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.com
2014 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 AdjtProf. Family and Preventative Medicine, Division of Epidemiology, University of San Diego. Internationally recognized expert on the disease implications of vitamin D.
Dr. Chris Masterjohn
PhD in Nutritional Science and Assistant Professor of Health and Nutrition Sciences at Brooklyn College.
Dr. Bruce Hollis PhD
Professor 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 Vieth
Professor 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 Grimes
consultant Gastroenterologist at Blackburn Hospital in the UK. Expert in Vitamin D for the developing foetusand the implications for infections, diabetes, heart disease, liver disease and Crohn'sdisease.

Prelude
1.The Centrality of the Sun
2.25(OH)D –The Creation
3.25(OH)D –The Power
4.25(OH)D –The Human Cost
5.Anatomy of a Debacle
6.The Solution
Epilogue
Q&A
The “D”ebacleContent:
2014 Ivor Cummins BE(Chem) C(Eng) MIEI

Prelude
6.The Solution
Epilogue
Q&A

Prelude –Critical Human Hormone
D3 –The Hormone Precursor
•“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)Dis 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)Dis 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 Dis 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…

USA
25(OH)D
Distribution
(NHANES III Seasonal Sampling)

~70% of US Population Insufficient
( 15 Years Previously was ~50% )
USA
25(OH)D
Distribution

Requires
Engineering
USA
25(OH)D
Distribution

Requires
Engineering
RICKETS
USA
25(OH)D
Distribution

Prelude
6.The Solution
Epilogue
Q&A

Skin Pigmentation Hypotheses –to ~40kYrs ago
Evolutionary
Drivers
LOSS OF BODY HAIR (~1M Yrsago)
•Striding Bipedalism
•Sweat Gland System
•Whole Body Cooling
•Critical Brain Cooling
~1 million years…

Evolutionary
Drivers
•Skin generally non- pigmented
•Hairlessareas pigmented
•Sun Protection Robust Overall
•Vitamin D accessed via Grooming, as for dogs etc
•Captive animals require D Supplementation!
~1 million years…

Evolutionary
Drivers
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 damage
And 25(OH)D Synthesis?
•Equatorial Sun still provides adequate amounts of UV in spite of pigmented skin
•Engineering “Tradeoff” thus achieved
~1 million years…

Evolutionary
Drivers
•Also need to protect hugely increased Sweat Gland System from damage
~1 million years…

Evolutionary
Drivers
•Also need to protect Homo Sapiens’ hugely increased Sweat Gland System from damage
~1 million years…

Evolutionary
Drivers
~1 million years…

Evolutionary
Drivers
•Engineering “Trade-off” thus achieved
~1 million years…

Skin Pigmentation Hypotheses –~30-40k Yrsto present
Evolutionary
Drivers
Migration from Equator
•Increasing weakness of UVB
•Use of Clothing increases
•Adaptive Pressure Deployed
•Fishing Ability Offsets
<40k years…

Evolutionary
Drivers
•Skin Heavily Pigmented
•Protection Robust Overall
•Vitamin D synthesis adequate
•Trade-off Optimised
<40k years…

Evolutionary
Drivers
Trade-offs change with Latitude:
•Studies strongly link availableUV 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…

Evolutionary
Drivers
<40k years…

Evolutionary
Drivers
•Note: alternative hypotheses suggest many things: “simply lost pigmentation because unneeded” etc
<40k years…

Evolutionary
Drivers
•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:

Luxwoldaand Muskiet,
Submitted Manuscript
60
MAASAI MEDIAN 25(OH)D = 42ng/ml
MAASAI
BANTU
20
40
30
50
25(OH)D ng/ml

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/day
Baby: Only Breast Milk
MODERN REALITY
Mother: 400 IU/day Supplement
Baby: 300 IU/day Supplement

Mother: 6400 IU/day
MODERN REALITY

“MIMIC EVOLUTIONARY SUN”
Mother: 6400 IU/day
MODERN REALITY

Mother: 6400 IU/day
MODERN REALITY
V5=
~620
V5=
~70

Mother: 6400 IU/day
MODERN REALITY
Thus with Mediocre Nutrition in Northern Latitudes, we needed to rapidly devolve
Pigmentation 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)
16
12
20
24
32
28
36
40
44
Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes1–3.
Am J ClinNutr2006;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)
16
12
20
24
32
28
36
40
44
Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes1–3.
Am J ClinNutr2006;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

How This Most Critical Hormone is Made
7 DeHydroxyCholesterol
Primary Source is Sun UVB
(Sunscreen Prevents Synthesis)

Cholecalciferol
(“Vitamin” D3)
Catalyzes “Cholesterol” to D3

D3/D2
Supplements
Cholecalciferol
(“Vitamin” D3)
Dietary contribution is limited
Dietary Fatty Fish, Organ Meats, etc

D3/D2
Supplements
Cholecalciferol
(“Vitamin” D3)
Liver then makes 25(OH)D
21stCentury Science:
In-Cell Local 1,25 D Production on Demand
25(OH)D !

D3/D2
Supplements
Cholecalciferol
(“Vitamin” D3)
25(OH)D !
25(OH)D is The KEY METRIC

D3/D2
Supplements
Cholecalciferol
(“Vitamin” D3)
25(OH)D !
1,25 D
Kidney then makes 1,25
DihydroxyVitamin D

D3/D2
Supplements
Cholecalciferol
(“Vitamin” D3)
25(OH)D !
1,25 D
1,25 is ACTIVE Form of D
Liver then makes 25(OH)D :
DihydroxyVitamin D

D3/D2
Supplements
Cholecalciferol
(“Vitamin” D3)
25(OH)D !
1,25 D
DihydroxyVitamin D
20th Century
Science: Mainly CaRegulation

D3/D2
Supplements
Cholecalciferol
(“Vitamin” D3)
25(OH)D !
1,25 D
DihydroxyVitamin D
1,25 does far more than Ca++ regulation !!!
20th Century
Science: Mainly CaRegulation

What the Most Critical Hormone Regulates
ValdivielsoJ M et al. Am J PhysiolRenal Physiol2009;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
3.25(OH)D –Control System Criticality
4.25(OH)D –The Consequences
6.The Solution
Epilogue
Q&A

Central Control System of the Human Machine
UNIQUE
DNA
CODE

35
TRILLION
CELLS
!
UNIQUE
DNA
CODE

35
TRILLION
CELLS
!
BLOOD
SERUM 25(OH)D
25(OH)D
UNIQUE
DNA
CODE

35
TRILLION
CELLS
!
BLOOD
SERUM 25(OH)D
25(OH)D
1,25 D
UNIQUE
DNA
CODE
ON
DEMAND

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
SERUM 25(OH)D
25(OH)D
1,25 D
UNIQUE
DNA
CODE
ON
DEMAND

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
SERUM 25(OH)D
25(OH)D
1,25 D
+SAFETYSWITCH
UNIQUE
DNA
CODE
ON
DEMAND

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
SERUM 25(OH)D
1,25 D
VDR
RXR
VDRE
25(OH)D
1,25 D
+SAFETYSWITCH
UNIQUE
DNA
CODE
ON
DEMAND

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
SERUM 25(OH)DTranscription!!
1,25 D
VDR
RXR
VDRE
25(OH)D
1,25 D
+SAFETYSWITCH
UNIQUE
DNA
CODE
ON
DEMAND

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
1,25 D
VDR
RXR
VDRE
25(OH)D
1,25 D
+SAFETYSWITCHSAFETYSWITCH
UNIQUE
DNA
CODE
ON
DEMAND

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
1,25 D
VDR
RXR
VDRE
25(OH)D
1,25 D
UNIQUE
DNA
CODE
ON
DEMAND
CRITICAL PROTEINS
e.g. CATHELICIDIN

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
1,25 D
VDR
RXR
VDRE
25(OH)D
1,25 D
UNIQUE
DNA
CODE
ON
DEMAND
CRITICAL PROTEINS
e.g. CATHELICIDINReplication!!

35
TRILLION
CELLS
!
VDR
RXR
BLOOD
1,25 D
VDR
RXR
VDRE
Blood Pressure
Cancer
Heart Disease
MS, TB, Flu
Asthma
T1 Diabetes
T2 Diabetes
Obesity
Met Syndrome
Alzheimers
25(OH)D
1,25 D
UNIQUE
DNA
CODE
ON
DEMAND
CRITICAL PROTEINS
e.g. CATHELICIDINReplication!!

2014 Ivor Cummins BE(Chem) CEng MIEI SAFETYSWITCH↑↑CATHELICIDIN

Prelude
6.The Solution
Epilogue
Q&A

Survival Outcome for low 25(OH)D reminiscent of Smokers VsNon-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, and
Joseph B. Muhlestein, MDa,b, for the Intermountain Heart Collaborative (IHC) Study Group
(Am J Cardiol2010;106:963–968)
Population 25(OH)D Levels
Adequate
>30ng/ml
36.4%
V. Low <16
16.7%
Low
16-30 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 CollCardiol2011;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 Colon
Cancer Risk associated with 38ng/ml 25(OH)D
Odds Ratio of Colorectal Cancer
P trend <0.0001
COLON CANCER INCIDENCE
10
20
40
30

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 Colon
Cancer Risk associated with 38ng/ml 25(OH)D
Odds Ratio of Colorectal Cancer
P trend <0.0001
COLON CANCER INCIDENCE
COLON CANCER MORTALITY
RR = 0.28
RR = 0.44
Relative risk
10
20
40
30
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,EdwardL. 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 risk
with 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,EdwardL. 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 risk
with 48 ng/ml
P trend <0.002
R2= 0.94
50% lower risk
with 52 ng/ml

Association is Dramatic, and mechanism’s available.
Key Takeaways:
Where would you rather be?
BREAST CANCER MORTALITY
RR = 0.28
P <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 AdvNeurolDisord
(2013) 6(2) 81–116
DOI: 10.1177/
1756285612473513
Ireland
53O 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 AdvNeurolDisord
(2013) 6(2) 81–116
DOI: 10.1177/
1756285612473513
NO
MS
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) vs273 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

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) CengMIEI
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 1stYear 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 1styear 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 vsType1 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 VitD

Summary:
Incidence Rate studied for 1978 onwards, & some Trend Messing about…
10
20
30
40
50
60
70
IU/Day VitD

Summary:
Conclusion: Not quite clear? Questioned. Supplemented Dairy acknowledged.
Incidence Rate studied for 1978 onwards, & some Trend Messing about…
D-fortified
Dairy
IU/Day VitD
10
20
30
40
50
60
70

Remove the inappropriate inferences, and plot a natural curve
EngineeringStyle Summary:
D-fortified
Dairy
IU/Day VitD
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-fortified
Dairy
IU/Day VitD
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-fortified
Dairy
IU/Day VitD
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: HypovitaminosisD 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: HypovitaminosisD 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 ng/ml
0
5
10
15
20
% Respiratory Infection
Month
Season
0
5
10
15
20
% Respiratory Infection
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 Nutr106, 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
AloiaJF, Li-Ng M: Epidemic influenza and vitamin D. EpidemiolInfect 2007; 135: 1095–1096
Cannellet al. VirologyJournal 2008 5:29 doi:10.1186/1743-422X-5-29.
Increased to 2000 IU/day in 3rdYear

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”

Witness An Unfolding Catastrophe….
NHANES III (1988-1994)
SERUM 25(OH)D: % >30ng/ml
10
20
30
40
50
NHANES (2001-2004)

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
Pineal Hormone
Vitamin D
SKIN

doi:10.1038/ejcn.2012.78
Pineal Hormone
Vitamin D
SKIN

USA
25(OH)D
Distribution
< 32ng/ml > 32ng/ml
Recall Where We Are Now…..
doi:10.1038/ejcn.2012.78
Pineal Hormone
Vitamin D
SKIN

doi:10.1038/ejcn.2012.78
Recall Where We Are Now…..
Pineal Hormone
Vitamin D
SKIN

The Skin Cancer / Melanoma Hysteria
J Am AcadDermatol. 2006 Feb;54(2):301-17
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)

330
340
350
360
360
370
380
390
400
Green is zone that theoretical modelling suggests “Cosmetic” Skin Cancers

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
~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
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
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 MelanomaVictim 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:
HR

Int. J. Cancer: 87, 145–150 (2000)
Generally Higher Risk of Cancer with increased sunscreen use
HR

Int. J. Cancer: 87, 145–150 (2000)
this also applied after adjustment for Skin, Exposure Frequency and Duration
HR

Int. J. Cancer: 87, 145–150 (2000)
UVA Mechanism, Lack of UVA Protection, Vitamin D and OverExpHighlighted
this also applied after adjustment for Skin, Exposure Frequency and Duration
HR

HR

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 Halvedin 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
6.The Solution
Epilogue
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 Fat
Diet
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 Fat
Diet
Low Calcium
Diet
HIGH25(OH)D
>60? ng/ml
Excess SUN Exposure LG
Excess D3Supplements
AND
/OR
Low
VitK2
Excessive
Calcification?

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 Ratio
Low Fat
Diet
Low Calcium
Diet
OPTIMUM25(OH)D
32-50 ng/ml
Fat-Nutrient Dense Diet
Oily Fish, Cod Liver, Pate, etc
CorrectD3Supplements
HIGH25(OH)D
>60? ng/ml
AND
AdequateCalcium
AND
/OR
AdequateVitA
AdequateVitK2
Excessive
Calcification?
Low
VitK2

LOW25(OH)D
<32 ng/ml
Blood Pressure
Cancer
Heart Disease
MS, TB, Flu
Asthma
T1 Diabetes
T2 Diabetes
Obesity
Met Syndrome
Alzheimers
Low Fat
Diet
Low Calcium
Diet
OPTIMUM25(OH)D
32-50 ng/ml
Fat-Nutrient Dense Diet
Oily Fish, Cod Liver, Pate, etc
CorrectD3Supplements
HIGH25(OH)D
>60? ng/ml
AND
AdequateCalcium
AND
/OR
AdequateVitA
AdequateVitK2
Immune Function
Bone Strength
Disease Protection
Cancer Resistance
Vigour & Longevity
Healthy Sun Exposure
UVB/UVA Ratio
Excessive
Calcification?
Low
VitK2

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

•Calciumis 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

•VitaminK2 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

•VitaminK2 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
•VitaminA 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 AdjtProf. Family and Preventative Medicine, Division of Epidemiology, University of San Diego. Internationally recognized expert on the disease implications of vitamin D.
Dr. Chris Masterjohn
PhD in Nutritional Science and Assistant Professor of Health and Nutrition Sciences at Brooklyn College.
Dr. Stephanie Seneff
Senior Research Scientist at MIT.
BS (Biophysics), MS/EE and Ph.Din Electrical Engineering and Computer Science MIT.
Prof. Reinhold Vieth
Professor 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.
DrGrimes
ccccc.

Coronary Vascular Disease
Vitamin D and Cardiovascular Disease
Carl J. Lavie, MD, John H. Lee, MD, Richard V. Milani, MD
(J Am CollCardiol2011;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 NatlCancer Inst2007;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?
Borderline
Significant
Estimated D Intake
Non-Supplement Users Subgroup with poor VitD intake showed signal

Statistically
Significant
Estimated D Intake
Borderline
Significant
Estimated D Intake
Supplement Users Subgroup with poor VitD Intake showed signal

Supplement Users Subgroup with poor CaIntake showed signal
Statistically
Significant
Statistically
Significant
Estimated D Intake
Estimated CaIntake
Borderline
Significant
Estimated D Intake

Conclusion: Engineering Signal There, but study is otherwise Near-Worthless
Statistically
Significant
Statistically
Significant
Estimated D Intake
Estimated CaIntake
Borderline
Significant
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?

2014 Ivor Cummins BE(Chem) CEng MIEI ↑↑CATHELICIDIN

The Centrality of the Sun
….A Profound Evolutionary Paradigm
HEALTHY
Sun Exposure
But NO
BURNING!

HEALTHY
Sun Exposure
But NO
BURNING!
D
Synthesis
Plus
Cholesterol

HEALTHY
Sun Exposure
But NO
BURNING!
D
Synthesis
Plus
Cholesterol
Cholesterol
Sulfate
Plus
Cholesterol / Sulfur

HEALTHY
Sun Exposure
But NO
BURNING!
D
Synthesis
Plus
Cholesterol
Cholesterol
Sulfate
Plus
Health
+Longevity

HEALTHY
Sun Exposure
But NO
BURNING!
D
Synthesis
Plus
Cholesterol
Cholesterol
Sulfate
Plus
Health
+Longevity
B.S. degree in Biophysics in 1968
M.S. and E.E. degrees in Electrical Engineering in 1980
Ph.Ddegree in Electrical Engineering and Computer Science in 1985
(All from MIT)
MIT Senior Research Scientist who has spent 3 decades
at 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, TakaakiSegawa, Minoru Okazaki, ManaKurihara, YasuyukiWada, and Hiroyuki Ida
Am J Clin Nutr 2010;91:1255–60.

Key Takeaways:
Am J Clin Nutr 2010;91:1255–60.
In a (rare) experiment, D3 supplements reduced Influenza A by >40%

Key Takeaways:
Am J Clin Nutr 2010;91:1255–60.
Marked in Children not receiving existing supplements –reduction of ~ 65%

Key Takeaways:
Am J Clin Nutr 2010;91:1255–60.
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
•Calcitrioldecreases 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 ofUVradiation. Dashed and dotted line (blue) shows spectrum of previtaminD3 formation obtained from plotting reciprocal of photoenergy(1/w cm_2). Dashed line ( green) represents both action spectrum of induction ofsquamouscell carcinoma in human beings mathematically derived from experimental data obtained from murineskin, and wavelength dependence of induction of DNA damage, in this case cyclobutanepyrimidine 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 HydroxyVitamin 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 ?

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

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