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Bruce N. Ames
Children’s Hospital Oakland Research Institute
Professor, University of California, Berkeley
A DIET FOR HEALTH AND
LONGEVITY
18 November 2010
Chicago NHRI
~40 Essential Micronutrients
• Biotin
• Folic acid
• Niacin
• Pantothenate
• Riboflavin
• Thiamine
• VitA
• VitB6
• VitB12
• VitC
• VitD
• VitE
• VitK
• Calcium
• Chloride
• Chromium
• Cobalt
• Copper
• Iodide
• Iron
• Magnesium
• Manganese
• Molybdenum
• Phosphorus
• Potassium
• Selenium
• Sodium
• Zinc
• Linolenic acid/DHA [ -3]
• Linoleic acid [ -6]
• Isoleucine
• Leucine
• Lysine
• Methionine
• Phenylalanine
• Threonine
• Tryptophan
• Valine
• Histidine
• Choline
Micronutrient Undernutrition in Americans
Nutrient Population Group
% Ingesting
< EAR *
From Food
Iron Menstruating Women 16 %
Magnesium All 56 %
Zinc All 12 %
B6 Women > 70 years 49 %
Folate Adult Women 16 %
E All 93 %
C All 31 %
Minerals
Vitamins
Very low intake:vitamins D & K, calcium, potassium, omega-3
•USDA What we Eat in America (NHANES 2001-2002) Sept. 2005
Micronuclei in: RNA positive erythrocytes
RNA negative erythrocytes
Folic AcidFolinic
Acid
TIME (DAYS)
1 year
preRx
Normal
range
Mic
ron
ucle
i p
er
1000
cells
20
50 100 150 200 250 300 350
0
30
40
80
130
Everson RB, Wehr CM, Erexson GL, and MacGregor JT. (1988) J Natl Cancer Inst 80:525-9.
dUMP dTMP
Methionine
SHMT
B6
Serine
MTHFR
Homocysteine
(polymorphism)
TS
MS
CH2=THF
B12CH3-THF
Dose-response on micronuclei induction in cultured lymphocytes
Acute exposure to X-rays vs. Folic Acid deficiency
Fenech 2003, Nutrition Research Reviews
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 all
DCF-PMNs
DCF-Lymph
Rh123-PMNs
Rh123-Lymph
mtDNA damage
1/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 s
co
re
normal
20
40
60
80
100
120
140
Control ZnAD ZnDF
DC
F F
luo
res
ce
nc
e
Inte
ns
ity (
RF
U)
Zinc Deficiency Induces Increased
Oxidative Stress in C6 Glioma Cells
*
Zinc Deficiency Induces Fapy Glycosylase (Fpg)-sensitive
Single Strand Breaks in Human Lung Fibroblasts
0
40
80
120
160
200
Control ZnAD ZnDF
Co
me
t S
co
re
Control (+Fpg) ZnAD (+Fpg) ZnDF (+Fpg)
*
Mitochondrial
Matrix
Cellular Cytoplasm
Mitochondrial Outer Membrane
Inner Membrane
Intermembrane
Space
V
I
IIIII
IV
CytCCoQ
H+
Pyruvate
Dehydrogenase
complex
Citrate
Synthase
-Ketoglutarate
Dehydrogenase
Complex
Fumarate
L-Malate
Oxaloacetate
Acetyl-Co-A Citrate Isocitrate
-Ketoglutarate
Succinyl-Co-A
Succinate
FADFADH2
CITRIC
ACID
CYCLE
H2OO2 ADP
ATP
ATP
NADH
NADH
NADH
NAD+
NADHNADH
H+
H+
H+ H+
H+H+H+
H+
H+H+
H+ H+H+
H+
H+
H+
H+ H+H+
H+
H+
H+
9
Magnesium Deficiency Induces DNA-Protein Cross-links
Calcium Deficiency Vitamin B12 Deficiency Fenech: chromosome breaks Fenech: Chromosome breaks
Lipkin: colon cancer mice
Folate Deficiency Selenium DeficiencyMacGregor/Ames/Fenech: chromosome Rao: DNA damage
breaks mice/humans Combs/Trumbo: Cancer humans
Willett: epi colon cancer humans
Vitamin D Deficiency Omega-3 FA DeficiencyHolick: epi many types of cancer Denkins: Cancer
Magnesium Deficiency Niacin DeficiencyBell: chromosome breaks humans Kirkland/Depeint: DNA damage
Larsson: epi colorectal cancer humans
Zinc Deficiency Choline DeficiencyFong: esophageal cancer humans/rodents da Costa: DNA damage in humans
Potassium DeficiencyChang: Cardiovascular Disease
Proc. Natl. Acad. Sci. USA
Vol. 103, pp. 17589-17594, November 2006
Low micronutrient intake may accelerate the degenerative diseases
of aging through allocation of scarce micronutrients by triage
Bruce N. Ames
Children’s Hospital of Oakland Research Institute, Nutrition and Metabolism Center,
5700 Martin Luther King Jr. Way, Oakland, CA 94609
• Most of the world’s population has inadequate intake of one or more micronutrients.
• Triage theory posits as a results of recurrent shortages of micronutrients during evolution, natural
selected developed a metabolic rebalancing response to shortage.
• The rebalancing favors micronutrient-dependent protein needed for short term survival while
those only required for long-term health are starved.
• This impairment results in insidious damage (e.g. increased DNA damage) that, over time, leads
to the acceleration of age-associated diseases (e.g. increased cancer).
40 Essential Micronutrients
• Biotin
• Folic acid
• Niacin
• Pantothenate
• Riboflavin
• Thiamine
• Vitamin A
• Vitamin B6
• Vitamin B12
• Vitamin C
• Vitamin D
• Vitamin E
• Vitamin K
• Calcium
• Chromium
• Cobalt
• Copper
• Fluoride
• Iodine
• Iron
• Magnesium
• Manganese
• Molybdenum
• Phosphorus
• Potassium
• Selenium
• Sodium
• Zinc
• Linolenic acid/DHA [ -3]
• Linoleic acid [ -6]
• Isoleucine
• Leucine
• Lysine
• Methionine
• Phenylalanine
• Threonine
• Tryptophan
• Valine
• Histidine
• Choline
16 Vitamin K Dependent Proteins
F2 (Prothrombin)
F7
F9
F10
(Anticoagulant protein C)
Osteocalcin
Gas 6 protein
Matrix Gla protein
TGFBI
Periostin
(Anticoagulation Protein Z)
Coagulation Factors Other Proteins
glutamyl-carboxylase, vitK quinone reductase
and vitK epoxide reductase)
5 Lethal KO 6 nonlethal KO
Non-lethal
VKD-
protein
Function Mouse
Knockout
Phenotypes
Human
Mutants
Anticoagulant
Therapy
Modest
VitK
deficiency
Osteocalcin
Matrix Gla
Protein
(Mgp)
Bone struct.
Glucose
homeostasis
Negative
regulator of
vascular
calcification
Fragile bones
Insulin
resistance
Arterial
calcification
BMD loss
(SNPs)
Abnormal soft
tissue
calcification
(Keutel
Syndrome;
SNPS)
Bone health
(men/children/rats)
Arterial
calcification
(humans/rats)
Bone health
Insulin
resistance
Arterial
calcification
Four Causes of Functional Deficiency of VKD-
Proteins in Humans
McCann & Ames (2009) Vitamin K, an example of triage theory: is micronutrient
inadequacy linked to diseases of aging? Am J Clin Nutr 90,889-907.
Natto
Selenoprotein genetic loss Se dietary loss
Rodent Human Human
Gpx1 Knockdown: UV-induced
micronuclei
Gpx1 SNP, heterozygosity loss,
hypermethylation: Various cancers
DNA damage/Cancer
Gpx2 KO: UV-induced cancer
Gpx1 Heterozyg: Heart Abnormalities Heart disease: hypertension,
mortality;
Keshan’s cardiomyopathy
(severe def)Gpx3 SNP: Stroke & thrombosis
Dio2 SNP: Hypertension (?)
Gpx1 KO: Viral induced myocarditis
Sensitivity to virus infection
Gpx2 KO: Airway inflammation
McCann, JC & Ames, BN. An examination of selenoprotein biology from the perspective of the triage theory: Why modest selenium deficiency may increase risk of diseases of aging. October, 2010 (to be submitted)
Modest Selenium deficiency, genetic impairment of nonessential
selenoproteins, and diseases of aging
An overview of evidence for a causal relationship
between iron deficiency
during development and cognitive or behavioral
function in children
Joyce C McCann and Bruce N Ames
(2007) AJCN
Is docosahexaenoic acid, an n-3 long-chain
polyunsaturated fatty acid, required for development
of normal brain function? An overview of evidence
from cognitive and behavioral tests in humans and
animals
Joyce C McCann and Bruce N Ames
American Journal of Clinical Nutrition (2005)
82:281-95
Is there convincing biological or behavioral evidence linking
Vitamin D deficiency to brain dysfunction?
Joyce C McCann and Bruce N Ames
Faseb J 22, 982-1001 (2008)
Neurons Contain The Enzyme That Activates Vitamin D
Eyles, DW et al (2005) J Chem Neuroanat 29, 21-30
Calcitriol Target Genes in the Brain
Gene products whose expression in the brain or brain cells has been reported to be affected by calcitriol
Neurotrophins and other growth factors:
NGF; NT-3 & NT-4/5; GDNF; TGF-β2
Calcium-binding proteins:
Calbindin D28K, parvalbumin, calretinin;
Protein sub-units for L-Type Voltage Sensitive Ca++Channels (L-type VSCCs);
Transcription factors or enzymes involved in signal transduction pathways:
N-myc, c-myc, protein kinase C family (PKC);
Other enzymes:
Choline acetyltransferase, responsible for synthesis of the neurotransmitter acetylcholine;
γ-Glutamyltranspeptidase, involved in recycling of the reactive oxygen species scavenger glutathione);
Hormones:
[Oxytocin, the “trust hormone”]
Biochemical or cellular brain functions in which calcitriol target gene products are involved
Synaptogenesis (formation of synaptic connections); Synaptic plasticity (e.g., memory formation); Calcium
signaling and homeostasis; Neurotransmission and neurotransmitter synthesis; Survival and differentiation of
dopaminergic and other neurons; Control of toxic free radicals;
Behavior affected by target gene product dysfunction
Learning and memory; Motor control; Maternal or social behavior; Aging (neuronal density);
Immune Risk Phenotype of Aging
Lower CD4 and CD8 T-lymphocytes
Increase in anergic effector (CD8+CD28-) T-cells
Low lymphoproliferative response
Decline in antigen-presenting cells
Decreased expression of co-stimulatory molecules
Decline in IL-12 production and Th1 response
Immune Risk Phenotype of Aging
Lower CD4 and CD8 T-lymphocytes
Def: vit A., zinc, folate
Increase in anergic effector (CD8+CD28-) T-cells
Def: tryptophan, zinc,
Low lymphoproliferative response
Def: vit C, vit E, zinc. Vit B6
Decline in antigen-presenting cells
Def: vit E
Decreased expression of co-stimulatory molecules
Def: vit E, tryptophan. zinc
Decline in IL-12 production and Th1 response
Def: vit B6, Vit E, zinc
Fenech 2007, Forum Nutr.
Healthy Non-smoking
Males
Healthy Non-smoking
Females
Variation in chromosomal DNA damage rates within and between age
groups measured as MNC frequency.
The Economist, December 13, 2003
Dr. Allen Spiegel, NIDDK/NIH
Top Sources of “Nutrition” for 20-30 year olds
NHANES III (1988-1994) Wakimoto P & Block G. J Gerontol A Biol Sci Med Sci, 2001
% total energy
1. Regular soft drinks 8.8
2. Pizza 5.1
3. Beer 3.9
4. Hamburgers, meat loaf 3.4
5. White bread 3.3
6. Cake, doughnuts, pastries 3.3
7. French fries, fried potatoes 3.0
8. Potato chips, corn chips, popcorn 2.7
9. Rice 2.6
10. Cheese or cheese spread 2.5
38.6%
Supplementation Strategies
Conventional
• cumbersome
• compliance
• incomplete
CHORI Bar
• convenient
• complete
1. Moderate micronutrient deficiencies are widespread.
2. Triage theory postulates that moderate micronutrient deficiencies
can lead to accelerated aging and age-related diseases.
3. RDAs and EARs should be re-examined on the basis of triage theory,
which would put nutrition on a firm foundation.
4. The optimum intake of micronutrients will vary among people
due to polymorphisms.
CONCLUSIONS
• Bring the world’s population up to optimal intake with
inexpensive micronutrients.
• Identify people who need increased intakes of micronutrients
due to polymorphisms.
GOALS
80
75
70
65
60
55
50
45
401900 1910 1920 1930 1940 1950 1960 1970 1980 1990
46.4
4950.1
53.654.5
56.3
5861.3 61.4
65.7 65.666.7
71.173.2
74.9
77.5
78.9
71.4
69.967.1
Life Expectancy of Men and Women at Birth
SOURCE: National Institute on Aging
New Yorker, June 6, 2005
“You’re fifty-seven years old.
I’d like to get that down a bit.”
Jung
Suh
Mark
Shigenaga
Ash
Lal
Michele
Mietus-Snyder
Nutrition & Metabolism Center
Scientists
Sandy
Calloway
Joyce
McCannBruce Ames
Swapna
Shenvi
David
Killilea
END
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