Over the past century, industrialized societies have seen a meteoric rise in the so-called diseases of civilization: obesity, cardiovascular disease, osteoporosis, autoimmune disease and cancer. These disorders are often associated with apparent "deficiencies" in critical nutrients such as vitamins, minerals and hormones. This talk will examine the arguments for and against supplementation, together with the evidence from interventional studies. The focus will be on the supplementation with Vitamin C, Vitamin D, and calcium. I will argue that the case for supplementation as a long-term preventive strategy has not be made, and often overlooks the compensating effects of homeostatic regulation.

1. The case against
nutritional supplements
Todd Becker
gettingstronger.org
Ancestral Health Symposium
August 17, 2013

2. How did our ancestors thrive without supplements?
Do we really need them?

3. Main Thesis
• For most* people, routine supplementation with
vitamins, minerals and essential fatty acids is
unnecessary and may be counterproductive
• A paleo diet and lifestyle – enhanced by hormesis –
reduces or eliminates the need for supplementation
* Caveat: Short term supplementation may be advisable in cases of
malnutrition, infection, illness, pregnancy or special athletic goals.

4. Outline
• The case for nutritional supplements
• General doubts and objections
• Four examples
– Antioxidants
– Vitamin D
– Calcium
– Omega-3 fatty acids
• The role of hormesis

5. The “paleo” case for nutritional supplements
• Inability to synthesize (vitamin C)
• Inefficient synthesis (vitamin D, omega-3)
• Deficient soils and oceans (minerals, omega-3)

6. General doubts and objections
1. You are not what you eat
You are what your body does with what you eat
This applies to macronutrients
• Excess glucose   triglycerides
• Excess protein   glucose
• Soluble fiber   short chain fatty acids

7. General doubts and objections
1. You are not what you eat
You are what your body does with what you eat
But it also applies to micronutrients
• Malabsorption / excretion (calcium)
• Oxidation (antioxidants, fatty acids)
• Hormone signaling (vitamin D)
• Gene expression (antioxidants, vitamin D)

8. General doubts and objections
2. Nutrients are regulated homeostatically
Exogenous nutrients
can downregulate
endogenous defenses
Examples
– Antioxidants
– Vitamin D

9. The case for antioxidants
• Reactive oxygen species (ROS)
• Can’t synthesize our own vitamin C
• Mega doses suggested for:
– Common cold
– Infections
– Cancer
• Other antioxidants
• Vitamin A
• Vitamin E
• Beta carotene
• Co-Q10
• Alpha lipoic acid

10. Fruits & vegetables
• Health benefits of fruits and vegetables
“ associated” with antioxidant content
?

11. Interventional studies show no benefit
…or even positive harm
AMA (2004):
Meta-analysis 20 studies: C, E beta carotene
> No reduction in CVD, stroke or mortality
Cochrane (2008):
Meta-analysis 67 studies: A, C, E, selenium
> No reduction in mortality
Antioxidants adversely impact exercise!
Ristow (2009):
Vitamins C and E + exercise for 4 weeks
> decreased insulin sensitivity improvement
> reduced antioxidant enzyme levels
Before
exercise
After
exercise

12. What could be going wrong?
• Oxidative “stress” by ROS is not always bad!
• ROS are essential for cell signaling, exercise regulation,
and fighting infection
• Moderate ROS plays a hormetic role in improving
mitochondrial function and upregulating endogenous
antioxidant enzymes
• Antioxidant supplements indiscriminately suppress cell
signaling and downregulate endogenous antioxidant enzymes

13. Endogenous Antioxidants
• The xenobiotic metabolism produces Phase II antioxidant
enzymes to catalytically neutralize chemical toxins:
– Superoxide dismutase (SOD), glutathione reductase (GSH), etc.
• We have co-evolved with certain edible plants to tolerate
modest amounts their polyphenolic “toxins”
• Exposure to these polyphenolic “hormetins” activate the Nrf2
pathway, which produces the endogenous antioxidants
• Hormetins are abundant in pigmented, bitter plants and herbs
• Resveratrol
• Sulforaphane
• Curcumin
• Green tea

14. Supplements vs. Hormetins
Supplements: Antioxidants, minerals,
vitamins and essential fatty acids taken to
correct apparent deficiencies
Hormetins: Spices, herbs, phytonutrients
that activate and strengthen the body’s
endogenous processes of defense, repair,
and tolerance and performance.
Typically hormetins work synergistically
and at low dose

15. Hormetins are agents of hormesis
• Dose-response effect
• Stressors we’ve evolved with
• Activate Defense & repair mechanisms
Edward Calabrese
Suresh Rattan

16. Many examples of hormesis
• Chemicals
• Sunlight (UV)
• Ionizing radiation
• Exercise
• Barefoot running
• Fasting / Ketosis
• Cold exposure
• Immunotherapy
• Vision Improvement

17. Vitamin C recycling
• Vitamin C (ascorbate) neutralizes oxidants 1-for 1
• Dehydroascorbate (oxidized vitamin C) is readily recycled
thousands of times by endogenous glutathione reductase
• Elevated blood glucose inhibits reuptake and recycling of
dehydroascorbate
ROS

18. Vitamin C storage
• Advocates of mega dose vitamin C note that most primates
(simians) consume 10-20X the RDA of vitamin C
• But humans can efficiently store 10-100X the blood levels of
vitamin C in adrenal, thymus, pituitary and other glands –
enough to ward of scurvy for 3-8 months
Antioxidants: Take home message
• Based upon adequate storage and catalytic recycling, a low
glycemic diet rich in hormetic polyphenols greatly decreases
the daily need for dietary and supplemental vitamin C

19. The case for vitamin D
• From diet or action of UV on skin
• D3 itself is not biologically active
– Requires liver & kidney conversions
– Active form (1,25-D) binds VDR
receptor
• Vitamin D has a dual function
– Low dose: calcium absorption
– Higher dose: immune function (VDR)

20. Correlation and causation
• Low vitamin D3 levels correlate with higher heart
disease, stroke, immune problems, infection & overall
mortality
• But is low vitamin D3 a cause – or a consequence – of
ill health?
– Healthy people may get more sun and exercise,
elevating D3
– People with low D3 often have elevated 1,25-D
• Could 25-D be a mere “biomarker” for health status?

21. Vitamin D risks & questions
• Interventional studies show no benefit, possible harm:
– AMA(2010): Supplements for 5 years in women over 70
produced 15% more falls and 26% more fractures
– NCI (2012): Elevated 25-D linked to aggressive prostate cancer
• Vitamin D is a secosteroid – binds the VDR receptor
– VDR activation dampens the innate immune response
– Provides short term control of infection and autoimmunity
– Long term supplementation with the inactive 25-D might
inhibit 1,25-D action and/or down-regulate VDR function

22. An alternative to vitamin D?
• Can we get the benefits of Vitamin D without the
risks of daily supplementation or sun exposure?
• Hoyer-Hansen studied the pathways activated by the
VDR receptor and noted that
“Autophagy could be a general mediator of the
health-promoting effects of 1,25-(OH)2 (D3).
Accordingly, there is a striking overlap among
the diseases promoted by VD deficiency and
defective autophagy.”

23. Autophagy
• A cellular housecleaning process
– Recycles damaged cytoplasmic matter
– Activated by calorie restriction and exercise
• Regulates the same pathways as vitamin D receptor
– Inhibits mTOR, bcl-1, bcl-2
– Inhibition of carcinogenesis and tuberculosis
Take home message – Vitamin D
• Be wary of supplementing , especially at high doses
• Consider that intermittent fasting and exercise might
activate the same metabolic benefits

24. The case for calcium supplements
• Strong bone formation requires an adequate supply
of calcium
• Deficiencies of calcium (and vitamin D) lead to rickets
and osteoporosis

25. What do interventional studies show?
• Harvard study of 77,761 nurses for 12 years showed
no protection from bone fractures at any dose of
calcium (from dairy or supplements)
• Confirmed by similar studies in Australia and the UK

26. Is calcium getting to where it is needed?
• Blood levels of calcium are tightly regulated
• High levels of vitamin D deplete vitamin K2 and
promote calcification of vascular tissue
• On a standard diet high in grains, phytates bind
calcium, leading to poor absorption
• High blood glucose and insulin levels “leach” calcium
from bones
• In short, taking calcium supplements doesn’t ensure
it will get into bones

27. A better way to build bones
• The solution is not supplementation, but a whole
food diet of “available” calcium, with vits. D, A, K2
• Weight bearing exercise is the most practical way
to stimulate uptake of calcium into bones

28. The case for omega-3 supplements
• EPA and DHA are long chain essential N-3 fatty
acids (EFAs), critical to brain, eye and heart
function
• A low n-3/n-6 ratio has been linked to CVD,
Alzheimer’s, depression, autoimmune disorders
• Most Westerner’s show poor enzymatic
conversion of shorter chain n-3s to the EFAs
• EFAs from consumption of fatty fish is inadequate
Hence, dietary supplementation is recommended

29. Stillwell, William. “The role of polyunsaturated lipids in membrane raft
function”, Scandinavian Journal of Food and Nutrition, 2006; 50 (S2): 107 -113.

30. However EFA supplements have a downside
• A 2013 JAMA study of 2000 men found that men
with the highest blood levels of EPA and DHA had
– 71% higher risk of aggressive prostate cancer
– 44% higher risk of low-grade prostate cancer
• These results replicate earlier findings from a
2011 study
• Under-reported: The increased risk appears
associated only with the more easily oxidized
DHA, not EPA (Nina Bailey)

31. Diet impact on DHA “survival”
• Low carbohydrate diets
dramatically increase “end product”
DHA in muscle membranes
– This improves insulin sensitivity and
inhibits lipogenesis
• This happens despite reduced
enzymatic synthesis of DHA under
carbohydrate restriction
• Low carb diets appear to help
“preserve” DHA by suppressing
ROS-driven lipid peroxidation
From Volek and Phinney, “The Art and Science of Low Carbohydrate Living” (2011)

32. Diet controls fate of EFAs
• DHA is less stable than EPA to lipid peroxidation. The
higher association of DHA with cancer may reflect
this fact.
• Low carb/paleo/non-inflammatory diets result in a
reduced dietary requirement for EFAs because they
are better “preserved” against oxidative damage and
inter-conversion is optimized
• Thus, a non-inflammatory diet may be critical to
getting EFA benefits without the risks posed by
unstable and “damaged” DHA

33. Parting thoughts
• Recommended Daily Allowances for supplements
came from studies of people eating Western diets
• Those diets oxidize nutrients, impair absorption
and recycling, and downregulate endogenous
defenses
• A low insulinogenic, non-inflammatory, whole food
diet greatly improves micronutrient utilization
• Phytonutrients and hormesis can boost
endogenous antioxidants and other defenses

34. For further reading
Related articles on my blog
gettingstronger.org
“The case against antioxidants”
“Why I don’t take vitamin D supplements”
“An alternative to vitamin D supplements”

35. References
Antioxidants
1. Kris-Etherton, Penny M. et al, “Antioxidant vitamin supplements and cardiovascular disease”
Circulation 2004, 110: 637-641.
2. Bjelakovic, Goran et al, “Antioxidant supplements for prevention of mortality in healthy
participants and patients with various diseases”. Cochrane Database of Systematic Reviews 3:
John Wiley & Sons, 2008 and updated 2012.
3. Cheung, M.C. et al, “Antioxidant supplements block the response of HDL to simvastatin-niacin
therapy in patients with coronary artery disease and low HDL” Arterioscler Thromb Vasc Biol,
2001, Aug; 21 (8) 1320-6,
4. Ristow, Michael et al., “Antioxidants prevent health-promoting effects of physical exercise in
humans” PNAS 2009 ; published ahead of print May 11, 2009, doi:10.1073/pnas.0903485106
5. Mendriatta, S. et al. “Erythrocyte ascorbate recycling: antioxidant effects in blood”, Free Radic
Biol Med. 1998, 24 (5): 789-97.
6. Wang, Yaohui et al. “Ascorbate recycling in human neutrophils: Induction by bacteria” Proc. Nat
Acad Sci of U.S.A., 1997, 94 (25) 13816-9.
7. Li, Guolin, “The Positive and Negative Aspects of Reactive Oxygen Species in Sports
Performance”, Ch. 6 in Michael Hamlin et al., ed, Current Issues in Sports and Exercise
Medicine, ISBN 978-953-51, 2013, -1031-6,, 2013

36. References
8. Rountree, Robert, “Beyond Antioxidants: Nutrigenomic Regulation of the Adaptive Stress
Response.” Integrative Practitioner, 2010.
http://www.integrativepractitioner.com/article.aspx?id=17183
Vitamin D
9. Sanders, K.M. et al., “Annual High-Dose Oral Vitamin D and Falls and Fractures in Older
Women: A Randomized Controlled Trial. JAMA 2010, 303 (18) , 1815-1822.
10. Masterjohn, C. “Vitamin D toxicity redefined: vitamin K and the molecular mechanisms” Med
Hypotheses 2007, 8 (5): 1026-34.
11. Agus, David B., The End of Illness. New York: Simon & Schuster, 2011.
12. Hoyer-Hansen, M.D. “Autophagy as a basis for the health-promoting effects of vitamin D”.
Trends in Molecular Medicine (2010) 16:7, 295-302
Calcium
13. Feskanich, D. et al. “Milk, dietary calcium and bone fractures in women: a 12-year prospective
study” Am J Public Health, 1997, 87 (6) 992-7.

37. References
Omega-3 fatty acids
14. Stillwell, William. “The role of polyunsaturated lipids in membrane raft function”, Scandinavian
Journal of Food and Nutrition, 2006; 50 (S2): 107 -113.
15. Brasky, T. M. et al. “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT
Trial” Journal of the National Cancer Institute, Aug 7; 105 (15) 1132-1141, 2013
16. Bailey, Nina. “DHA, not EPA, responsible for omega-3 prostate cancer risk. Igennus Healthcare
Nutrition blog, http://www.igennus-hn.com/dha-not-epa-responsible-for-omega-3-prostate-
cancer-risk-by-dr-nina-bailey/
17. Volek, Jeff S. and Stephen D. Phinney. The Art and Science of Low Carbohydrate Performance: A
Revolutionary Program to Extend your Physical and Mental Performance Envelope.
Createspace.com, Chapter 9 and references, 2012
Hormesis
18. Calabrese, Edward J., and Linda A. Baldwin. "Hormesis: The Dose-Response Revolution." Annu.
Rev. Pharmacol. Toxicol. 43: 175-97, 2003.
19. Rattan, Suresh I and Dino Demirovic. “Hormesis Can and Does Work in Humans.” Dose-
Response. 8(1): 58-63, 2010.