The Art and Science of Supplementation

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The Art and Science of Supplementation

• Priorities, Pitfalls, Practice
• Michael Rae
• CR Society IIIrd Conference

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The Dream
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The Reality (So Far!)
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For more than 60 years the only dietary
manipulation known to retard aging was caloric
restriction, in which a variety of species
respond to a reduction in energy intake by
demonstrating extended median and maximum life
span.
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Supplement Fallacies

• It cant hurt, and it might help
• You cant win if you dont play
• In vitro mechanistic speculation (Its an
  antioxidant! Kills cancer cells! Affects gene
  X! Modulates biochemical pathway Y! etc etc).
• Correction of disease - enhancement of normals

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Basic No-Nos

• Retinol 2000 IU
• Synthetic Beta-Carotene
• Excess Mn (UL 11 mg)
• Excess Beta-Carotene (15 000 IU)
• Excess Alpha-Tocopherol
• Substances with no human data
• Graviola
• DHA?

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The Nature of EvidencePrevent What is Going
to Kill You

• RCTs
• Prospective epidemiology strong
  mechanistic/animal evidence
• Studies in genetically normal, healthy,
  well-cared-for mammals

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TIER 1Essential Supplements

• Orthomolecules Only
• Avoid Deficiency
• Biochemical individuality
• Specific disease/risk factors, if evidence of
  safety efficacy strong

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I(a) Avoid Frank Deficiencies

• Scurvy, beriberi, pellagra will kill you dead
• Much cancer heart disease from micronutrient
  deficiency
• Adult-onset CR fails without generous
  micronutrient supply

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Unrecognized Essentials

• Lithium
• Pyrroloquinoline Quinone (PQQ)
• Boron

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Tier 1 Targets

• New IOM Dietary Reference Intakes (DRIs)
• 
  1000IU vitamin D3
• Crunch the numbers! DWIDP Nutribase
• http//www.nutritiondata.com
• Common CR diet deficiencies Mg, Zn, B1, B2, B6,
• proteins impaired metabolism of Ca, Fe, A.
• Get ferritin test! Dean anemic _at_ 36mg Fe/day
  (242 DRI ) -- largely non-heme.
• But gives protection against B1, Mg, Cu
  deficiencies

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Biochemical Individuality

• Extra folate for MTHFR polymorphism
• Riboflavin for NQO
• Other, speculative cases
• Common variance in requirements? RDAs meet 95th
  percentile of population average person will
  have an unusual need for 1 in 20 nutrients.
• Insurance Intuition 1.5X slop factor for
  minerals up to 10 fold for water-soluble
  vitamins

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Balance! Overdose!

• ZnCu
• B vitamins megadose of 1 depresses others
• Ca vs P, Zn, Cu, Fe
• Vitamin A vs bones 2000 IU
• Mn neurotoxic?
• Fe CHD?
• Alpha-tocopherol overdose?

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Specific Diet Styles
Walford Protein? Atkins fiber, vitamin D, B1,
B5, Cu, Mg, Mn, K, Ca too much SaFA.Zone
Copper Ornish B1, B12, EFAs, Zn, E, A,
protein Veg(etari)ans Omega-3, vitamins D, B1,
B12, retinol, protein, Fe, Ca, Zn taurine (250
mg), creatine (5 g), carnitine (ALCAR pref) (500
mg), carnosine (500 mg), choline (200-500 mg).
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I (b) Pharmacologic Supplements for Specific
Diseases/Risk Factors
Bone Health Age, low DXA, very slim, significant
weight loss Strontium Menatetrenone (animal
K2). Dyslipidemia Niacin, pantethine. Diabetes
Lipoic acid, Cr, benfotiamine pyridoxamine? CHF
CoQ10, ALCAR
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Tier 2Good-Diet-In-A-Pill
Dietary Supplements Small number of specific
nutrients with safety efficacy from combination
of prospective epidemiology, with independent
variables, and experimental studies
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Evidence-Based Phytochemicals

• I3C (Brassica, raw vegetables) 20 mg
• Sulforaphane (Brassica, raw vegetables) 7 mg
• Allyl sulfides (garlic) 55 mcg
• Limonene (citrus) 20 mg
• Trans-Resveratrol (wine) 1.8 mg
• Chlorophyll(in) (green vegetables) 300 mg
• Lycopene (tomatoes) 18 mg
• EgCG (green tea) 1500 mg
• Flavonoids (onions, apples, tea, wine)
• D-Glucarate (?) 15 mg

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Where to find ?

• OrthoCore Most
• Trans-Resveratrol Network Synergy (AOR)
• Limonene
• BioCare Vitasorb CoQ10
• Ingredients typically per 10 drops
• 10mg Co Enzyme Q10
• 10mg Vitamin E 15i.u. (d-alpha tocopherol)
• 4mg Limonene
• Pinnacle Cold Immune 5 mg much else
• Allyl sulfides ??

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Is the Curve Squared?
Is the Curve Squared?
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Tier 3Sensible Megadose Supplementation

• Dietary Supplements Large Human Clinical Trial
  Evidence of Safety ( Efficacy?)
• R()-lipoic acid (diabetic neuropathy)
• CoQ (CHF)
• NAC (pulmonary disease)
• Complete E Complex (heart disease)
• Selenium (cancer).

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Selenium Cancer

• Clarke et al 200 mcg Se cut incidence of new
  cancers by 37, cancer deaths by 50, total
  mortality 17 vs placebo in large human RCT
• No effect on skin cancers (subjects had history)
• Reductions appeared to be in Se-deficient
  subpopulation

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Selenium Pharmacodynamics
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Selenium Form

• Diet and Se in Clarke et al almost all
  selenomethionine hard to form methylselenol
• SeMC much more effectively converted, better
  anticancer agent in animal models
• SeMC effective in inducing DNA repair
  triggering apoptosis in cancer cells at 0.5-1micM
• Unsupplemented plasma levels 5-10 micM 10-20
  micM after 200 mcg Se-methionine
• Selenomethionine cannot trigger apoptosis within
  physiological range

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Stuff I Like

• Arginine 4 g/day vs dicarbonyls
• IP6, 500-2000 mg (esp if avoiding grains)
• Methylcobalamin, 0.5-5 mg
• Carnosine, 1500 mg
• Pyroglutamate, ALCAR, Tyrosine, DMAE to taste
• Mystery tablets

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Tier 4 Life Extension??

• No conclusive evidence!
• Candidates
• R()-lipoic acid
• CoQ10
• Resveratrol
• Benfotiamine Pyridoxamine
• Metformin

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R()-Lipoic Acid

• The Argument
• Rejuvenation of normally-aging rats
• Reduced mtROS production (?)
• The Data
• Weindruch Prolla No effect of racemate on
  mortality or pathology
• Ames (via Arlan Richardson, unpublished) No
  effect on Mortality for R()-LA.

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Survival Curves Dont Lie
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Do They??
strictly speaking it only shows that to be true
in the laboratory mouse. The appropriate
reaction is thus to examine whether these mice
s lifespan may largely be determined by
processes not similarly dominant in mammals in
general, or in humans in particular. The clearest
candidate for such a process is cancer, which is
by far the leading cause of death in lab mice.
Future lifespan experiments should be done
either not in mice at all or in mice engineered
to be highly cancer resistant (such as the p53
overexpressers recently developed by two
groups. -Aubrey de Grey cf Ames, Weindruch,
Spindler
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Cancer, Cancer, Cancer
In the three groups consuming a control caloric
intake, 98 of the control mice, 95 of LA
treated mice, and 97 of CQ treated mice
developed tumors, as compared with only 64 of CR
mice ( p V .001 by Fishers exact test for CR vs.
each other group). -Weindruch Prolla
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CoQ10 The Argument
Mitochondrial Function or Antioxidant No.
Supplements do not increase mt CoQ except in
severe deficiency. CoQ routinely produces mtROS
during electron transport.
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CoQ10 The Data

• Bliznakov, 1981 IV CoQ in midlife normalizes LS
  in rats (mean LS 734 vs 657 d longest-lived
  individual 1084 vs 769 d)
• Lonnrot, 1995 Absolutely no effect of oral CoQ
  equivalent (under Kleibers Law) to 700 mg/d in
  mild-CR rats.
• Steve Harris, 1996 Impressive curve-squaring in
  mild-CR mice of oral CoQ (or folate!) equivalent
  (Kleibers Law) to 700 mg/d.

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Harris CoQ10 Results
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CoQ10 The Data Cntd (Weindruch
Prolla)Mild-CR mice, 600 mg/d
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CoQ10 Yikes!

• Weindruch Prolla, 2004 No effect of oral CoQ
  equivalent to 600 mg/d.
• But
• One notable finding was that 16 mice in the
  Q10-supplemented group showed deposition of a
  crystalline-appearing, insoluble material in
  areas of the heart, liver, and kidney.

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Resveratrol

• The Argument
• Sirtuin activation Linked to LS in yeast (but
  see Kaeberlein et al, 2004), roundworms
  epidemiology for genotype in human longevity
• CRed rodent serum activates sirtuins in human
  cells
• PPAR-g (Guarente), apoptosis resistance
  (Sinclair)
• The Implementation?
• Trans-isomer
• No mammalian LS study
• Fly study only corrective
• Pharmacokinetics/Pharmacodynamics!

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Resveratrol Pharmacokinetics

• Heavy conjugation (sulfation glucuronidation)
  reduces bioavailability ipresumably bioactivity
  (structure-function).
• Total plasma levels peak at 450 mcg/L free
  at 7
• Rapid clearance, rebound 4-8h later after IV
  admin
• The in vitro activity of glucuronides may not
  necessarily reflect their in vivo function,
  granted that ubiquitously exisinting human
  beta-glucuronidase could convert the metabolites
  back to resveratrol locally or systemically in
  vivo.
• Large variations in organ-specific disposition
  much in GI contradictory data in kidney, liver,
  heart low in lung, brain.

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Resveratrol Pharmacodynamics
Next, we assessed whether resveratrol could
activate SIRT1 in vivo Treatment of cells with
a low concentration (0.5 µM) of resveratrol
increased cell survival after ionizing
irradiation Human cells treated with 0.5 µM
resveratrol showed a marked decrease (about 75)
in the level of an acetylated target of SIRT1
deacetylase activity. At higher concentrations
of resveratrol ( 50 µM) the effect was reversed,
which may explain the dichotomy in the literature
regarding the effects of resveratrol on cell
viability.
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Resveratrol Pharmacodynamics II
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Resveratrol Pharmacodynamics III
exquisitely low daily doses of resveratrol
(between 200 mg/kg and 2 mg/kg), which give
peak plasma concentrations of free resveratrol
of probalbly20 nM up to, at the very most, 2 mM
exert potent cancer chemopreventive efficacy and
pharmacodynamic activity In contrast, most
mechanistic studies in vitro suggest that these
effects require the sustained presence of 5-100
mM.
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Resveratrol Efficacy

• We have no mammal results
• Sinclair, NPR, 2003-09-16 "something more like a
  50 increase" in Drosophila LS.
• Nature 430(7000)686-9 lifespan was extended up
  to 29 with resveratrol averaged across
  these trials lifespan was extended 20 in
  females and 16 in males). A restricted diet
  increased lifespan by 40 in females and by 14
  in males (averaged across trials), and under
  these conditions neither resveratrol nor fisetin
  further increased longevity. The lack of an
  additive effect of resveratrol and a low calorie
  diet suggests that resveratrol extends lifespan
  through a mechanism related to caloric
  restriction.
• Increased longevity was associated with reduced
  mortality before day 40.

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Resveratrol Variability
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Benfotiamine Pyridoxamine

• Real anti-glycation nutrients documented in
  diabetic animals and humans
• Benfotiamine intracellular PM extracellular
  (vasculature, heart, joints)
• 150-300 mg Benfo 200 mg PM

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Mystery Contaminant 5-10 of PM
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Closeup
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Metformin

• Ingram et al did not show any real LS gains
• Very safe drug in diabetics
• No increaed risk of lactic acidosis

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Case Study 1 (Judy Dunn), Tier 1

• Food
• Protein IMO RDA 1.5 g/kg needs 30 g more on
  day 2
• EFAs (1/2 T flax oil). Doing 1 g flax oil, 1 g
  fish oil fish IMO bad idea, possibly
  excessive, leaves n6 overbalanced
• Fiber

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Judy, Tier 1

• Pills
• 50 of well-designed multi
• All Bs
• E complex, Cu, Zn, Fe
• 227 mg Sr 5-15 mg menatetrenone?

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Judy, Tiers 2-3

• Tier 2
• 75 OrthoCore as basic multi
• EgCG, Limonene
• Tier 3
• Network Synergy
• 200-600 mcg Se (as SeMC)

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Judy, Tier 4

• R()-LA Top up to 500-600 mg, extra biotin
• Benfotiamine 300 mg
• Trans-resveratrol, when available?
• Metformin (1500 mg)??

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What Shes Doing Now
OrthoCore 9 x Calcium citrate 400
mg Magnesium citrate 200 mg B12 shot
1cc once a month Folic Acid 5
mg Flax oil 1 g Iron 10 mg Fish
oil 1 g EGCG 3 x
day CoQ10 30 mg R()-Lipoic Acid
3 x SeMC _ Benfotiamin
2 x Carnosine 2
x OrthoMind 3 x MSM
1000 mg l-Tyrosine 500 mg Kyolic
garlic extract 600 mg
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Case Study 2 (April Smith)
I am scared of screwing up all the work I've put
into my diet by taking the wrong supplements
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April Smith, Tier 1

• Tier 1
• 50 of well-designed multi, incl. retinol
• Calcium (63-80) D, Iron (89-149 non-heme
  woman, but ), Zinc (76-82) -- Copper 146-163
• Fiber
• Nearly vegetarian taurine (250 mg), creatine (5
  g), carnitine (ALCAR pref) (500 mg), carnosine
  (500 mg), choline (200-500 mg).
• 227 mg Sr 5-15 mg menatetrenone

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April Smith, Tier 2

• Tier 2
• 50 OrthoCore as basic multi
• EgCG, Limonene

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April Smith, Tiers 2-3

• Tier 2
• 50 OrthoCore as basic multi
• EgCG, Limonene
• Tier 3
• Network Synergy
• 200-600 mcg Se (as SeMC)

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April Smith, Tier 4

• R()-LA Top up to 500-600 mg, extra biotin
• Benfotiamine 300 mg
• Trans-resveratrol, when available?
• Metformin (1500 mg)??

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What Shes Doing Now
Tablula rasa!
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Case Study 3 (Dean), Tier 1

• 50 of well-designed multi, incl. retinol
• Iron (history of anemia)
• Small dose of flax oil (Omega-3 (g) 3.14 Omega-6
  (g) 7.28. Shorts (vegan)).
• Vegan taurine (250 mg), creatine (5 g),
  carnitine (ALCAR pref) (500 mg), carnosine (500
  mg), choline (500 mg).
• ALCAR (1500 mg total) Lp(a), in which case 600
  mg R()-LA
• Niacin (2000-4000 mg, niacin or inositol
  hexanicotinate) if Lp(a) doesnt normalize.
• 227-545 mg Sr 15 mg menatetrenone (weight loss
  known low DEXA Fosamax use).
• Low-dose Ca before sleep

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Dean, Tiers 2-3

• Tier 2
• 50 OrthoCore as basic multi ( extra choline)
• EgCG ?
• Tier 3
• Network Synergy
• 200-600 mcg Se (as SeMC)

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Dean, Tier 4

• R()-LA Top up to 500-600 mg, extra biotin
• Benfotiamine 300 mg
• Trans-resveratrol, when available?
• Metformin (1500 mg)??

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What Hes Doing Now
OrthoCore 9 x Ortho-Bone 5
x L-Methionine (LIVD) 500mg Flax seed oil 3x1g
gelcaps Iron Niferex 150 -
Prescription 150mg (elem) DHA 400mg/wk Strontiu
m 227mg Carnosine (LIVD) 500mg ALCAR (Lower
Lp(a) LIVD) 500mg R Lipoic Acid (balance
ALCAR) 300mg
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Bottom Line

• Dont be malnourished
• Dont count on pills -- and dont kill yourself
  with them!
• Cut your Calories -- but understand it to be
  unproven, weak, crude medicine.
• Participate in CR List support CRS
• Support Methuselah Foundation

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What is life extension? -Not accident
avoidance, hygiene -Not correction for genetic
disorders -Not correction for poor
lifestyle -Extension of health (and therefore
lifespan) beyond expectations for a basically
healthy person living a basically healthy
lifestyle.Anti-Aging -a stochastic process
caused by the escalating loss of molecular
fidelity that ultimately exceeds repair
capacity and increases vulnerability to
pathology or age-associated diseases