fruit Nutritional Information

Relative to White, non-Hispanic households,Asian and Hispanic ones purchase more variety, Black

households buy fewer types of vegetables, but spread out their purchases more evenly across what they do buy

Demographics Are Key to Variety

Race & Ethnicity Are ImportantAs measured by the Simpson index, Asian and Hispanic

households spread out their vegetable purchases 23 percent and 6.5 percent more evenly than White, non-Hispanic

households do.

Best Sources Of Food AntioxidantsAs Measured By Total Antioxidant Capacity Per Serving Size

Rank Food Item Serving Size

1 Small Red Bean (Dried) Half cup

2 Wild Blueberry 1 cup

3 Red Kidney Bean (Dried) Half cup

4 Pinto Bean Half cup

5 Blueberry (Cultivated)

1 cup

6 Cranberry 1 cup (whole)

7 Artichoke (Cooked) 1 cup (hearts)

8 Blackberry 1 cup9 Prune Half cup

10 Raspberry 1 cup

Fruit & Vegetable ConsumptionPer Capita Percent Change, 2000 to 2020

Citrus Apples Grapes Other Fruit

-8.6%

Fried Potatoes & Chips

Other Potatoes

Tomatoes Lettuce Other Vegetables

7.4% 7.8%

5.1%

7.0%

1.3%

5.1%3.6%

-3.0%

Effects of Rising IncomeOn Per Capita Fruit & Vegetable Consumption

Commodities

Total Income Effect

Direct Income Effect Eating Out Knowledge

Fruit Citrus 1.87 1.85 -1.77 1.83 Apples 1.93 1.95 -1.81 1.81 Grapes 1.23 1.21 -1.42 1.48 Other Fruit 1.48 1.36 -1.22 1.36

Vegetables Fried Potatoes and Chips 0.19 -0.47 1.75 -1.08 Other Potatoes -1.86 -2.53 0.49 0.19 Tomatoes 0.86 0.76 -0.01 0.11 Lettuce 2.12 1.42 0.18 0.5 Other Vegetables 0.65 0.63 -0.46 0.47

Indirect Income Effects

Percent

Carotenoids

Alpha-Carotene Carrots Neutralize Free Radicals

Beta-Carotene Fruits, Vegetables

Neutralize Free Radicals

LuteinGreen

Vegetables

Reduced Risk Of Macular

Degeneration

LycopeneTomato Products

(Ketchup, Sauces)

Reduced Risk Of Prostate Cancer

Examples of Functional Components

Fatty Acids

Omega-3 Fatty Acids-DHA/EPA

Tuna And Other Fish Oils

Reduced Risk Of Cardiovascular

Disease And Improved Mental, Visual Functions

Conjugated Linoleic Acid CLA

Cheese, Meat Products

May Improve Body Composition, May Decrease Risk Of Certain Cancers

Examples of Functional Components

Flavonoids

Anthocyanidins Fruits

Catechins Tea

Examples of Functional Components

Neutralize Free Radicals, May Reduce

Risk Of Cancer

Prebiotics/Probiotics

Fructo-Oligosaccharides

(FOS)

Jerusalem Artichokes,

Shallots, Onion Powder,

Lactobacilius Yogurt, Other Dairy

Examples of Functional Components

May Improve Quality Of Intestinal Microflora

The Power of Diet & Lifestyle Changes

Dean Ornish, M.D.President, Preventive Medicine Research Institute

Clinical Professor of Medicine, UCSFMilken Institute Global Conference

April 18, 2005

Your body has a remarkable capacity to begin healing itself if you give it a chance to do so.

Optimal Lifestyle Program

• Diet (low-fat, whole foods, plant based)• Stress management training • Moderate exercise• Smoking cessation• Psychosocial support groups• Supplements

High fat, Low-fat, Meat-based Plant-based

• High in cholesterol• High in saturated fats• High in oxidants• Low in antioxidants• Inflammatory• Low in fiber

• No cholesterol• Low in saturated fats• Low in oxidants• High in antioxidants• Prevents

inflammation• High in fiber

Omega-3 Fatty Acids (“Good Fats”)

• May reduce sudden cardiac death by 50-80% or more

• May reduce risk of prostate cancer, breast cancer, and colon cancer

• Only 3 grams/day provide protective benefits

An Optimal Diet is—• Low in refined (“bad”) carbohydrates• High in unrefined (“good”) carbohydrates• Low in meat-based proteins• High in plant-based proteins• Low in saturated fats and trans fats• 3 grams/day of omega-3 fatty acids

To the degree you move in this direction on the food spectrum, you lose weight, feel better, and gain health.

Can Lifestyle Changes Reverse Coronary

Heart Disease?

201 Thallium Myocardial ScintigraphyCase D

May 15, 1978 June 15, 1978

Changes in Quantitative Coronary Arteriography

5 y (P=.001)1 y ( P=.02)Baseline (n.s.)

52

50

48

46

44

42

40

38

36

Percent Diameter Stenosis

ControlTreatment

Conclusions: More regression of coronary atherosclerosis occurred after 5 years than after 1 year in the experimental group. In contrast, in the control group, coronary atherosclerosis continued to progress and more than twice as many cardiac events occurred.

JAMA. 1998;280:2001-2007

Adherence and Change in Coronary Atherosclerosis After 5 years

High (>88%)Intermediate (56-88%)Low (<56%)

2

0

-2

-4

-6

-8

Percent

Control

1% Experimental

55% 45%

99%

100 80 60 40 20 20 40 60Better or No Change, % Worse, %

P=.03

There was a 40% reduction in LDL-cholesterol in the Lifestyle Heart Trial after one year without drugs.

Ornish D et al. JAMA. 1998;280:2001-2007.

$20 billion were spent last year on statin drugs, most of which could be avoided by

making comprehensive lifestyle changes instead.

The Multicenter Lifestyle

Demonstration Projects

Medical EffectivenessDemonstration Projects

• Three demonstration projects• More than 2,000 patients• Greater changes in diet and lifestyle,

larger improvements in risk factors and quality of life, and bigger cost reductions than have ever before been reported in an ambulatory group of patients.

Implementation of Demonstration Projects

A physician supervises and directs the behavioral intervention, assisted by a team of health professionals:– Nurse case manager– Registered dietitian– Clinical psychologist (support groups)– Exercise physiologist– Stress management instructor– Program director

1. The Multicenter Lifestyle Demonstration Project

•Almost 80% of 333 patients who were eligible for bypass surgery or angioplasty were able to safely avoid it for at least three years with comparable safety & benefits compared to a matched control group.•Ornish D. Avoiding revascularization with lifestyle changes: The Multicenter Lifestyle Demonstration Project. American Journal of Cardiology. 1998;82:72T-76T. •Koertge J, Weidner G, Elliott-Eller M, et al. Improvement in medical risk factors and quality of life in women and men with coronary artery disease in the Multicenter Lifestyle Demonstration Project. American Journal of Cardiology. 2003;91:1316-1322.

1. The Multicenter Lifestyle Demonstration Project

• Mutual of Omaha calculated saving an average of $29,529 per patient.

•Ornish D. Avoiding revascularization with lifestyle changes: The Multicenter Lifestyle Demonstration Project. American Journal of Cardiology. 1998;82:72T-76T. •Koertge J, Weidner G, Elliott-Eller M, et al. Improvement in medical risk factors and quality of life in women and men with coronary artery disease in the Multicenter Lifestyle Demonstration Project. American Journal of Cardiology. 2003;91:1316-1322.

2. The Highmark Blue Cross Blue Shield Demonstration Project: Cost Comparisons After 3 Years

Experimental Group (CAD) vs. Matched Cohort (CAD) Members Year by Year

Experimental Group (CAD) (N=75) Baseline vs. 3 year average = 8.7% decrease in costs

Matched Cohort Members (CAD) (N=75) Baseline vs. 3 year average = 47.2% increase in costs

Year 3Year 2Year 1Baseline

9000

8000

7000

6000

5000

4000

US$

Ornish Members CADMatched Cohort Members

3. The Medicare Lifestyle Demonstration Project (MLMPD)

•The risks of bypass surgery & angioplasty increase with age but the benefits of comprehensive lifestyle changes are as great in older patients as in younger ones

•Therefore, comprehensive lifestyle changes are especially beneficial in Medicare patients

WeightAll Participants (N = 2,108)

1 Year12 WeeksBaseline

200

195

190

185

180

175

LBS

Body Mass IndexAll Participants (N = 2,108)

1 Year12 WeeksBaseline

32

31

30

29

28

27

BMI

AnginaAll Participants (N = 2,108)

1 Year12 WeeksBaseline

30

25

20

15

10

5

% of Participants with Any Angina in Preceding 30 Days

Functional Capacity (METs)All Participants (N = 2,108)

1 Year12 WeeksBaseline

11.0

10.5

10.0

9.5

9.0

8.5

8.0

7.5

METs

SF-36 General Health/Quality of LifeAll Participants (N = 1,908)

1 Year12 WeeksBaseline

75

70

65

60

55

1 Year12 WeeksBaseline

150

145

140

135

130

125

mm HG

Hypertensives – Systolic BP

N at 1 year is not comparable to baseline because many patients have not yet finished 1 year of intervention

All p<.001

1 Year12 WeeksBaseline

86

84

82

80

78

76

74

mm HG

Hypertensives – Diastolic BP

N at 1 year is not comparable to baseline because many patients have not yet finished 1 year of intervention

All p<.001

Diabetics - HbA1c

All p<.001Data to be presented at APS, 2005

Data for patients who have reached 1 year of testing

1 Year12 WeeksBaseline

7.6

7.4

7.2

7.0

6.8

6.6

6.4

Percent

Summary of These Three Demonstration Projects:

• “Medicare coverage of this program would reduce Medicare expenditures even under a set of more pessimistic assumptions then I felt were appropriate.”

--Roland E. (“Guy”) King Chief Actuary, Medicare, 1978-1994

Can Lifestyle Changes Reverse the Progression of

Prostate Cancer?

• Principal Investigator: • Dean Ornish, M.D.Clinical Professor of Medicine, UCSF• Co-Principal Investigators:• Peter Carroll, M.D.Chairman & Professor, Dept. of Urology, UCSF • William Fair, M.D.Chairman & Professor, Dept. of Urologic SurgeryMemorial Sloan-Kettering Cancer Center

Patient Selection Criteria

• 90 men with biopsy-proven prostate cancer, PSA 4-10, Gleason <7

• All patients chose to do watchful waiting for reasons unrelated to this study

• Randomly assigned to comprehensive lifestyle changes or usual care

None of the experimental group patients but six

control group patients had conventional treatment

during the first year.

Changes in PSA

P = 0.002

12 MonthsBaseline

6.80

6.60

6.40

6.20

6.00

5.80

Control (n=41)Experimental (n=43)

Degree of Lifestyle Change and Changes in PSA

P= 0.001

High (>88%)Medium (48-88%)Low (<48%)

8

6

4

2

0

-2

-4

-6

Percent

Change in Prostate Tumor Growth

t = -6.9, P = .000

-9%

-70%

-70%

-55%

-40%

-25%

-10%

%FBS

ControlExperimental

Degree of Lifestyle Change and Inhibition of LNCaP Tumor Growth

0

-20

-40

-60

-80Baseline-12m change in LNCAP cell growth

Dietary Adherence and Changes in C-Reactive Protein

High (>97%)Medium (81-97%)Low (<81%)

0.00

-0.10

-0.20

-0.30

-0.40

Baseline-12m change in (log)CRP

1 year laterPSA - 4.5 ng/ml

BaselinePSA - 6.4 ng/ml

Can Pomegranate Juice Affect the Progression

of Coronary Heart Disease?

Blow Flow to the Heart

+1.18

-0.70

-0.80

0.20

1.20

%FBS

ExperimentalControl

P < 0.05

Threat of Litigation & Legislation

Diet and Diabesity

Francine Ratner Kaufman, M.D.Professor of Pediatrics

The Keck School of Medicine of USCHead, Center for Diabetes and Endocrinology

Childrens Hospital Los Angeles

Geneticsusceptibility Environmentalfactors

AtherosclerosisHyperglycemiaHypertension

RetinopathyNephropathyNeuropathy

BlindnessRenal failureCHDAmputation

Onset ofdiabetes

Complications

Disability

DeathOngoing hyperglycemiaPRE

Obesity Insulin resistance

Risk forDisease

MetabolicSyndrome

Natural History of Diabesity

Male Teens12-17

Female Teens12-17

Percentage of Overweight Children Youth3-4 Fold Increase in 30 Years

Perc

enta

ge

Boys 6-11 Girls 6-110

2

4

6

8

10

12

14

16

1963–70 1971–74 1976–80 1988–94 1999–2000

Health and Healthy Weight

Diabetes Trends Among Adults in the USBRFSS 1990, 1995 and 2001

Burden of Diabetes in USA

• 18.2 Million Americans Have Diabetes • 5.2 Million Unaware of Diagnosis• 40 Million Americans Have Prediabetes• 239,000 Diabetes-Related Deaths/Year• 2-to-6-Fold More Likely to CVD• 75% of Diabetes Deaths Associated With

CVD • Cost $132 Billion/2002

The U.S. Diabetes Prevention ProgramIntensive Lifestyle Intervention: Goals

• > 7% loss of body weight and maintenance of weight loss– Dietary fat goal -- <25% of calories from fat– Calorie intake goal -- 1200-1800 kcal/day

• > 150 minutes per week of physical activity

0 1 2 3 40

10

20

30

40PlaceboPlaceboLifestyleLifestyle

Years on TrialYears on Trial

Cum

ulat

ive

Inci

denc

e (%

)C

umul

ativ

e In

cide

nce

(%)

U.S. Diabetes Prevention ProgramEffect of Intensive Lifestyle on Diabetes Rates

58% Relative Risk Reduction

Finnish Diabetes Prevention StudyEffect of Intensive Lifestyle on Diabetes Rates

0.5

0.6

0.7

0.8

0.9

0 1 2 3 4 5 6

Years on Trial

Intensive LifestyleControl

Frac

tion

With

out D

iabe

tes

58% Relative Risk

Reduction

US National Weight Control Registry

• Lost and maintained minimum weight loss of 13.5 kg for 5 years

• 1380 calories 24% from fat = standard carbohydrate and low fat diet

• Very active expend - 400 kcal/d in PA• Physical activity predicted weight

maintenance

IOM, ADA and ADietA Nutrition Recommendations

• Carbohydrate – 45-65%

• Fat – 20-35%

• Protein – 0.8 g/kg body weight/d– 10-35%

Carbohydrate Recommendations from ADA for Diabetes

• Amount (grams) of carbohydrate and type of carbohydrate influence blood glucose levels

• Monitoring total grams of carbohydrate a key strategy

• Use of glycemic index/glycemic load provides additional benefit – 37% increased risk of type 2 diabetes for women

with highest dietary glycemic index• Low carbohydrate diets (restricting total

carbohydrate to <130 g/day) not recommended

Low Carbohydrate• Low carbohydrate diets may enable short term weight

loss• Poor dietary compliance over long term• Foster, et al NEJM, 2003:

– < 10% carbohydrate, 50-60 fat, 30-35 protein– Greater weight loss at 6 months - very low carb diet

vs low fat – No difference at 1 year between groups

• Bravata, et al JAMA, 2003:– Meta analysis of low carbohydrate diet <60 g – Weight loss associated with reduced calories and

longer duration of diet rather than carbohydrate intake

– Of 2681 who lost >13 kg for 1 year, less than 1% maintained weight loss

• CARDIA Study – Fasting Insulin and 2-Hour glucose levels inversely

related to amount of fiber • Reduces Risk of Diabetes

– RR for >8.1 g/day versus <3.2 g/d was 0.70, 95% CI: 0.51–0.96, p 0.007

• Improves Hyperinsulinism– High fiber diet reduced insulin responses in

hyperinsulinemic men– Dark yellow and green leafy vegetables reduce risk

FIBER

Red Meat and Processed MeatWomen’s Health Study

• 37,309 participants over 8.8 years > 45 years of age• During 326,876 person-years of follow-up , 1558

cases of diabetes documented.• Adjusted for age, BMI total energy intake,

exercise, alcohol, cigarettes, FH of type 2• Positive association between red meat and

processed red meat and type 2 • Similar to Health Professionals Follow-up Study

for men

Fruits and Vegetables• 577 adults, diet high in fruits and

vegetables reduce 6-year incidence of type 2 by 24%– Da Qing IGT and Diabetes Study Total

fruit and vegetable intake

• Women’s Health Study – 39,876 subjects – 2.2 + 1.6 fruits; 3.9 + 2.6 vegetables– Dark yellow and green leafy vegetables – RR .8 even for overweight women

Fat and Diet• Irrefutable -high fat diets cause insulin resistance• Low fat diets safe, weight and improve CVD

– Diets with 20-30% of energy from fat• Dutch and Finnish Cohorts - Seven Countries Study

– 30-year follow-up - role of dietary fat intake in glucose intolerance and diabetes incidence

• San Luis Valley Diabetes Study – Increase in fat intake of 40 grams per day associated with 3.4-

fold increase in type 2 diabetes risk • Health Professionals Follow-up Study

– Positive relationships between total and saturated fat and risk of type 2 diabetes

Overweight Children Compared to Normal Weight

• Ate fewer fruits and vegetables (2.9 vs. 3.3/day)• Drank more sweetened beverages (1.3 vs.

1.1/day)• Ate more high-fat snacks (64 vs. 56 %)• Ate more fast food (1.4 vs. 1.1/week)• Less likely take part in lessons on nutrition • (50 vs. 64 %)

Teenage boys 2.2 sodas/day = 800 cans/year• Teenage girls 1.7 sodas/day• Teens consume 2X amount of sugar than

recommended = 44% from soft drinks• Evidence – 1 extra soda increases risk for

overweight by 60%

Sweetened Beverage Consumption

School-based Program to Decrease Soda Consumption

• 644 children (7-11 years old), 6 schools• Program to decrease regular and diet soda

intake delivered in 1-hour sessions 4 times per year

!!!! 7.5!!!! 0.2 Control"""" 0.2"""" 0.6Intervention

% Overweight and Obese

# Glasses of Soda Per Day

Nutrition Practices to Combat Diabesity –ADA Recommendations

• Decrease total calories • Decrease dietary fat• Decrease energy density of foods • Increase fruits and vegetables • Decrease sweetened beverages including juice• Decrease fast food consumption • Avoid skipping meals, particularly breakfast• Decrease snacking on unhealthy foods

Effects of Food Preferences and Aversions on Healthy Eating

• Alexandra W. Logue, Ph.D.Vice President for Academic Affairs and ProvostNew York Institute of Technology

Food Preferences and Aversions

• Salty food

• Sweet food

• High-density calorie food

• Bitter food

Number of People for Whom a Given Concentration of PTC is the Lowest Concentration Tasted

Bruce N. AmesChildren’s Hospital Oakland Research InstituteProfessor, University of California, Berkeley

A Major Role For MicronutrientsIn Disease Prevention

18 April 2005Milken, LA

O2 O2-

e- e- e- e-H2O2 •OH H2O

~30% Smoking~35% Unbalanced Diets

Too Many Calories: ObesityToo Little Fiber & Micronutrients

~20% Chronic InfectionsMostly in Poor Countries

~20% HormonesBreast, Endometrial, Etc.

~2% Occupation<1% Pollution

Mostly Heavy Air Pollution

The Causes of Cancer

Total = 107% because of multiple causes

Micronutrient Undernutrition in Americans

• Wakimoto and Block (2001) J Gerontol A Biol Sci Med Sci. Oct; 56 Spec No 2(2):65-80.** Before U.S. Food Fortification

25%50%90; 75 mgMen; WomenC

5; ~10-25%10-20; 25-50 %2.4 mcgMen; WomenB12

25%; 50%75%400 mcgMen; WomenFolate**

10%50%1.7; 1.5 mgMen; WomenB6 Vitamins

5-10%25%8 mgWomen 50+ years

25% 75%18 mgWomen 20-30 years Iron Minerals

<50% RDA% ingesting< RDAPopulation GroupNutrient RDA

% ingesting

Zinc Men; Women 50+ years 11; 8 mg 50% 10%

dUMP dTMP

Methionine

SHMT

B6

Serine

MTHFR

Homocysteine

(polymorphism)

TS

MS

CH2=THF

B12CH3-THF

Micronuclei in: RNA positive erythrocytesRNA negative erythrocytes

Folic AcidFolinic Acid

TIME (DAYS)

1 yearpreRx

Normalrange

Mic

ronu

clei

per

100

0 ce

lls

20

50 100 150 200 250 300 350

0

30

40

80

130

xx

PLASMA FOLATE (NG/ML)

MIN

PC

Es/

1000

PC

Es

60

50

40

30

20

10

00 5 10 15 20 25 30

0

0.5

1

1.5

2

2.5

3

3.5

0 2 4 6 8 10 12

Avg

50 c

omet

sHuman Lymphocyte DNA Strand Breaks

(Comet Assay) vs. B-6 Intake

Vitamin B-6 Intake

Folate, Vitamin B12, Homocysteine Status and Chromosome Damage Rate in Lymphocytes of Older MenMichael Fenech, Ivor Dreostl, and Josephine Rinaldi, Carcinogenesis 13:1329-1336, 1997

Folate, Vitamin B12, Homocysteine Status and DNA Damage in Young Australian AdultsMichael Fenech, Claire Aitken, and Josephine Rinaldi, Carcinogenesis 19:1163 - 1173, 1998

Micronucleus Frequency in Human Lymphocytes is Related to Plasma Vitamin B12 and Homocysteine

Michael Fenech, Mutation Research 42: 299 - 304, 1999

In a series of studies, we have been able to confirm that the micronucleus index in cytokinesis-blocked lymphocytes is significantly negatively correlated with plasma vitamin B12 (B12) concentration and significantly positively correlated with plasma homocysteine (HC). Furthermore we have shown in a randomized double-blind placebo-controlled dietary intervention study that intake of 3.5 times the RDI of folic acid and B12 significantly reduces the micronucleus index only in those with above average levels of micronucleus frequency. Micronucleus frequency is minimized when plasma HC is below 7.5 µmol/l and plasma B12 is above 300 pmol/l. Therefore, it is important to take account of the effect of B12 and HC when using the micronucleus assay for human biomonitoring studies.

Vitamin B12 Deficiency

Mean intake by ethnic group (mg)20 yrs 40 yrs 60 yrs

RDA 2.4 2.4 2.4

White 6.8 6.9 6.3Black 7.2 6.2 5.2Hispanic 6.3 5.6 6.1

Mean intake by ethnic group (mg)20 yrs 40 yrs 60 yrs

RDA 2.4 2.4 2.4

White 3.7 3.7 4.1Black 5.3 3.9 3.8Hispanic 4.2 3.6 3.4

. Each of the six dependent variables (that were analyzed by nonlinear regression in former figures) were transformed to Z scores and modeled as a quadratic function of the ln-liver nonheme iron as the independent variable. The equation for the RCR ratio's Z score was obtained from inverted RCR values (1/RCR) so that normal rats had the lower instead of the higher values. For presentation purposes each model line was obtained from 9 values of liver iron. All statistics were performed as in materials and methods.

Analysis of nonlinear regression models: comparison of an overall model and individual models of Z-transformed values vs. ln-

nonheme liver iron

Over allDCF-PMNsDCF-LymphRh123-PMNsRh123-LymphmtDNA damage1/RCR

-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

3

-1.5 -1 -0.5 0 0.5 1 1.5 2 2.5

LN nonheme Fe (µmol/g wet liver)

Z sc

ore

normal

Succ-CoA + GlyALA

2ALA

PBGPorphyrins

Cytosol

PPIX PPGIX

Heme-b

FeII

MitochondriaFC

Synthesis of Heme

Heme-a

PLP

ALA

CH

CH2

CH2

CH2

COOH COOH

CH2

CH2

CH3

CH3

H3C

Fe

N N

N N

CH CH

CH

CH

H3C

CH

CH2

(1) Farnesylation

(2) Oxidation

Heme-b Heme-a(Only in complex IV)

Maturation of heme-b to heme-a is rate limiting for the assembly of complex IV

Micronutrient requirements for heme synthesis

[++][++]Pantothenate

[++]Lipoic acid++++++Biotin

[++][++]Copper++++++++Iron

Riboflavin+++++?+?Zinc

++[++]Pyridoxine

DNA damage

Oxidative stress

Complex IVHeme-aMicronutrient

++ = Atamna/Ames [++] Literature

0.0 2.5 5.0 7.5 10.0 12.5 15.020253035404550556065

cdFBS-BD

nFBS-BSnFBS-+B--BS

Weeks

cdFBS+B-BS

Biotin deficiency accelerates cell senescence

9) Atamna et al (2001) JBC. 10) Atamna et al (2002) ABB.

Similarity Between the Consequences of Heme Deficiency and Normal

Aging/neurodegenerationFactor in Study Heme Deficiency Aging/Neurodegeneration

Complex IVIronOxidative StressAPP

NOSCell-cycle anddifferentiationMetabolismCalciumFerrochelataseHeme synthesis

Loss of complex IVAccumulationIncreased Decreased andaggregate appearIncreasedDisabled differentiationor proliferationMitochondrial declineCorruptedIncreasedDecreased

Loss of complex IVAccumulationIncreaseddimmer or aggregate

IncreasedLoss of Axons; neuronal deathHypometabolismCorruptedIncreased in senescent cellsDecreased with age**

*

*Not Determined in vivo. **Not determined in the aging brain

1994-96, 1998 CSFII Study, USDA

“The main distinguishing characteristicbetween man and the lower animals

is the desire to take pills”

Mark Twain

The Economist, December 13, 2003

Dr. Allen Spiegel, NIDDK/NIH

Energy Sources - 1999-2000Food

1. Regular soft drinks 7.1

2. Cake, sweet rolls, doughnuts, pastries 10.6

3. Hamburgers, cheeseburgers, meatloaf 13.8

4. Pizza 16.8

5. Potato chips, corn chips, popcorn 19.7

6. Rice 22.4

7. Rolls, buns, English muffins, bagels 25.0

8. Cheese or cheese spread 27.6

9. Beer 30.2

10. French fries, fried potatoes 32.4

Gladys Block from National Health and Nutrition Examination Survey (NHANES) 2000.

Cumulative Percentage

THE SEARCH FOR THE WEAPONSOF MASS REDUCTION

“Things sweet to taste prove in digestion sour.”

Shakespeare (King Richard the Second)

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