WHAT WOULD IT LOOK LIKE

IF EVERYONE HAD SUFFICIENT

VITAMIN D?

Robert P. Heaney, MD, FACP, FASN

Creighton University Osteoporosis Research Center

CU ORC

2

VIT D & CARDIOVASCULAR DISEASE

1739 Framingham

Offspring members

age: 59 yrs

follow-up: 5.4 yrs

120 individuals developed

a CV event

HR calculated against

25(OH)D values > 15 ng/mL

Wang et al. Circulation

2008

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Hazard

R

atio

< 10

ng/mL

< 15

ng/mL

> 15

ng/mL

80 % increase

in risk

53 % increase

in risk

BREAST CANCER RISK

Case-control study

1394 cases

1365 controls

Odds ratio for CA

inversely

associated with vit

D status [25(OH)D]

Abbas et al.,

Carcinogenesis (2008)

29:93–99

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Hazard

R

atio

< 3

0

30–4

5

45–6

0

60–7

5

> 7

5

69 % decrease

in risk

Serum 25(OH)D (nmol/L)

CU ORC

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VITAMIN D & INFLUENZA*

208 African-American,

postmenopausal women

3 yr DB-RCT

placebo or vit D3

800 IU/d – 2 yrs

2000 IU/d – 3rd

yr

basal 25(OH)D: 18.8 ± 7.5

0

5

10

15

20

25

30

35

Placebo Vitamin D

*Aloia & U-Ng (2007) Epidemiol & Infect

P < 0.002

CU ORC

5

VITAMIN D & THE COMMON COLD*

18,883 individuals

in NHANES-III

tested association

between serum

25(OH)D & recent

URTI

0

5

10

15

20

25

% w

ith

U

RT

I

< 10 10–29.9 30+

Serum 25(OH)D (ng/mL)

P < 0.001

association stronger

for those with

asthma & COPD

Ginde et al., Arch Int Med 2009 169:

29 % reduction

CU ORC

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DIABETES & 25(OH)D

Scragg et al., 2004

Diabetes Care

27:2813–18

NHANES-III

6,228 adults

plasma glucose

independently

predicted by BMI

& serum 25OHD

(fasting and 2 hr

post load)0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Relative R

isk

1st 2nd 3rd 4th

25(OH)D Quartiles

White

Hispanic

NEONATAL VIT D & DIABETES*

10,366 northern

Finnish children

2000 IU Vit D/d 1st

year of life

prevalence of

type I diabetes

assessed at age 31

RR calculated vs. no

supplementation

Vitamin D Administration

Regular

Irregular

? rick

ets

Rel

ativ

e R

isk

0.01

0.1

1

10

Zero

*Hypponen et al., Lancet 2001;358:1500–03

88% lower risk

3-fold higher risk

Similar clinical study results are being published weekly

Two questions: –

How can a single nutrient have such diverse effects in so many different tissues ?

If these effects are correct, why haven’t they been apparent previously ?

Two questions: –

How can a single nutrient have such diverse effects in so many different tissues ?

If these effects are correct, why haven’t they been apparent previously ?

THE VITAMIN D ICEBERG

cell cycle regulation

gene control

Ca economy

THE VITAMIN D ICEBERG

autocrine

endocrine

CU ORC

13

25(OH)D3D

31,25(OH)

2D

3

skin liver kidney gut

CaBP

VIT D – CANONICAL SCHEME

CU ORC

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25(OH)D3D

3

1,25(OH)2D

3

skin liver

periphery

gut

CaBP

VIT D – EXPANDED SCHEME

kidney

1,25(OH)2D

3

varioustissues

cell

signals

endocrine

autocrine

Autocrine functions

CU ORC

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AUTOCRINE ACTION

25(OH)D

VDR

1,25D

VDR

1,25D

RXR

VDRE

Transcription

CU ORC

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AUTOCRINE ACTION

25(OH)D

VDRE

Transcription

cell proliferation

cell differentiation

apoptosis

immune response

24-hydroxylase

CU ORC

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AUTOCRINE ACTION

25(OH)D

VDRE

Transcription

~ 800 genes

have VDREs

CU ORC

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AUTOCRINE ACTION

25(OH)D

VDR

1,25D

VDR

1,25D

RXR

VDRE

Transcription

1,25D

25OHD 25OHD

CU ORC

20

AUTOCRINE ACTION

25(OH)D

VDR

VDR

1,25D

RXR

VDRE

Transcription

1,25D

25OHD 25OHD

1,25D

This scheme means that each tissue

has the amount of 1,25(OH)2D it needs

when it needs it

and is not dependent upon a “one-size-fits all” systemic level of circulating1,25(OH)2D

CU ORC

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VITAMIN D & INNATE IMMUNITY*

activated Toll-like receptor

*Liu et al., Science 2006

CU ORC

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VITAMIN D & INNATE IMMUNITY*

25(OH)D

bactericidal peptide

Cathelicidin

*Liu et al., Science 2006

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VITAMIN D & INNATE IMMUNITY*

25(OH)D

human

monocytes

in fetal calf

serum

Cyp27B1VDR

*Liu et al., Science 2006

the Vit D1-a hydroxylase

the Vit D receptor

CU ORC

25

VITAMIN D & INNATE IMMUNITY*

25(OH)D

human

monocytes

in fetal calf

serum

Cyp27B1VDR

*Liu et al., Science 2006

…………

fetal calf

serum is low

in both

25(OH)D &

1,25(OH)2D

CU ORC

26

VITAMIN D & INNATE IMMUNITY*

25(OH)D

human

monocytes

in fetal calf

serum

add

1,25(OH)2D

to the

system

Cyp27B1VDR1,25D

*Liu et al., Science 2006

CathelicidinCyp24

CU ORC

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VITAMIN D & INNATE IMMUNITY*

25(OH)D

human

monocytes

in fetal calf

serum

add

25(OH) D to

the system Cyp27B1VDR1,25D

*Liu et al., Science 2006

CathelicidinCyp24

25OHD

CU ORC

28

human monocytes

activated with M.

Tuberculosis and

incubated in human

serum

African-American

White

African-American

with added

25(OH)D

VITAMIN D & TUBERCULOSIS

0

1

2

3

4

A- A W A- A

+ 25D

Cathelicidin mRNA

*Liu et al., Science 2006

serum 25(OH)D: 22 nmol/L

serum 25(OH)D: 78 nmol/L

CU ORC

29

VITAMIN D & TUBERCULOSIS

vit D is an essential mediator in the innate

immune response

serum 25(OH)D is the critical variable

at least some of the increased sensitivity to

infection in vit D-deficiency is due to reduction

in response to infectious agents because

25(OH)D is rate-limiting

the greater tuberculosis susceptibility of blacks

is due in part to their low vit D status

these experiments show that:

If this new understanding is correct,

do we see evidence of impaired function in patients with low vitamin D status?

CU ORC

31

VITAMIN D & TUBERCULOSIS*

67 pts with pulmonary

TB

standard treatment

for all

in addition,

randomized to either

vit D 10,000 IU/d or

placebo

50

60

70

80

90

100

Placebo Vit D

Sputum Conversion (%)

*Nursyam et al., Acta Med Indones 2006

P = 0.002

CU ORCCU ORC

CELL MODELS

old: DNA in somatic cells functions mainly to make faithful copies for tissue repair or replacement

DNA functions constantly in synthesis of needed cellular apparatus

new:

CU ORC

33

Signal/

Demand

HOW A CELL RESPONDS

newly synthesized cellular equipment

I don’t have

the equipment

I need . . . .

Response

. . . but I do have

the plans for what

I need in my DNA

library. . . .

CU ORC

34

HOW A CELL RESPONDS

25(OH)D

newly synthesized cellular equipmentResponse

Signal/

Demand

1,25(OH)2D is the key

that unlocks the DNA library

CU ORC

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PERSPECTIVE

vitamin D is an integral component of the

mechanism whereby cells control gene

transcription in response to a variety of

extracellular stimuli

adequate vitamin D status enables optimal

response to a broad variety of signals

deficiency will manifest itself differently,

depending upon the tissue being stressed,

thus explaining the diversity of responses

Two questions: –

How can a single nutrient have such diverse effects in so many different tissues ?

If these effects are real, why haven’t they been apparent previously ?

CU ORC

37

VITAMIN D & INFLUENZA*

208 African-American,

postmenopausal women

3 yr DB-RCT

placebo or vit D3

800 IU/d – 2 yrs

2000 IU/d – 3rd

yr

basal 25(OH)D: 18.8 ± 7.5

0

5

10

15

20

25

30

35

Placebo Vitamin D

*Aloia & U-Ng (2007) Epidemiol & Infect

P < 0.002

Such differences would not be apparent in ordinary medical practice because people who don’t get sick do not see the doctor –are not tracked and would not be recognized as having been protected.

The protection is seen only when a cohort of well individuals is followed prospectively.

Endocrine mechanism

CU ORC

42

SERUM 25(OH)D (nmol/L)

0 20 40 60 80 100 120 140 160

ABSO

RPT

IO

N FR

AC

TIO

N

0.0

0.1

0.2

0.3

0.4

0.5

A VITAMIN D THRESHOLD

CU ORC

43

SERUM 25(OH)D (nmol/L)

0 20 40 60 80 100 120 140 160

ABSO

RPT

IO

N FR

AC

TIO

N

0.0

0.1

0.2

0.3

0.4

0.5

A VITAMIN D THRESHOLD

physiological regulation no longer limited by vit D availability

CU ORC

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SERUM 25(OH)D (nmol/L)

0 20 40 60 80 100 120 140 160

ABSO

RPT

IO

N FR

AC

TIO

N

0.0

0.1

0.2

0.3

0.4

0.5

A VITAMIN D THRESHOLD

VITAMIN D – Sources

?Body D

3

stores25(OH)D

VITAMIN D – Sources

?Body D

3

stores25(OH)D

VITAMIN D – Sources

150

Body D3

stores25(OH)D

VITAMIN D – Sources

150

Body D3

stores25(OH)D

typical input, all sources: ~2350 iu

VITAMIN D – Sources

150

Body D3

stores25(OH)D

needed input, all sources: ~4000 iu

CU ORC

50

25(OH)D3D

3

1,25(OH)2D

3

skin liver

periphery

gut

CaBP

VIT D – EXPANDED SCHEME

kidney

1,25(OH)2D

3

varioustissues

cell

signals

endocrine

autocrine

25(OH)D3D

3

1,25(OH)2D

3

skin liver

periphery

gut

CaBP

VIT D – EXPANDED SCHEME

kidney

1,25(OH)2D

3

varioustissues

cell

signals

endocrine

autocrine

Won’t calcitriol meet the body’s need for vitamin D?

NO!

CU ORC

53

25(OH)D3D

31,25(OH)

2D

3

skin liver kidney gut

CaBP

VIT D – CANONICAL SCHEME

Why not just give 1,25(OH)2D?

It’s the active agent, isn’t it?

Answer: you can’t give enough

to achieve needed levels.

This is the value that

needs to be optimized

Bone strength

Serum 25(OH)D and Hip BMD

NHANES-III

Adults Age

20 – 49 yrs

LOWESS plot

of difference

from lowest

quantile

Bischoff-Ferrari HA. Am J Med 2004; 116: 634-9.

Non-Hispanic whites

African-Americans

Hispanics

CU ORC

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VITAMIN D & FRACTURE RISK

0 25 50 75 100 125 150

(nmol/L)

FR

AC

TU

RE R

ELA

TIV

E R

ISK

(h

ip

, fo

rearm

, sp

in

e)

0.0

0.2

0.4

0.6

0.8

1.0

N = 2,686

ages 65–85

5 yr RCT

Vit D 800

IU/d

Trivedi et al.

BMJ 2003;

326:469

–33%

CU ORC

VITAMIN D & FRACTURES

meta-analysis

9 RCTs

Vit D doses

> 400 IU (but

none > 800 IU)

n = ~ 32,000

Bischoff-Ferrari et al.

Arch Int Med

(2009);169:551

0.0

0.2

0.4

0.6

0.8

1.0

Non-vertebral Hip

Relative Risk

57

CU ORC

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VITAMIN D & RISK OF FALLING*

122 women

Age: 63–99

DB-RCT

Ca 1,200 mg/d

Ca + 800 IU Vit D

12 week duration

25(OH)D 12 ng/mL

at baseline0.0

0.2

0.4

0.6

0.8

1.0

Fall R

isk

Ca only Ca + D

*Bischoff et al. JBMR. 2003;18:343–351.

–49%

VIT D & NEUROMUSCULAR FUNCTION*

1359 men & women;

mean age 75.5

Amsterdam longitud.

aging study

neuromuscular

performance

measured on a scale

of 0 to 12 (higher is

better)

0

1

2

3

4

5

6

7

8

9

<25 25–50 50–75 >75

SERUM 25(OH)D

Performance Score

each step statistically

significant

*Wicherts et al. JBMR. 2005.

In brief, raising serum 25(OH)D from 50 to ~80 nmol/L

improves Ca absorption, raises BMD, and reduces falls and osteoporotic fracture risk

CU ORC

61

OTHER CHRONIC DISEASES?

osteoporosis

osteoarthritis

falls/neuromusc. fcn

multiple sclerosis

fibromyalgia-like syndrome

type I diabetes

insulin sensitivity

cardiovascular disease

periodontal disease

various cancers

tuberculosis

hypertension

++++

+

++++

++

++

++

++

+++

++++

++++

++++

++++

Disease Status of Evidence

Cardiovascular effects

VIT D & BLOOD PRESSURE*

148 women, aged

74 ± 1

DB–RCT

baseline 25(OH)D <

50 nmol/L

treated for 8 wks

with:

Ca 1200 mg/d or

Ca + 800 IU vit D/d

*Pfeifer et al., JCEM 2001; 86:1633–37INTERVENTION

Ca only Ca+D

Systo

lic B

P (

mm

Hg)

0

125

150

P < 0.01

P < 0.01

P < 0.02

–5.7 –13.1

VIT D & BLOOD PRESSURE*

1811 men & women

with measured

25(OH)D levels**

4 yrs’ observation

97 cases of incident

hypertension

RR computed for

25(OH)D <15ng/mL

vs. >30 ng/mL

*Forman at al., 2007;Hypertension 49:1063

** Health Profs Follow-up Study & Nurses Health Study

>30 <15

Rela

tive R

isk

0.1

1

10

3.18

Anti-promotion for cancer

VITAMIN D & PROSTATE CA*

13 yr

longitudinal

study

19,000 men

149 cases

prostate CA

*Ahonen et al., CancerCauses&Control 11:847-852 (2000) 25(OH)D QUARTILES

1 2 3 4

RELA

TIV

E R

ISK

0.0

0.5

1.0

1.5

2.0

2.5

VITAMIN D & PROSTATE CA*

those below

the median

25(OH)D level

were 70%

more likely to

develop

prostate CA

than those

above

*Ahonen et al., CancerCauses&Control 11:847-852 (2000) 25(OH)D QUARTILES

1 2 3 4

RELA

TIV

E R

ISK

0.0

0.5

1.0

1.5

2.0

2.5

COLORECTAL CANCER

Nurses’ Health Study

ages 46–78

nested case-control

study

193 incident cases

25(OH)D measured

twice, prior to

diagnosis

Feskanich et al., Cancer

Epidemiol Biomarkers Prev

2004 13:1502–080.0

0.2

0.4

0.6

0.8

1.0

Od

ds R

atio

1st–16

2nd–22

3rd–27

4th–31

5th–40

25(OH)D Quintiles (with medians*)

*ng/mL

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COLORECTAL CANCER

5 prospective

studies

> 200,000

individuals

430 cases

ORs computed

for 25(OH)D

quantiles

Garland et al,

2005

Serum 25(OH)D (nmol/L)

0 20 40 60 80 100 120

Od

ds R

atio

0.0

0.2

0.4

0.6

0.8

1.0

P < 0.001

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MAMMOGRAPHIC DENSITIES

543 women aged 40–60

1989–90

dietary intakes assessed

with FFQ

odds ratios developed

for <30% vs. >70% of

film with densities

[Berube et al., 2004; Cancer

Epidemiol Biomarkers Prev

13:1466–72]

0.0

0.2

0.4

0.6

0.8

1.0

Od

ds R

atio

1st 2nd 3rd 4th

Quartiles

Vit D

Ca

CU ORC

71

VITAMIN D & CANCER*

1179 healthy women

aged 66.7 ± 7.3

four year trial

1032 finished (87.5%)

baseline 25(OH)D: 71.8 nmol/L ± 20.3

three treatment groups:

control

Ca (1400–1500 mg/d)

Ca plus D3

(1100 IU/d)

achieved 25(OH)D: 96 nmol/L ± 21.4

*Lappe et al. AJCN 2007

VITAMIN D & CANCER*

Time (yrs)

0 1 2 3 4

Fra

cti

on C

ancer-

Fre

e

0.90

0.92

0.94

0.96

0.98

1.00

Ca+D

Placebo

Ca-only

P < 0.01RR = 0.402

*Lappe et al. AJCN 2007

VITAMIN D & CANCER*

Time (yrs)

0 1 2 3 4 5

Fra

cti

on C

ancer-

Fre

e

0.90

0.92

0.94

0.96

0.98

1.00

Ca+D

Placebo

Ca-onlyRR = 0.232

*Lappe et al. AJCN 2007

VITAMIN D & CANCER*

Time (yrs)

0 1 2 3 4 5

Fra

cti

on C

ancer-

Fre

e

0.90

0.92

0.94

0.96

0.98

1.00

Ca+D

Placebo

Ca-only

*Lappe et al. AJCN 2007

96 nmol/L

71.8 nmol/L

CANCERS BY TREATMENT (YRS 2–4)

SitePlacebo

(n=266)

Ca+D

(n = 403)

Breast 7 (2.6%) 4 (1.0%)

Colon 2 (0.7%) 0 (0.0%)

Lung 3 (1.1%) 1 (0.2%)

Marrow/Lymphoma 4 (1.5%) 2(0.5%)

Other 2 (0.7%) 1 (0.2%)

Total 18 (6.8%) 8 (2.0%)*

* P < 0.05

Safety

0

200

400

600

800

1,000

1,200

1,400

1,600

1,800

1,000 10,000 100,000 1,000,000 10,000,000

Vitamin D Intake (IU/day)

Seru

m 25(O

H)D

(n

mol/L)

15 studies of adultsreceiving vitamin Dsupplementation(means)

8 studies reportingtoxicity (individualvalues)

VITAMIN D INTAKE & TOXICITY*

* Hathcock JN et al. Am J Clin Nutr. 2007;85:6–18.

no toxicity below 500 nmol/L (200 ng/mL)

no toxicity below 30,000 IU/d

TUIL: 10,000 IU/d*

*Hathcock et al.,(2007) AJCN 85:6–18

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79

TWO KEY QUESTIONS

assuming a target value of 80 nmol/L:

how much of an increase in daily inputs

would be required to ensure that no

more than 2.5% of the population fell

below the target value?

what , if anything, is the risk of raising

their 25(OH)D in those who already are

at or above the target value?

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80

25(OH)D IN OLDER WOMEN*

1168 women

aged 55 &

older

latitude 41º N

25(OH)D

values

adjusted for

season

median vit D

supplement

dose = 200 IU

25(OH)D (nmol/L)

0 40 80 120 160

Freq

uen

cy

0

20

40

60

80

100

*Lappe et al., JACN 2006

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81

SHIFTING THE DISTRIBUTION

improving

vitamin D

status at a

population

level means

raising

everybody’s

value, i.e.,

moving the

distribution

to the right

25(OH)D (nmol/L)

0 20 40 60 80 100 120 140 160 180

RELA

TIV

E FR

EQ

UEN

CY

0.000

0.005

0.010

0.015

0.020

0.025

CU ORC

82

SHIFTING THE DISTRIBUTION

using an effect

size of

1 nmol/L/mg/d

it would require

~2000 IU of

additional D each

day to shift the

distribution

sufficiently to

ensure that no

more than 2.5 %

fell below 80

nmol/L

25(OH)D (nmol/L)

0 50 100 150 200

RELA

TIV

E FR

EQ

UEN

CY

0.000

0.005

0.010

0.015

0.020

0.025

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83

SHIFTING THE DISTRIBUTION

taking an effect

size of

1 nmol/L/mg/d

it would require

~2000 IU of

additional D each

day to shift the

distribution

sufficiently to

ensure that no

more than 2.5 %

fell below 80

nmol/L

25(OH)D (nmol/L)

0 50 100 150 200

RELA

TIV

E FR

EQ

UEN

CY

0.000

0.005

0.010

0.015

0.020

0.025

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84

SHIFTING THE DISTRIBUTION

what about those

already 2 SD above

the mean?

25(OH)D (nmol/L)

0 50 100 150 200

RELA

TIV

E FR

EQ

UEN

CY

0.000

0.005

0.010

0.015

0.020

0.025

the rise with an

extra ~2000 IU/d

would be

predicted to bring

them to no more

than 170–180

nmol/L – well

below the toxic

range

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86

CONCLUSIONS

vitamin D acts in multiple systems

serum 25(OH)D levels below 80 nmol/L

are not adequate for any body system

levels of as high as 120 nmol/L may be

closer to optimal

inputs from all sources combined

(needed to sustain 80 nmol/L) are in

the range of ~4,000 IU/d and higher

CU ORC

87

WHAT IS THE OPERATIVE MODEL?

for the media?

for regulators?

for nutritional policy makers?

for nutritional physiologists?

CU ORC

88

WHAT IS THE OPERATIVE MODEL?

for the media and for regulators

nutrition is about killing yourself

with a fork

it’s about avoiding risks

it’s about warnings & cautions

For a package of

macaroni & cheese

http://vm.cfsan.fda.gov/~dms/foodlab.html

Limit these

nutrients

Get enough of

these

nutrients

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91

MEDIA REPORTING

the overwhelming majority of media

reports about nutrition emphasizes harm

and risk

while the explanation is partly that harm

is more newsworthy than benefit (and the

media battens on controversy)

still the impression unwittingly conveyed

to the general public is one of concern

and danger

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92

WHAT IS THE OPERATIVE MODEL?

for nutritional policy makers

nutrition is about determining

the least one can get by on

without suffering overt disease

(once called MDRs)

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93

WHAT IS THE OPERATIVE MODEL?

for nutritional physiologists

adult nutrition is about preventive

maintenance of tissues and organs

it’s about keeping them from wearing

out or breaking down prematurely

its referent is the intake that prevailed

when human physiology evolved

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94

THE PREVENTIVE MAINTENANCE MODEL

foundational premises:

all tissues need all nutrients

shortages impair the functioning of all

body systems

premature organ/system “wearing out”, as

a consequence of nutrient deficiency, will

vary from person to person, depending on

variable genetic composition; and

therefore, expression of nutrient deficiency

will usually be pluriform – both between

and within individuals

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95

THE PREVENTIVE MAINTENANCE MODEL

also recognizes that:

the organism will work perfectly well

without maintenance – for a while . . .

it thus reconciles the seeming paradox that

an organism can be “deficient” without

being clinically “sick”

– for a while . . .

it’s also about squaring the morbidity/

mortality curve

CU ORC

96

THEORETICAL MORTALITY CURVE

AGE (yrs)

0 20 40 60 80 100

CU ORC

97

THEORETICAL MORTALITY CURVE

AGE (yrs)

0 10 20 30 40 50 60 70 80 90 100

SU

RV

IVA

L (

%)

0

20

40

60

80

100

CU ORC

98

Age (yrs)

0 10 20 30 40 50 60 70 80 90 100

Perc

ent

alive/w

ell

0

20

40

60

80

100

SQUARING THE MORTALITY CURVE

Certainly, NCEP and DGA take this for granted

Optimal nutrition has the potential to contribute to

this improvement

CU ORC

99

WHAT WOULD IT BE LIKE?

fewer cancers

less diabetes

fewer osteoporotic fractures

less hypertension & CV disease

less periodontal disease

less multiple sclerosis

less severe infectious disease

We don’t really know the true burden of chronic disease.

And we won’t, until everyone has enough vitamin D.

Thank you . . .