D is for Debacle - The Sun, Vitamin D, 25(OH)D and Health

“D” is for DebacleThe Crucial Story of 25(OH)D

www.thefatemperor.com2014 Ivor Cummins BE(Chem) CEng MIEI

A Thank-You to Some Experts:Prof. Michael HolickEndocrinologist and Professor of Medicine, Physiology and Biophysics. Currently director at Boston University Medical Center. Internationally recognized expert on all aspects of vitamin D.

Dr. Edward GorhamAssociate Professor in the Department of Family and Preventive Medicine at the University of California

Prof. Robert P Heaney Clinical Endocrinologist, Professor of Medicine and John A. Creighton University Professor Emeritus, Creighton University School of Medicine. Internationally recognized expert on vitamin D.

Dr. Cedric F Garland Adjt Prof. Family and Preventative Medicine, Division of Epidemiology, University of San Diego. Internationally recognized expert on the disease implications of vitamin D.

Dr. Chris MasterjohnPhD in Nutritional Science and Assistant Professor of Health and Nutrition Sciences at Brooklyn College.

Dr. Bruce Hollis PhDProfessor of Pediatrics, Biochemistry and Molecular Biology at The Medical University of South Carolina as well as the Director of Pediatric Nutritional Sciences. Vitamin D research for the past 35 years and has published >200 peer reviewed articles.

Prof. Reinhold ViethProfessor in the Department of Nutritional Sciences, and the Department of Laboratory Medicine and Pathobiology, University of Toronto. Internationally recognized expert on the clinical nutrition of vitamin D as well as its pharmacology and safety.

Dr. David Grimesconsultant Gastroenterologist at Blackburn Hospital in the UK. Expert in Vitamin D for the developing foetus and the implications for infections, diabetes, heart disease, liver disease and Crohn's disease.

Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power4. 25(OH)D – The Human Cost5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A

The “D”ebacle Content:

2014 Ivor Cummins BE(Chem) C(Eng) MIEI

Prelude1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power4. 25(OH)D – The Human Cost5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A


The Literature is Exploding

Prelude – Critical Human Hormone

D3 – The Hormone Precursor

2014 Ivor Cummins BE(Chem) CEng MIEI

• “Vitamin” D3 (Cholecalciferol) is the hormone-precursor molecule required to synthesize 25(OH)D

• This is the crucial element provided mostly by UVB light on skin, but can be taken in supplement form & diet

• 25(OH)D is the pre-hormone substrate.

• Is produced in the Liver from D3 Cholecalciferol

• Enabled us to leave the seas, and a lot more besides

• Is used all over the body for critical functions

• An analogy might be “Ammunition Pack”


25(OH)D – The Pre-Hormone





• 25(OH)D is the pre-hormone substrate.

• Is produced in the Liver from D3 Cholecalciferol

• Enabled us to leave the seas, and a lot more besides

• Is used all over the body for critical functions

• An analogy might be “Ammunition Pack”

• 1,25 (OH)2 D is the active Hormone

• Is produced in the Kidney and elsewhere from 25(OH)D

• Is at 1000x lower concentration than 25(OH)D

• An analogy might be “precision bullet”1,25 (OH)2 D – The Active Form


25(OH)D – The Pre-Hormone





Prelude – The Implications of Low…




USA25(OH)D

Distribution(NHANES III Seasonal Sampling)

~70% of US Population Insufficient ( 15 Years Previously was ~50% )



USA25(OH)D





RequiresEngineering

USA25(OH)D


RequiresEngineering


RICKETS


USA25(OH)D


Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power4. 25(OH)D – The Human Cost5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A


Skin Pigmentation Hypotheses – to ~40kYrs ago

EvolutionaryDrivers

LOSS OF BODY HAIR (~1M Yrs ago)• Striding Bipedalism• Sweat Gland System• Whole Body Cooling• Critical Brain Cooling


~1 million years…


EvolutionaryDrivers

• Skin generally non-pigmented

• Hairless areas pigmented

• Sun Protection Robust Overall

• Vitamin D accessed via Grooming, as for dogs etc

• Captive animals require D Supplementation!



~1 million years…


EvolutionaryDrivers






Hair Loss – Key Downside:• Human Origin had Equatorial Sun • Ubiquitous powerful UV penetrates to Blood Vessels

and damages Folate (photolysis) • Lack of folate causes Neural Tube Birth Defects• Other Reproductive Impacts from excessive UV• Also need to protect hugely increased Sweat Gland

System from damageAnd 25(OH)D Synthesis?

• Equatorial Sun still provides adequate amounts of UV in spite of pigmented skin

• Engineering “Tradeoff” thus achieved



~1 million years…


EvolutionaryDrivers







and damages Folate (photolysis) • Lack of folate causes Neural Tube Birth Defects• Other Reproductive Impacts from excessive UV• Also need to protect hugely increased Sweat Gland

System from damageAnd 25(OH)D Synthesis?





~1 million years…


EvolutionaryDrivers







and damages Folate (photolysis) • Lack of folate causes Neural Tube Birth Defects• Other Reproductive Impacts from excessive UV• Also need to protect Homo Sapiens’ hugely

increased Sweat Gland System from damageAnd 25(OH)D Synthesis?





~1 million years…


EvolutionaryDrivers












~1 million years…


EvolutionaryDrivers










• Engineering “Trade-off” thus achieved



~1 million years…

Skin Pigmentation Hypotheses –~30-40k Yrs to present

EvolutionaryDrivers


Migration from Equator• Increasing weakness of UVB• Use of Clothing increases• Adaptive Pressure Deployed• Fishing Ability Offsets

<40k years…

EvolutionaryDrivers

• Skin Heavily Pigmented

• Protection Robust Overall

• Vitamin D synthesis adequate

• Trade-off Optimised




<40k years…

EvolutionaryDrivers





Trade-offs change with Latitude:• Studies strongly link available UV on Earth’s surface

to indigenous Skin Coloration• Increasing Loss of Vitamin D Synthesis as we leave

Equator – combined with poor nutrition, Rickets and many other issues ensue – we’ll look at those shortly

• In Northern Hemisphere particularly severe effect• Acknowledgement: alternative hypotheses suggest

many things: “simply lost pigmentation because unneeded” etc)




<40k years…

EvolutionaryDrivers











<40k years…

EvolutionaryDrivers








• In Northern Hemisphere particularly severe effect• Acknowledgement: alternative hypotheses suggest

many things: “simply lost pigmentation because unneeded” etc)




<40k years…

EvolutionaryDrivers








• In Northern Hemisphere particularly severe effect• Note: alternative hypotheses suggest many things:

“simply lost pigmentation because unneeded” etc




<40k years…

EvolutionaryDrivers








• In Northern Hemisphere particularly severe effect• Note: alternative hypotheses suggest many things:

“simply lost pigmentation because unneeded” etc• But Timeframe and Logic indicate Key Driver, &

emerging hypotheses suggest Sun is critical beyond D




<40k years…

Human Evolutionary Environment:

Assmann G, Schulte H. Am J Cardiol. 1992;70:733–737.

We originally evolved in an intense UVB environment – part of our design

Migration over millennia drove commensurate skin pigmentation adaptation

Tradeoff: Between UV Excess (e.g. Folate), and adequate synthesis of 25(OH)D

Key Takeaways:


Luxwolda and Muskiet,Submitted Manuscript

60

MAASAI MEDIAN 25(OH)D = 42ng/ml

MAASAIBANTU

20

40

30

50

25

(OH

)D n

g/m

l

Wyoming Woman Athletes 25(OH)D

0

40

20

60

100

80

25

(OH

)D (

ng

/ml)

120

Why is Breast Milk now D Deficient?MIMIC EVOLUTIONARY SUN

Mother: 6400 IU/dayBaby: Only Breast Milk

MODERN REALITYMother: 400 IU/day Supplement

Baby: 300 IU/day Supplement


Why is Breast Milk now D Deficient?“MIMIC EVOLUTIONARY SUN”










V5=~620

V5=~70





Thus with Mediocre Nutrition in Northern Latitudes, we needed to rapidly devolvePigmentation to enhance D3 synthesis for Infant Needs


V5=~620

V5=~70

Evolution…….Matters.


Bone Mineral Density (g/cm2)

Fracture (RR)

Colon Cancer (RR)

8’ Walk Time (s)

Attachment Loss (mm)

Median 25(OH)D Concentration (ng/ml)

1612 20 24 3228 36 40 44

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes1–3. Am J Clin Nutr 2006;84:18 –28. Printed in USA. © 2006 American Society for Nutrition.

Adapted from :

And: Nutrients, Endpoints, and the Problem of Proof – Prof. Robert P. Heaney - 2008

Another Evolutionary View…


Bone Mineral Density (g/cm2)

Fracture (RR)

Colon Cancer (RR)

8’ Walk Time (s)

Attachment Loss (mm)

Median 25(OH)D Concentration (ng/ml)

1612 20 24 3228 36 40 44

Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes1–3. Am J Clin Nutr 2006;84:18 –28. Printed in USA. © 2006 American Society for Nutrition.

Adapted from :

And: Nutrients, Endpoints, and the Problem of Proof – Prof. Robert P. Heaney - 2008

Prelude

1. The Centrality of the Sun

2. 25(OH)D – The Creation3. 25(OH)D – The Power4. 25(OH)D – The Human Cost5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A



How This Most Critical Hormone is Made

7 DeHydroxyCholesterol Primary Source is Sun UVB

(Sunscreen Prevents Synthesis)



7 DeHydroxyCholesterolCholecalciferol(“Vitamin” D3)

Primary Source is Sun UVB

Catalyzes “Cholesterol” to D3




7 DeHydroxyCholesterol

D3/D2Supplements

Cholecalciferol(“Vitamin” D3)

Dietary contribution is limited




Dietary Fatty Fish, Organ Meats, etc



D3/D2Supplements




Liver then makes 25(OH)D




21st Century Science:In-Cell Local 1,25 D

Production on Demand


25(OH)D !



D3/D2Supplements



25(OH)D !



25(OH)D is The KEY METRIC









D3/D2Supplements



25(OH)D !

1,25 D




Kidney then makes 1,25 Dihydroxy Vitamin D









D3/D2Supplements



25(OH)D !

1,25 D

1,25 is ACTIVE Form of D


Liver then makes 25(OH)D :











D3/D2Supplements



25(OH)D !

1,25 D











20th CenturyScience: Mainly Ca Regulation




D3/D2Supplements



25(OH)D !

1,25 D






1,25 does far more than Ca++ regulation !!!






20th CenturyScience: Mainly Ca Regulation


What the Most Critical Hormone Regulates

Valdivielso J M et al. Am J Physiol Renal Physiol 2009;297:F1502-F1509

Low 25(OH) D Invites in: Cancer (esp. Colon/Breast)

TB/Influenza/Infections General

Various Blood Disorders

T1 (and T2) Diabetes

Osteomalacia/Osteoporosis

Asthma / Autoimmune Diseases

Multiple Sclerosis

Heart Disease in General

Thyroid Issues / Chronic Fatigue

Inflammation

Obesity/Hypertension

Metabolic Syndrome

Pre & Post Natal Issues


Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation

3. 25(OH)D – Control System Criticality 4. 25(OH)D – The Consequences5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A


Central Control System of the Human MachineUNIQUE

DNACODE


Central Control System of the Human Machine

35TRILLION

CELLS

!

UNIQUEDNA

CODE



35TRILLION

CELLS

!

BLOODSERUM

25(OH)D25(OH)D

UNIQUEDNA

CODE



35TRILLION

CELLS

!

BLOODSERUM

25(OH)D25(OH)D

1,25 D

UNIQUEDNA

CODE


ONDEMAND


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D25(OH)D

1,25 D

UNIQUEDNA

CODE


ONDEMAND


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D25(OH)D

1,25 D + SAFETYSWITCH

UNIQUEDNA

CODE


ONDEMAND


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D

1,25 D

VDRRXR

VDRE

25(OH)D


UNIQUEDNA

CODE


ONDEMAND


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D

Transcription!!

1,25 D

VDRRXR

VDRE

25(OH)D


UNIQUEDNA

CODE


ONDEMAND


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D

Transcription!!

1,25 D

VDRRXR

VDRE

25(OH)D


SAFETYSWITCH

UNIQUEDNA

CODE


ONDEMAND


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D

Transcription!!

1,25 D

VDRRXR

VDRE

25(OH)D


SAFETYSWITCH

UNIQUEDNA

CODE


ONDEMAND

CRITICAL PROTEINSe.g. CATHELICIDIN


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D

Transcription!!

1,25 D

VDRRXR

VDRE

25(OH)D


SAFETYSWITCH

UNIQUEDNA

CODE


ONDEMAND


Replication!!


35TRILLION

CELLS

!

VDRRXR

BLOODSERUM

25(OH)D

Transcription!!

1,25 D

VDRRXR

VDRE

Blood Pressure

Cancer

Heart Disease

MS, TB, Flu

Asthma

T1 Diabetes

T2 Diabetes

Obesity

Met Syndrome

Alzheimers

25(OH)D


SAFETYSWITCH

UNIQUEDNA

CODE


ONDEMAND


Replication!!



SAFETYSWITCH↑↑CATHELICIDIN

Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power

4. 25(OH)D – The Consequences5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A


Survival Outcome for low 25(OH)D reminiscent of Smokers Vs Non-Smokers

Doesn’t Prove Causality

Summary:

HEART and GENERAL MORBIDITY

Relation of Vitamin D Deficiency to Cardiovascular Risk Factors, Disease

Status, and Incident Events in a General Healthcare Population

Jeffrey L. Anderson, MDa,b,*, Heidi T. May, PhD, MSPHa, Benjamin D. Horne, PhD, MPHa,c,

Tami L. Bair, BSa, Nathaniel L. Hall, MDa,b, John F. Carlquist, PhDa,b, Donald L. Lappé, MDa, andJoseph B. Muhlestein, MDa,b, for the Intermountain Heart Collaborative (IHC) Study Group

(Am J Cardiol 2010;106:963–968)

Population 25(OH)D Levels

Adequate>30ng/ml

36.4% V. Low <16

16.7%

Low16-30 ng/ml

46.4%


Majority Population Insufficient

Remember D is a proxy for Sun(!)

>30

16-30

<16

Vitamin D and Cardiovascular Disease Carl J. Lavie, MD, John H. Lee, MD, Richard V. Milani, MD (J Am Coll Cardiol 2011;58:1547–56)

Survival trends stronger than Non-Smoker versus Smoker

Dose-Response Relationship with Accelerated Effect in lowest Quartile

Key Takeaways:


CVD and All Cause Death


Incidence Rate Average of 6 Studies, consistent association throughout

Key Takeaways:

COLON CANCER – Incidence Rate


55% reduction in ColonCancer Risk associated with 38ng/ml 25(OH)D

Od

ds

Rat

io o

f C

olo

rect

al C

ance

r P trend <0.0001

COLON CANCER INCIDENCE

10 20 4030


Incidence Rate Average of 6 Studies, consistent association throughout

Mortality strongly associated with 25(OH)D levels, but multi-factor phenomenon

Key Takeaways:

COLON CANCER – Incidence Rate


55% reduction in ColonCancer Risk associated with 38ng/ml 25(OH)DO

dd

s R

atio

of

Co

lore

ctal

Can

cer

P trend <0.0001

COLON CANCER INCIDENCECOLON CANCER MORTALITY

RR = 0.28

RR = 0.44

Rel

ativ

e ri

sk

10 20 4030

P trend =0.02

Strong, Linear association – & D mechanism directly tied to cell proliferation

Key Takeaways:

BREAST CANCER - Mortality

Vitamin D and prevention of breast cancer: Pooled analysis (2007)

Cedric F. Garland,, Edward D. Gorhama, Sharif B. Mohra, William B. Grant b,Edward L. Giovannucci,

Martin Lipkin, Harold Newmarke, Michael F. Holick, Frank C. Garland

Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 708–711


P trend <0.001

R2 = 0.9

50% lower riskwith 48 ng/ml

Strong, Linear association – & D mechanism directly tied to cell proliferation

Key Takeaways:


Vitamin D and prevention of breast cancer: Pooled analysis (2007)

Cedric F. Garland,, Edward D. Gorhama, Sharif B. Mohra, William B. Grant b,Edward L. Giovannucci,

Martin Lipkin, Harold Newmarke, Michael F. Holick, Frank C. Garland

Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 708–711


P trend <0.001

R2 = 0.9


P trend <0.002

R2 = 0.94


Association is Dramatic, and mechanism’s available.

Key Takeaways:



Where would you rather be?

BREAST CANCER MORTALITY

RR = 0.28P <0.05

Enormous body of evidence linking MS to 25(OH)D Status

MULTIPLE SCLEROSIS


Contribution of vitamin D

insufficiency to the

pathogenesis of Multiple Sclerosis

Ther Adv Neurol Disord(2013) 6(2) 81–116DOI: 10.1177/1756285612473513

Ireland53O N

Enormous body of evidence linking MS to 25(OH)D Status:

MULTIPLE SCLEROSIS


25(OH)D Interacts with risk of MS from conception thru life via different mechs

Contribution of vitamin D

insufficiency to the

pathogenesis of Multiple Sclerosis

Ther Adv Neurol Disord(2013) 6(2) 81–116DOI: 10.1177/1756285612473513

NOMS

MS

MULTIPLE SCLEROSIS

Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study

BMJ VOLUME 327 9 AUGUST 2003 bmj.com

N=136 MS Cases (in their 30’s) vs 273 Matched Controls

Summary:


MULTIPLE SCLEROSIS




Summary:


Consistent Dose-Response Benefit primarily for exposure age 6-10 and 10-16

P<0.01 for trend

MULTIPLE SCLEROSIS




Summary:


Even more marked when Actinic Damage was used as independent measure

P<0.01 for trend P<0.01 for trend


MULTIPLE SCLEROSIS




Summary:


Even more marked when Actinic Damage was used as independent measure

Conclusion: UVB and/or D critical for Adaptive Immune System Development

P<0.01 for trend P<0.01 for trend


MS MS

Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power

4. 25(OH)D – The Consequences5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A


Correctly executed, difference controlled to be primarily D and Ca.

Key Takeaways:

ALL CANCER MORTALITY (Experiment)

Baseline 25(OH)D = 29ng/ml

1100 IU Vitamin D + 1450 Ca / day

Randomized Control Trial

N = 1179 Healthy Women

2014 Ivor Cummins BE(Chem) Ceng MIEI

Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial

Correctly executed, difference controlled to be primarily D and Ca.

Key Takeaways:

ALL CANCER MORTALITY (Experiment)

Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial

Baseline 25(OH)D = 29ng/ml

1100 IU Vitamin D + 1450 Ca / day

Randomized Control Trial

N = 1179 Healthy Women


Clear impact on Cancer and Overall mortality, especially with 1st Year removed

TYPE 1 DIABETES


The most common serious chronic disease in children, esp. in Northern Latitude

TYPE 1 DIABETES - Finnish Study

Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study

THE LANCET • Vol 358 • November 3, 2001

N=12,055 Births in 1966, Supplementation 1st year of life, follow-up to 1997

Summary:






Summary:


Note: Vitamin D known to prevent Type 1 Diabetes in animals





Summary:


Adjusted for Social Status, Birth Weight, Growth Rate etc.






Summary:


Adjusted for Social Status, Birth Weight, Growth Rate etc.


Conclusion Clear – Verified Vitamin D critical for Immune System Development


FINLAND GUIDELINE VIT D vs Type1 Diabetes Incidence in <15 Year Olds

Northern Latitude, very poor UVB. Supplement Strategy collapsed since 1950’s

Summary:

Incidence of Type 1 Diabetes in Finland

JAMA July 24/31, 2013 Volume 310, Number 4

TYPE 1 DIABETES - Supplementation History?IU

/Day

Vit

D




Summary:

Incidence Rate studied for 1978 onwards, & some Trend Messing about…



TYPE 1 DIABETES - Supplementation History?

10

20

30

40

50

60

70

IU/D

ay V

itD




Summary:

Conclusion: Not quite clear? Questioned. Supplemented Dairy acknowledged.

Incidence Rate studied for 1978 onwards, & some Trend Messing about…



D-fortifiedDairy


/Day

Vit

D

10

20

30

40

50

60

70



Remove the inappropriate inferences, and plot a natural curve

Engineering Style Summary:



D-fortifiedDairy


/Day

Vit

D

10

20

30

40

50

60

70






Add in the earlier historical data from another source that had it…


Diabetes December 2002 vol. 51 no. 12 3353-3361

The Rise of Childhood Type 1 Diabetes in the 20th Century

D-fortifiedDairy


/Day

Vit

D

10

20

30

40

50

60

70






Conclusion: - go figure.

Diabetes December 2002 vol. 51 no. 12 3353-3361

The Rise of Childhood Type 1 Diabetes in the 20th Century


Add in the earlier historical data from another source that had it…

D-fortifiedDairy


/Day

Vit

D

10

20

30

40

50

60

70

Strong Hypothesis that Flu Outbreaks are mediated by 25(OH)D levels

Summary:

INFLUENZA – Seasonal Triggering

Hypponen E, Power C:

Hypovitaminosis D in British

adults at age 45 y: nationwide

cohort study of dietary and lifestyle predictors

Am J Clin Nutr 2007, 85: 860–868


Strong Hypothesis that Flu Outbreaks are mediated by 25(OH)D levels

Summary:


Hypponen E, Power C:

Hypovitaminosis D in British

adults at age 45 y: nationwide

cohort study of dietary and lifestyle predictors

Am J Clin Nutr 2007, 85: 860–868

Latitude Simultaneity, Transfer Dynamics, etc




16

20

24

28

32

25

(OH

)D n

g/m

l

0

5

10

15

20

% R

esp

irat

ory

Infe

ctio

n

MonthSeason

0

5

10

15

20

% R

esp

irat

ory

Infe

ctio

n

Berry DJ, Hesketh K, Power C, et al. (2011) Vitamin D status has a liner

association with seasonal infections and lung function in British adults.Br J Nutr 106, 1433–1440

208 randomised individuals to placebo or 800 IU/day of D3 over 2 years

Key Takeaways:

INFLUENZA – Hospital Experiment

Re: epidemic Influenza and vitamin D

Aloia JF, Li-Ng M: Epidemic influenza and vitamin D. Epidemiol Infect 2007; 135: 1095–1096

Cannell et al. Virology Journal 2008 5:29 doi:10.1186/1743-422X-5-29.


Increased to 2000 IU/day in 3rd Year


Key Takeaways:








Key Takeaways:






25(OH)D acts via multiple mechanisms as discussed



Key Takeaways:






25(OH)D acts via multiple mechanisms as discussed

Very few studies done (and mouse/rat/dog lack the VDR for this mechanism, so much data is worthless…)



The Bottom Line: “Mechanisms From pre-Cradle to Grave”

Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power4. 25(OH)D – The Consequences

5. Anatomy of a Debacle6. The Solution

Epilogue

Q&A


Witness An Unfolding Catastrophe….

NHANES III (1988-1994)

SER

UM

25

(OH

)D:

% >

30

ng/

ml

10

20

30

40

50

NHANES (2001-2004)

The Literature is Exploding


European Journal of Clinical Nutrition (2012)

doi:10.1038/ejcn.2012.78

Vitamin D and the scientific calcium dogma: understanding the ‘Panacea’ of the sun

Pin

eal

Ho

rmo

ne

Vit

amin

D

SKIN




doi:10.1038/ejcn.2012.78

Pin

eal

Ho

rmo

ne

Vit

amin

D

SKIN


USA25(OH)D

Distribution


< 32ng/ml > 32ng/ml

Recall Where We Are Now…..



doi:10.1038/ejcn.2012.78

Pin

eal

Ho

rmo

ne

Vit

amin

D

SKIN




doi:10.1038/ejcn.2012.78

Recall Where We Are Now….. P

ine

al H

orm

on

e

Vit

amin

D

SKIN

The Skin Cancer / Melanoma Hysteria

J Am Acad Dermatol. 2006 Feb;54(2):301-17 2014 Ivor Cummins BE(Chem) CEng MIEI

330 340 350 360 360 370 380 390 400

Blue is UV-B zone that enables Vitamin D Synthesis (and Cholesterol Sulphate)



330 340 350 360 360 370 380 390 400

Red is zone that enables tan protection, and warning Erythema (Sunburn) Blue is UV-B zone that enables Vitamin D Synthesis (and Cholesterol Sulphate)



330 340 350 360 360 370 380 390 400

Green is zone that theoretical modelling suggests “Cosmetic” Skin Cancers Red is zone that enables tan protection, and warning Erythema (Sunburn) Blue is UV-B zone that enables Vitamin D Synthesis (and Cholesterol Sulphate)



330 340 350 360 360 370 380 390 400

UV-A is currently deemed the primary driver of Cutaneous Malig. Melanoma Green is zone that theoretical modelling suggests Squamous Skin Cancer Red is zone that enables tan protection, and warning Erythema (Sunburn) Blue is UV-B zone that enables Vitamin D Synthesis (and Cholesterol Sulphate)

~95% of Terrestrial UV Energy is from UVA. And it sails thru

Ozone, and even Glass



330 340 350 360 360 370 380 390 400

Green is zone that theoretical modelling suggests Squamous Skin Cancer Red is zone that enables tan protection, and warning Erythema (Sunburn) Blue is UV-B zone that enables Vitamin D Synthesis (and Cholesterol Sulphate)

UV-A is currently deemed the primary driver of Cutaneous Malig. Melanoma

Squamous and Basal cell Skin Cancers?

- <0.5% Mortality)USA: ~2k deaths/yr

Melanoma Zone – Serious Stuff

USA: ~9k deaths/yr



So who’s the idiot? (a) Evolution Itself, or (b) how humans have interpreted it??

330 340 350 360 360 370 380 390 400

Green is zone that theoretical modelling suggests Squamous Skin Cancer Red is zone that enables tan protection, and warning Erythema (Sunburn) Blue is UV-B zone that enables Vitamin D Synthesis (and Cholesterol Sulphate)

UV-A is currently deemed the primary driver of Cutaneous Malig. Melanoma

Squamous and Basal cell Skin Cancers?

- <0.5% Mortality)USA: ~2k deaths/yr

Melanoma Zone – Serious Stuff

USA: ~9k deaths/yr

Sunscreens Effective Most Sunscreens Not Effective

MELANOMA Versus Sun Exposure History

Eur J Cancer. Mar 2011; 47(5): 732–741

“Relationship between sun exposure and melanoma risk for tumors in different

body sites in a large case-control study in a temperate climate”

N=960 Melanoma Victim Study:



Eur J Cancer. Mar 2011; 47(5): 732–741





Healthy Sun Exposure, LOWER Risk


Eur J Cancer. Mar 2011; 47(5): 732–741






Strong Correlation to 25(OH)D Observed

This Effect Applied to BOTH Skin Types


Eur J Cancer. Mar 2011; 47(5): 732–741







One of many Studies illustrating this effect



Eur J Cancer. Mar 2011; 47(5): 732–741









The Real Risk Factors?


Eur J Cancer. Mar 2011; 47(5): 732–741










Significant Sun Burning Incidents


Eur J Cancer. Mar 2011; 47(5): 732–741







Light Skin; Freckles; Red Hair –Propensity to Burn


Significant Sun Burning Incidents



SUNSCREENS: A Counter-Intuitive Twist

Int. J. Cancer: 87, 145–150 (2000)“SUNSCREEN USE AND MALIGNANT MELANOMA”

N=571 Cutaneous Malignant Melanoma, Versus N=913 Healthy Controls:

2014 Ivor Cummins BE(Chem) CEng MIEI H

R




Generally Higher Risk of Cancer with increased sunscreen use


R





this also applied after adjustment for Skin, Exposure Frequency and Duration


R



UVA Mechanism, Lack of UVA Protection, Vitamin D and OverExp Highlighted



this also applied after adjustment for Skin, Exposure Frequency and Duration


R



R

The Bottom Line: All Cause Mortality

Journal of Internal Medicine: doi: 10.1111/joim.12251

“Avoidance of sun exposure is a risk factor for all-cause mortality: results from the Melanoma in Southern Sweden cohort”

N=29,518 Swedish Women: Prospective Study with 20 Year Follow-Up






All-Cause Mortality was Halved in UPPER Quartile of Sun Exposure


~2x Mortality Rate Throughout






this applied after adjustment for Co-Morbidity, Smoking, Education, Income etc






Dose-Response Relationship seen throughout









Dose-Response Relationship seen throughout






25(OH)D indeed Cited, but there are other benefits of Sun

2014 Ivor Cummins BE(Chem) MIEI

Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power4. 25(OH)D – The Consequences5. Anatomy of a Debacle

6. The SolutionEpilogue

Q&A

Optimising 25(OH)D – Synergy and Interaction

LOW25(OH)D

<32 ng/ml

Blood Pressure

Cancer

Heart Disease

MS, TB, Flu

Asthma

T1 Diabetes

T2 Diabetes

Obesity

Met Syndrome

Alzheimers

Lack of SUN Exposure

Low FatDiet

Low Calcium Diet

Racial factors & Genetics


LOW25(OH)D

<32 ng/ml

Blood Pressure

Cancer

Heart Disease

MS, TB, Flu

Asthma

T1 Diabetes

T2 Diabetes

Obesity

Met Syndrome

Alzheimers


Low FatDiet

Low Calcium Diet

HIGH25(OH)D

>60? ng/ml

Excess SUN Exposure LG

Excess D3Supplements

Racial factors & Genetics AND

/OR

Low

Vit K2

ExcessiveCalcification?


LOW25(OH)D

<32 ng/ml

Blood Pressure

Cancer

Heart Disease

MS, TB, Flu

Asthma

T1 Diabetes

T2 Diabetes

Obesity

Met Syndrome

Alzheimers

Healthy Sun Exposure

UVB/UVA RatioLack of SUN Exposure

Low FatDiet

Low Calcium Diet

OPTIMUM25(OH)D

32-50 ng/ml

Fat-Nutrient Dense Diet

Oily Fish, Cod Liver, Pate, etc

Correct D3Supplements

HIGH25(OH)D

>60? ng/ml




AND

Adequate

Calcium

AND/OR

Adequate

Vit AAdequate

Vit K2


Low

Vit K2


LOW25(OH)D

<32 ng/ml

Blood Pressure

Cancer

Heart Disease

MS, TB, Flu

Asthma

T1 Diabetes

T2 Diabetes

Obesity

Met Syndrome

Alzheimers


Low FatDiet

Low Calcium Diet

OPTIMUM25(OH)D

32-50 ng/ml

Fat-Nutrient Dense Diet

Oily Fish, Cod Liver, Pate, etc

Correct D3Supplements

HIGH25(OH)D

>60? ng/ml




AND

Adequate

Calcium

AND/OR

Adequate

Vit AAdequate

Vit K2

Immune Function

Bone Strength

Disease Protection

Cancer Resistance

Vigour & Longevity

Healthy Sun Exposure

UVB/UVA Ratio


Low

Vit K2


Prelude

1. The Centrality of the Sun2. 25(OH)D – The Creation3. 25(OH)D – The Power4. 25(OH)D – The Consequences5. Anatomy of a Debacle6. The Solution

EpilogueQ&A

Epilogue – Respecting Evolution and Science• Levels should be in 32-50ng/ml range (80-120nmol/L)


• “Short Shadow” Sun Exposure Without Burning is key

• Supplements: D3: new upper guideline is 4000 IU/day*

• Oily Fish, Organ Meats, Fortified Dairy etc. will help…25(OH)D





• Oily Fish, Organ Meats, Fortified Dairy etc. will help…

• Calcium is critical and works in tandem with 25(OH)D

• Too low is more likely than too high these days…

• Plenty Cheese/Yogurt/Milk, Sardines, Dark Leafy Greens.

• Supplements – medical guidance.

25(OH)D









• Vitamin K2 is key, possibly the most important besides D.


• Activates Matrix GLA Protein, for Calcium Management• Highly interactive with Vitamin D & Ca – need keep K2 high • Butter/Cheeses, Natto, Chicken Legs, Egg Yolks, Liver, etc

25(OH)D









• Vitamin K2 is key, possibly the most important besides D.


• Activates Matrix GLA Protein, for Calcium Management• Highly interactive with Vitamin D & Ca – need keep K2 high

• Vitamin A also important - highly interactive with Vitamin D

• D/A Ratio is source of problem when low – balance needed.• Sweet potato, carrots, Dark Leafy Greens, Dairy/Butter/Yolk

• Butter/Cheeses, Natto, Chicken Legs, Egg Yolks, Liver, etc

25(OH)D

A Thank-You to some Experts:Prof. Michael HolickEndocrinologist and Professor of Medicine, Physiology and Biophysics. Currently director at Boston University Medical Center. Internationally recognized expert on all aspects of vitamin D.

Dr. Edward GorhamAssociate Professor in the Department of Family and Preventive Medicine at the University of California

Prof. Robert P Heaney Clinical Endocrinologist, Professor of Medicine and John A. Creighton University Professor Emeritus, Creighton University School of Medicine. Internationally recognized expert on vitamin D.

Dr. Cedric F Garland Adjt Prof. Family and Preventative Medicine, Division of Epidemiology, University of San Diego. Internationally recognized expert on the disease implications of vitamin D.

Dr. Chris MasterjohnPhD in Nutritional Science and Assistant Professor of Health and Nutrition Sciences at Brooklyn College.

Dr. Stephanie SeneffSenior Research Scientist at MIT.BS (Biophysics), MS/EE and Ph.D in Electrical Engineering and Computer Science MIT.

Prof. Reinhold ViethProfessor in the Department of Nutritional Sciences, and the Department of Laboratory Medicine and Pathobiology, University of Toronto. Internationally recognized expert on the clinical nutrition of vitamin D as well as its pharmacology and safety.

Dr Grimesccccc.

BACKUP / OTHER MATERIAL

Backup / Other


Coronary Vascular Disease

Vitamin D and Cardiovascular Disease Carl J. Lavie, MD, John H. Lee, MD, Richard V. Milani, MD (J Am Coll Cardiol 2011;58:1547–56)

Coronary Vascular Disease strongly linked to admission level 25(OH)D

Synergy with Blood Pressure, also mitigated by Sun Exposure

Summary:

Colon Cancer has one of the strongest associations with 25(OH)D levels

Key Takeaways:

COLON CANCER – Survival Rate


Key Takeaways:

BREAST CANCER MORTALITY – A Null Result??

Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer

J Natl Cancer Inst 2007;100: 1581 – 1591

“Homeopathic” Dose used

Only 400 IU / day to D Group

~50% of BOTH Groups taking D in Supplements throughout trial (D levels not disclosed)


Null Response: Dosage near-irrelevant, poorly executed and controlled.

Key Takeaways:








Null Response: Dosage near-irrelevant, poorly executed and controlled.

Key Takeaways:








Supplemental Data and Subgroup Analysis tells a story…let’s dig, shall we?


BREAST CANCER MORTALITY – A Deeper Dive

How did the Intervention Affect Subgroups?

BorderlineSignificant

Estimated D Intake

Non-Supplement Users Subgroup with poor Vit D intake showed signal




StatisticallySignificant

Estimated D Intake


Estimated D Intake


Supplement Users Subgroup with poor Vit D Intake showed signal




Supplement Users Subgroup with poor Ca Intake showed signal




Estimated D Intake Estimated Ca Intake


Estimated D Intake




Conclusion: Engineering Signal There, but study is otherwise Near-Worthless



Estimated D Intake Estimated Ca Intake


Estimated D Intake





Sunlight UVB is the Primary Source of Human 25(OH)D….and a lot more, as recent understanding grows.


Another Evolutionary View…


0

16

32

48

60

32

ng/

ml

Land Mass in Southern Hemisphere retains high UVB year-round.

Annual Adequacy of UVB for Synthesis?


What the Most Critical Hormone Regulates

Valdivielso J M et al. Am J Physiol Renal Physiol 2009;297:F1502-F1509

Low 25(OH) D Invites in: Cancer (esp. Colon/Breast)

TB/Influenza/Infections General

Various Blood Disorders

T1 (and T2) Diabetes

Osteomalacia/Osteoporosis

Asthma / Autoimmune Diseases

Multiple Sclerosis

Heart Disease in General

Thyroid Issues / Chronic Fatigue

Inflammation

Obesity/Hypertension

Metabolic Syndrome

Pre & Post Natal Issues




↑↑CATHELICIDIN

The Centrality of the Sun


….A Profound Evolutionary Paradigm

HEALTHYSun Exposure

But NOBURNING!




HEALTHYSun Exposure

But NOBURNING!

DSynthesis

PlusCholesterol




HEALTHYSun Exposure

But NOBURNING!

DSynthesis

PlusCholesterol

CholesterolSulfate

PlusCholesterol

/ Sulfur




HEALTHYSun Exposure

But NOBURNING!

DSynthesis

PlusCholesterol

CholesterolSulfate

PlusCholesterol

/ Sulfur

Health+Longevity




HEALTHYSun Exposure

But NOBURNING!

DSynthesis

PlusCholesterol

CholesterolSulfate

PlusCholesterol

/ Sulfur

Health+Longevity

B.S. degree in Biophysics in 1968

M.S. and E.E. degrees in Electrical Engineering in 1980Ph.D degree in Electrical Engineering and Computer Science in 1985 (All from MIT)

MIT Senior Research Scientist who has spent 3 decadesat the intersection Of Biology and Computation

Supplementation started in December, which was rather late; still:

Key Takeaways:

INFLUENZA – Japanese Schoolchildren

Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren

Mitsuyoshi Urashima, Takaaki Segawa, Minoru Okazaki, Mana Kurihara, Yasuyuki Wada, and Hiroyuki Ida Am J Clin Nutr 2010;91:1255–60.



Key Takeaways:





In a (rare) experiment, D3 supplements reduced Influenza A by >40%


Key Takeaways:






Marked in Children not receiving existing supplements – reduction of ~ 65%


Key Takeaways:






Marked in Children not receiving existing supplements – reduction of ~ 65%

Asthma attacks significantly reduced also (no trial has ever assessed this)



Summary:

Conclusion: Engineering Signal There, but study is otherwise Near-Worthless





A Wider View

Hypothesis Summary from 2009 FDA Paper

US Food and Drug Administration, Center for Devices and Radiological Health

“Increased UVA exposures and decreased ..Vitamin D3 levels may be responsible for increasing incidence of melanoma”

• Outdoor workers generally have 2x the 25(OH)D of indoor workers


• Higher incidence of CMM in Indoor versus outdoor workers

• Melanoma patients have significantly lower blood 25(OH)D levels

• UVB-absorbing sunscreens promote the growth of melanoma in mice

• UVB-absorbing sunscreen users have significantly higher melanoma rates

• All-year tan is protective, and associated with 3-9 times the UV Dose

• No “critical period” for burns to increase CMM risk (e.g. in childhood)

• Childhood outdoor activity (excl. burns) decrease melanoma incidence

• Melanoma patients who receive regular sun live longer than those who don’t

• UVA promotes mice tumors after initiation, and causes twice as many

• Calcitriol decreases Stage II Carcinogenesis in Vivo, not Stage I

Making D and burning / Cancer Q

J Am Acad

Dermatol. 2006 Feb;54(2):301-17

Red is erythema (Sunburn)

Green is Math Simulation for Squamous Skin Cancer Promotion


Blue is 25(OH)D Production


Figure 4.4 – Caption of original article: Cutaneous vitamin D synthesis cannot be

dissociated from harmful effects ofUV radiation. Dashed and dotted line (blue) shows

spectrum of previtamin D3 formation obtained from plotting reciprocal of photoenergy

(1/w cm_2). Dashed line ( green) represents both action spectrum of induction

ofsquamous cell carcinoma in human beings mathematically derived from experimental

data obtained from murineskin, and wavelength dependence of induction of DNA

damage, in this case cyclobutane pyrimidine dimers, inhuman skin (adapted121). Solid

line (red) shows erythema action spectrum from human skin (m2/J) (adapted 26).

Note that peaks of these 3 curves all occur within UVB spectrum (290-320 nm) (dashed

gray lines). (FromWolpowicz & Gilchrest, The vitamin D questions: how much do you

need and how should you get it? J Am AcadDermatol. 2006 Feb;54(2):301-17. With permission).


Future “Biochemistry for Life” Topics:

• 25 Hydroxy Vitamin D The history, latest science, and significant mortality implications of this

critical agent

• Omega 6 Vegetable Oils The interesting story of how a machine lubricant became a health food

– but should have stayed in the machine….

• Insulin – a Billion Years in Service The evolutionary importance and critical functionality of Insulin,

increasingly dysfunctional and pathogenic in our modern environment

• Keto-Adaptation Living in an advantaged metabolic state – it’s much more than simply

having an edge


cccc

Key Takeaways:

COLON CANCER – New Discovery in 2000’s ?


BACKUP

D is for Debacle - The Sun, Vitamin D, 25(OH)D and Health

Health & Medicine

Transcript of D is for Debacle - The Sun, Vitamin D, 25(OH)D and Health