CRON-WEB's Definitive Guide to Supplementation
Tier II: Disease Risk Reduction in the Healthy?

The Supplement Paradox: massive epidemiological support for fruit and vegetable intake – and intake of many of the nutrients they contain – and lower cancer and CVD risk. Yet supplements keep failing! Why??

[Tautology]: Supplements fail to reflect the key aspects of healthy diets.

[Inference]: Supplement programs which better reflect healthy diets are more likely to yield risk reduction.

How to identify ‘healthy diets’? What are their key (supplementable) components? How can supplements better reflect them?

Best current long-term, healthy human evidence is epidemiology, testing  independent variables and clinical endpoints.

• Independent variables (nutrients and foods), not dependent variables (eg serum levels):
  • RAGE Polymorphism: “HbA(1c), Amadori, and AGE did not reveal any significant association with any of the polymorphisms analyzed. However, significant differences between … “wild-type majority” … and subjects with “mutated” genotypes were found for total carotenoids (P =.001), alpha-carotene (P =.046), beta-carotene (P =.028), lutein (P =.001), lycopene (P =.006), and alpha-tocopherol (P =.047). … The extent of diabetic vascular disease is related to the plasma levels of antioxidants.”[96]
  • Inflammation: “Serum vitamin C was strongly and inversely related to systemic inflammation [ie, CRP].”[97]
  • High-GI Diet: “The age-adjusted mean concentrations (micmol/L) for increasing quintiles of dietary GI were 29.3, 27.0, 25.5, 24.6, and 23.6 (p<0.0001 for trend) for serum alpha-tocopherol and 46.2, 43.2, 39.7, 37.9, and 34.8 for vitamin C (P<0.001 for trend). … [Persisted after] adjustment for sex, ethnicity, education, smoking status, BMI, alcohol intake, physical activity, percent calories from carbohydrates and fat, and total energy intake. [After] adjusting for the same covariates, higher … GI was also associated with lower … alpha-carotene, beta-carotene, cryptoxanthin, and lutein/zeaxanthin.”[98]

How do Supplements and Good Diets Differ?

• Different molecules: Food forms vs. supplement forms
  • Vitamin E: Numerous studies find dietary – and not supplement – “vitamin E” protects against CVD,[99] ,[100],[101] and AD.[102],[103],[104]
    • Alpha-tocopherol is the sole E vitamer in supplements in trials, epidemiology to date, but is minority of “vitamin E” in diet (gamma-tocopherol is plurality).[105],[106],[107],[108],[109]
    • High plasma gamma- – and not alpha- – tocopherol associated with reduced risk of CVD,[110],[111],[112],[113] MI,[114] prostate cancer.[115],[116]
    • Selective gamma-tocopherol depletion and nitration in AD.[117],[118]
    • Gamma-, not alpha-tocopherol reduces PGE2, LTB4, signs of inflammatory damage in vivo[119] and COX-2 activity in macrophages and epithelial cells ;[120] superior RNS-quenching capacity in vitro; [121],[122],[123] preferential uptake by macrophages;[124] more favorable effect on LDL metabolism in vitro.[125]
  • Beta-carotene: Extensive review of epidemiology finds b-c from food protective against lung and other cancers. [126]
    • Nearly all trials used synthetic (all-trans) b-c; food b-c is mixture (9,cis- and all-trans-).
    • Synthetic b-c has lower antioxidant activity in vitro[127] and in vivo.[128],[129]
    • Synthetic b-c genotoxic in vitro (!), unlike natural.[130]
  • Selenium: Extensive epidemiology for dietary inverse risk with cancer.
    • Much Se in diet is from grains, meat as selenomethionine – not foods associated with low cancer risk. Se in cruciferous and Allium vegetables (strong inverse association with cancer) contains Se-methylselenocysteine.
    • Animal studies show SeMC a superior anticancer form.[131]
  • Vitamin K: Phylloquinone must be metabolized into menatetrenone (MK-4).
    • ”The tissue specific localization of MK-4 and a metabolic pathway for its production from phylloquinone strongly suggest that there is a yet-to-be-discovered unique role for this form of vitamin K that is independent of the currently recognized coenzyme function.”[132]
    • MK-4 has unique effects on bone tissue and cells in vitro, despite similar gamma-carboxylation coenzymatic activity.[133]
    • Dietary MK-4, not phylloquinone, associated with reduced risk of aortic atherosclerosis.[134]
• Different dose: Just how much are “the group eating the most X” getting in the epidemiology?
  • Too much beta-carotene: Extensive review of epidemiology finds b-c from food protective against lung and other cancers. 126
    • Highest quintile intakes of 8950 mcg (2484 IU)/day,[135] 5902 mcg/day (older, incomplete database),[136] 11399 mcg/day;[137] trials and most supplements 25 mg (6937 IU).
    • Oxidative metabolites of b-c, if not detoxified by compensatory C and E, may increase carcinogenesis in smokers;[138] more b-c = more imbalance.
    • In ferrets, pharmacologic dose of synthetic b-c results in keratinized squamous metaplasia, with or without exposure to cigarette smoke; not observed with physiologic dose.[139]
  • Too little lycopene: Lots of good epidemiology for tomatoes, tomato paste, dietary and plasma lycopene vs. various cancers.[140]
    • Highest quintile intakes of 18, 135 9 (older, incomplete database), 136 13 137 mg/day; typical multis contain 0.3-6 mg (vs. lowest quintile intake of 6 mg! 135).
    • Very strong surrogate results in RCTs in prostate cancer patients with lycopene (30 mg/day led to lower DNA damage and incidence of high-grade carcinoma in situ, and PSA)[141] or tomato paste (22 mg lycopene from target 30 mg (3/4 C tomato paste) led to lower DNA damage &PSA).[142]
    • Earlier epidemiology underestimated lycopene intake due to incomplete database for tomato products. 29,[143]
  • Too little Se? Plenty of good epidemiology for Se intake (not tissue levels (eg toenail)) vs. cancer.[144]
    • Much, again, supports simple correction of deficiency, but world intakes often much higher (800-1600 mcg in China).
    • With bulk of dietary Se (SeMet, some inorganic), methylselenol (anticancer metabolite) only formed at extreme end and full benefits only seen at supranutritional levels – at or near toxic range.
    • SeMC forms methylselenol at much lower doses (above).
  • Excellent evidence for optimal vitamin C 100-200 mg.
    • LPI review of epidemiology: CVD, possibly cance4r benefits of ~90-100 vs ~<45 mg/day and no further.[145] Similar data, but ‘no conclusions can be drawn,’ from IOM; new DRI, 90 mg/day.[146]
    • Plasma levels do not increase at intakes >100 mg/day when tested 1 x 30 - 4 x 45 mg, but decreasing-returns increases from 4 x 250 and 4 x 500 mg;[147] plasma levels essentially plateau at 200 mg w/small increases 500-2500 mg, but tissue saturation (selective active transport into leukocytes) complete at ~100 mg/day and excretion of unmetabolized C jumps at >60 mg/day.[148]
      -No evidence for reduced DNA damage from 60-600 mg/day; lipid damage almost entirely bogus measures (ex vivo LDL oxidizability unphysiologic; TBARS, MDA reflect all kinds of other stuff); F2 isoprostanes inconsistent;145, 146 continues in later studies. 51,[149],[150],[151],[152]
    • Pauling et al ‘making the case’ from animals who synthesize their own C, etc – very weak ‘evidence.’
    • No data on humans consuming 10 g C/day! 95th percentile intake 1200 mg. 146
    • ‘Hypoascorbemic’ guinea pigs have shorter mean, max, minimum LS when given 10-20 ‘RDAs.’[153]
    • Uric acid and other factors may have replaced C in humans.[154]
  • B-Vitamin Doses Whacked: Many times greater than food intakes or RDAs with no good evidence of benefit for most.
    • Can’t absorb >~8-12 mg thiamin dose. [155],[156],[157],[158],[159],[160]
    • PABA of no nutritional value to humans: needed by bacteria to synthesize folate, but PABA-depleting sulfa drugs harmless to mammalian cells; ‘it’s an antioxidant!!’ – so??
    • Why 50 mg of everything?? Strange ‘coincidence:’ purely arbitrary.
• Missing molecules:
  • C and ‘E’ for detoxing oxidized b-c products. 138
  • b-c partly a ‘marker’ for other carotenoids.
  • Unknown dietary constituents: eg. new vitamin (?), pyrroloquinoline quinone.[161],[162],[163],[164]
  • Phytochemicals. A plethora! Which are important?
    • Mechanistic studies (esp in vitro, or in carcinogen-exposed animals) insufficient: must have epidemiological justification.
    • Key Criterion: consistent epidemiological support for foods rich in phytochemical, plus animal studies and mechanistic rationale.
      • Rules out ginger, curcumin, licorice, apigenin/luteolin, non-dietary herbs, etc.
      • Cancer: Strongest associations: vegetables more than fruits;[165],[166] raw vegetables; Allium and cruciferous vegetables; green vegetables; carrots, tomatoes (combine with newer data reviewed in ( 140, 135), and citrus fruits.165
        • Points to allyl sulfides, I3C (RCT for cervical carcinoma in situ 79 – but again, mixed benefits/risks 80 – stick to broccoli), IP6, sulforaphane (specific, gene-linked epidemiology[167]), limonene (separate epidemiology for citrus peels[168],[169]).165, 166,[170]
        • Major mechanism: altered carcinogen metabolism.
          • Phase I detoxification (CytP450/ MFO) polarizes ‘procarcinogens,’ making them more readily conjugated with eg. acetate, glycine, sulfate by Phase II detoxification.
          • Conjugated forms water-soluble: can’t cross cell membranes, and readily excreted in bile and urine.
          • Procarcinogens “activated” into carcinogens by Phase I enzymes.
          • Polymorphisms in biotransformation enzymes associated with cancer risk.[171]
          • Many putative anticarcinogens depress Phase I (I3C, allyl sulfides) or induce Phase II (sulforaphane, limonene).165, 166, 167, 170, 171,[172],[173]
        • D-Glucarate: Not mentioned in major reviews.
          • Found in citrus fruits, cruciferous vegetables.[174],[175],[176],[177]
          • Inhibits b-glucuronidase (undoes glucuronidation conjugation; releases original carcinogen).
          • High b-glucuronidase, low D-glucarate,[178],[179],[180] poor glucuronidation associated with cancer/cancer risk.
          • Extensive animal studies.83
        • Chlorophyll: rarely suggested in reviews, but evidence IMO strong:
          • Widespread in vegetables (esp green vegetables). Would explain specific association for green vegetables.
          • FWIW, “A close positive relationship between the chlorophyll content of various vegetable extracts and their ability to inhibit mutaions in the Ames Salmonella system.”[181]
          • Extensive rodent and mechanistic studies (largely using chlorophyllin): acts as an “interceptor molecule,” complexes with carcinogens.
          • Effective against real-world carcinogens (aflatoxin, HCAs, PAH).
          • Similar efficacy of food chlorophyll, chlorophyll metabolites, chlorophyllin in animal studies. 181,[182],[183],[184]
          • RCT for reduced aflatoxin-DNA adducts (high-exposure population).[185]
  • CVD and Stroke: less clear, beyond folate, minerals, antioxidant vitamins; likely much of inverse association due to low GI and GL of vegetables, displacement of saturated fat.
    • Strongest evidence for flavonoids: notably tea, onions (quercetin); berries?[186] – but ubiquitous and so hard to deconfound. 166

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