CRON-WEB's Definitive Guide to Supplementation
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.
CR [calorie restriction] “has been repeatedly shown
to increase life span and delay the onset of age-associated pathologies
in laboratory mice and rats.” “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.”
No confirmed evidence for life-extending effects of
any drug or supplement in normal, healthy mammals.
‘Successes’ in short-lived strains, suboptimal environments (well-cared-for,
normal mice, average LS ~900 days, max ~1200).
Failures in well-cared-for animals. Eg. “Mice were fed modified
AIN76 diet or modified AIN76 supplemented with vitamin E, glutathione
(GSH), vitamin E and GSH, melatonin, or strawberry extract starting at 18
of age [~54 human years]. … Lesion burden and incidence of specific lesions
observed amongst the various groups in this study did not differ. There
were no differences observed for longevity of any of the study groups.
The longevity observed in this study was similar to that previously reported
for male C57BL/6 mice.”
Eg. LEF LifeSpan Project:
melatonin; CoQ10; lipoic acid (racemate); aminoguanidine; lipoic acid
(racemate) + aminoguanidine + CoQ + Pregnenalone; ALCAR + lipoic acid
(racemate) + lycopene +
alpha-tocopherol; ALCAR + lipoic acid
(racemate) + CoQ +
NADH; melatonin + pregnenalone. No effect (see
Deprenyl: data reviewed in ().
Only Knoll (inventor has reported increased lifespan for deprenyl;
variations by strain, age, etc, in response; no reasonable basis for human
- Highly inconsistent; many negative findings; much weak design
(case-control, external referent population etc).
- Highly confounded. “[S]upplement use tended to increase with
age, education, physical activity, fruit intake, and dietary fiber intake
and to decrease with obesity,
smoking, and dietary fat intake.”
- Hidden vulnerable subpopulations. Eg folate and colon cancer
in Nurses' Health Study. Preliminary finding: “Higher … folate intake …
to a lower risk for colon cancer (RR, 0.69 ... for intake > 400 microg/d compared with intake < or = 200 microg/d) … [Among] Women who used multivitamins containing
folic acid … After 15 years of use … risk was markedly lower (RR,
0.25 [CI, 0.13 to 0.51]), … the benefit of long-term multivitamin
present across all levels of dietary intakes.”
- But: “Compared with women
without a family history who consumed 200 µg or less of folate/day
…, women without
a family history who consumed >400 µg/day experienced a multivariate
RR of 0.91 (95% CI, 0.69–1.19), … and women with
a family history who consumed >400 µg/day experienced a RR of 1.30 (95%
CI, 0.82–2.08). … Among women with a family history, the RR for those who
consumed >400 µg/day was 0.48 (95% CI, 0.28–0.83) when compared with
women with a family history who consumed 200 µg or less per day.”
- Most epidemiological results demonstrate danger of deficiency,
not protective effect of megadosing (eg. folate (<200 vs >400 mg (DRI)
and colorectal cancer, fish and CHD (no additional protective effect
beyond 2 servings/week), etc).
Randomized, Controlled Trials
- CHAOS: 400-800 IU RRR-alpha-tocopherol/d vs placebo: “a
significant reduction in the risk of non-fatal MI …; however, there was
a non-significant excess of cardiovascular deaths”.
- Several other large studies report no effect on any carciovascular outcome.,,,
- Antioxidant “Cocktails”
- WAVE: 400
IU alpha-tocopherol + 500 mg C ± HRT vs placebo.
“Death, nonfatal MI, or stroke occurred in … 26 vitamin patients and 18
vitamin controls (HR, 1.5; 95% CI, 0.80-2.9).”
- HATS: Simvastatin ± antioxidants
(800 IU alpha-tocopherol, 1000 mg C, 25 mg natural beta-carotene,
1000 mcg Se) ± placebo. “The average stenosis progressed
by 3.9 percent with placebos, 1.8 percent with antioxidants (P=0.16
… ), and 0.7 percent with simvastatin-niacin plus antioxidants (P=0.004)
and regressed by 0.4 percent with simvastatin-niacin alone (P<0.001). The frequency of the
clinical end point was 24 percent with placebos; 3 percent with
simvastatin-niacin alone; 21 percent in the antioxidant-therapy group;
and 14 percent in the
- Heart Protection Study: 600 mg alpha-tocopherol, 250 mg C, and 20 mg b-c
daily) vs. placebo. “[N]o significant differences in all-cause mortality
…, or in deaths due to vascular … or non-vascular … causes. Nor … in the
numbers of … non-fatal myocardial infarction or coronary death …, non-fatal
or fatal stroke …, or coronary or non-coronary revascularisation ...
For the first occurrence of any of these “major vascular events”, there
were no material differences … There were no significant effects on
cancer incidence or on hospitalisation for any other non-vascular cause.”
- ATBC: 20 mg synthetic b-c &/or 50 mg alpha-tocopherol vs. placebo in smokers. “No overall effect was
observed for lung cancer from alpha-tocopherol supplementation
… beta-carotene supplementation was associated with increased lung cancer
risk (RR = 1.16 …). The beta-carotene effect appeared stronger, … in participants
who smoked at least 20 cigarettes daily (RR = 1.25; …) compared with those
who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23)
and in those with a higher alcohol intake (> or = 11 g of ethanol/day
[just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared
with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24).” Later
reports: no effect on gastric, urinary
tract, colorectal, cataract, or maculopathy; no clear effect
on pancreatic or
50 mg alpha-tocopherol decreased, but synthetic b-c may have increased, clinical prostate cancer incidence and mortality.
- Physicians' Health Study: 50 mg synthetic b-c EOD vs. placebo. “Virtually no early or late differences in the overall incidence
of malignant neoplasms or cardiovascular disease, or
in overall mortality ... Among current and former smokers, there were also
no significant early or late differences in any of these end points.”
- CARET: 30 mg synthetic b-c and 25 000 IU of retinol in smokers, former smokers, and workers exposed
to asbestos vs. placebo. RR of lung cancer of 1.28; RR of death from any cause 1.17; of death
from lung cancer, 1.46; and of death from cardiovascular disease, 1.26
(95 percent confidence interval, 0.99 to 1.61).
- Supplementers lost benefit of fruits and
- Antioxidant Polyp Prevention Study: Actually
potentially positive (!): recurrence of colon adenoma. 25
mg synthetic b-c and/or vitamins
C and ‘E’ in vs. placebos. “Among subjects who neither smoked cigarettes
nor drank alcohol, beta-carotene was associated with a marked decrease
in the risk of one or more recurrent adenomas (RR = 0.56, 95% CI
= 0.35 to 0.89), but … a modest increase in the risk of recurrence among
who smoked (RR = 1.36, 95% CI = 0.70 to 2.62) or drank (RR = 1.13,
95% CI = 0.89 to 1.43). For participants who smoked cigarettes and also
more than one alcoholic drink per day, beta-carotene doubled the
risk of adenoma recurrence (RR = 2.07 … P for difference from nonsmoker/nondrinker
RR <.001).” Ambiguous
evidence from CARET and ATBC on role of alcohol – more distal sites?
- Clarke et al JAMA selenium trial:
200 micg Se/day vs. placebo in persons with a history of skin cancer. No
effect on primary end points (incidences of basal and squamous
cell skin cancer); post-hoc endpoints, “nonsignificant reduction in all-cause
mortality … [RR; 0.83; 95% CI, 0.63-1.08] and significant reductions
in total cancer mortality
… [RR, 0.50], total cancer incidence … [RR, 0.63], and incidences of
lung, colorectal, and prostate cancers.”
- “The patient population in this trial was recruited from the eastern coastal
plain of the [US], a region characterized by relatively low [Se] levels
in soil and crops [refs], and by high rates of [squamous cell
carcinoma] and [basal cell carcinoma] of the skin and cancer mortality.[ref]”
- “participants with baseline plasma selenium concentrations
in the lowest two tertiles (<121.6 ng/ml) experienced
reductions in total cancer incidence, whereas those in the
highest tertile showed an elevated incidence (HR = 1.20, 95%
CI = 0.77-1.86).”
- Linxian Trial: Also successful; also in an intentionally-selected
“Well, it Can’t Hurt,
and it Might Help” Mistake
Vitamin A (Retinol/Retinyl Esters)
- Higher Intake, or Serum Levels Increase Fracture
- ”For every 1 mg [3330 IU] increase in daily intake
of retinol, risk for hip fracture increased by 68% ... For intake > 1.5 mg [5000 IU]
/d compared with < 0.5 mg [1665 IU]/d, … risk for hip fracture was doubled”. 34
- Nurses’ Health Study: “women in the highest quintile
of total vitamin A intake … had a significantly elevated relative
risk (RR) of hip
compared with women in the lowest quintile of intake … attributable
primarily to retinol (RR, 1.89 … comparing >/=2000 mcg [6660 IU]/d vs <500
mcg [1665 IU]/d). 35
- Negative association of retinol intake with
BMD; 34,,, no
association for serum levels in NHANES III.
- In animal studies,, vitamin
D does not fully counteract; most of the excess retinol in the first
study 34 was from cod liver oil supplements taken for vitamin D in Nordic
- No risk from dietary carotenoids. 34,
Excess Zn or Zn:Cu
- Competition for ligands (for absorption and
- Frank Zn-induced Cu deficiency demonstrated in humans:
- Zn:Cu of 23.5 (24 subjects) led to low CuZnSOD,
high TC and LDL, low HDL, reduction in enkephalins,
cardiac abnormalities (heart block, tachycardia, MI) (reviewed in ()).
- Zn:Cu of 16 (one subject) led to decreases in ceruloplasmin,
increased TC and LDL, arrhythmia. (reviewed in
- 50 mg Zn/day depresses CuZnSOD 20%.
- Other Cu-deficiency sequelae likely: impaired bone metabolism, poor glucose control, increased AGE, etc.
- Welders, other
industrial inhalation exposure associated with manganism (Parkinsonian syndrome);
reproduced in high-dose animal feeding studies; ecological study showed
increased frequency of neurological symptoms in community with ~3.6-4.6 mg Mn/day from water
as vs. 0.0072-0.03 and 0.16-0.5 mg/day.
- New case-control
study links highest quartile [DEFINE THIS] Mn intake with 1.7-fold
increase in PD risk.
tea rich sources; vegetarian diets may contain 13-20 mg.
- LOAEL from diet
15 mg (increases in serum Mn (‘should’ be tightly regulated));
UL 11 mg from all
- Alpha-tocopherol depletes gamma-tocopherol levels below baseline levels at 100
IU  (& perhaps
After 1 y alpha-tocopherol supplementation (1200
IU), tissue gamma-tocopherol levels take 2y to
recover.  30%
depletion by 371 mg alpha-, even when balanced by >400 mg “other” tocopherols.  Alpha-tocopherol blocks tocotrienol action
on HMG-CoA reductase if >30%
of supplement.,, 
- Little evidence of adverse outcomes (no increased risk of MI etc among
supplement users; NS trend to dose-dependent increased risk of prostate
cancer progressing 100 IU-400 IU).
Synthetic beta-carotene (below)?
Should we supplement? What, and how much?
Tier I: Supplementation Necessities
- Correct deficiencies
- New IOM Dietary Reference Intakes (DRIs)
grounded in solid science.
- Exception: Vitamin D: Plenty of evidence for safety, clinical
efficacy (osteoporosis), and biochemical optimization (plateau of PTH)
at 1000 IU.,, Even
summer outdoor workers (agriculture, landscaping, etc) do not store up
enough D to lat through the winter. Canadians, Northern
US, sunscreen users are not getting enough; attempts
to do so increase skin cancer risk. Use a pill.
- Subclinical deficiencies and cancer: See
Clarke Se trial; 31 long-standing, Ames thesis (misappropriated
by supplement propagandists by implying “deficient” = “sub-megadose”).
- CR Folks (CRONies)!
- Common deficiencies in
low-Calorie diets: Ca, Fe, Mg, Zn, B1, B2, B6; B12 (semi-vegetarian); w3, fat-soluble vitamins (low-fat).
- CR-induced deficiencies: Evidence
of increased need for protein, Fe, Cu, Ca during
weight loss in ‘CR’ diet – others??
- OTOH, CR protects against
effects of some deficiencies: B1, Mg, Cu.
- 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.
- Strategy: get a balanced multiple (1.5-2
fold) of RDA for most nutrients; use verified testing (eg ferritin)
when warranted and verified.
- Selected ‘pharmacologic’
supplementation for high-risk/unwell individuals:
- CR-related disease susceptibility: Loss of bone mass. Especially critical
to ensure standard osteo support nutrients (Ca, Mg, vit D,
B, Zn, Cu, Si, Mn);
‘pharmacologic’ Sr,,,, and menatetrenone (MK-4).,,,
- I3C for cervical dysplasia (carcinoma in situ). (Animal
studies report good or bad effects on cancer risk, depending on site).
- Lipoic acid, benfotiamine for
- Pantethine, megadose niacin
- Epidemiology, animal
studies, and biochemistry for some nutrients vs. bad genes/family
history of diseases:
- Folate vs. colon cancer. 8
- D-glucarate vs. hormonal cancers (animal studies)?
This is what we know. Everything
beyond this is increasingly speculative.
“You can’t win if you don’t play” lottery
logic is very bad thinking for the life extensionist. Killing yourself with supplements is just too
damned stupid for words. If you’re going to take a supplement, insist on meaningful evidence
that it will help you. Human RCTs in healthy people with clinical endpoints > epidemiology
with clinical endpoints > studies in vivo in healthy people
and rodents showing health benefits/favorable surrogate endpoints. Make-the-case
mechanistic arguments, inbred genetic fuckup rodents, or animals exposed
to massive doses of hideous toxins may mean nothing at all.
Bad-Evidence Supplementation Schemes:
- Alpha-tocopherol succinate: “Better
- Extensive literature (eg. (,)),
but all in vitro.
- Physiologically irrelevant. All esters removed by GI esterases;
appear in plasma as free phenol.
- Kline: “vitamin E succinate … loses its anticancer properties when the succinate moiety is removed by cellular etherases”;
she’s accordingly working with a novel tocopherol analog
- Many Flavonoids: Test-tube
and rodent studies use pure compound – not good evidence, because
humans biotransform flavonoids much more heavily than rodents; can’t
extrapolate human results without human evidence.
- Curcumin requires multi-gram doses to elevate
blood levels in humans,,,,, unless
combined with piperine. See relative jump in curcumin bioavailability
with piperine (inhibits glucuronidation), humans 2000% vs.
rodents 154%. 90
(Yes, piperine is scary!).
- “Consumption of [500 mL] cranberry juice [total phenols
893 units/L; 1.53 mM vitamin C] resulted in a significant increase
in ... measures
of antioxidant capacity ... [which] corresponded to
a 30% increase in vitamin C and a small but significant increase in
in plasma. Consumption
of [500 mL] blueberry juice [2589 phenol units/L;
~0 C] had no such effects [my emphasis].” Cf.
rodent blueberry studies.
- “It’s an antioxidant!!”
- Many in vitro ‘antioxidants’
are not so in vivo; and
so what if it is? “Antioxidant” is not the same as
“beneficial.” Cyanide is a great antioxidant, etc.
- Acute, massive-dose
carcinogens do not reflect real etiology of disease in humans: low-level,
chronic, endogenous and exogenous factors. Want evidence it’s effective
in spontaneous carcinogenesis in healthy organisms.
- No record for long-term
use of herbals, or use of herbals by the healthy. “Natural,”
but xenobiotic. IMO life extensionists can’t
afford the risk of silymarin, ginseng, Ginkgo, St. John’s Wort etc.
if healthy and other remedies available: orthomolecules preferred,
but incl. often drugs, which are better-tested.
- Clinical endpoints (morbidity/mortality),
not putative surrogates.
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 &CVD
risk. Yet supplements keep failing! Why??
fail to reflect the key aspects of healthy diets.
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
- 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.”
- Inflammation: “Serum vitamin C was strongly and inversely related to
systemic inflammation [ie, CRP].”
- High-GI Diet: “The
age-adjusted mean concentrations (micmol/L) for increasing
quintiles of dietary GI were
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
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.”
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, ,, and
- 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
- High plasma gamma- – and not alpha-
– tocopherol associated with reduced risk of CVD,,,, MI, prostate
- Selective gamma-tocopherol depletion and
nitration in AD.,
- Gamma-, not alpha-tocopherol reduces PGE2,
LTB4, signs of inflammatory damage in vivo and
in macrophages and epithelial cells ; superior RNS-quenching capacity in vitro; ,, preferential uptake by macrophages; more
favorable effect on LDL metabolism in vitro.
- Beta-carotene: Extensive review of epidemiology finds b-c
from food protective against lung and other cancers.
- Nearly all trials used synthetic (all-trans) b-c;
is mixture (9,cis- and all-trans-).
- Synthetic b-c has lower antioxidant activity in vitro and in
- Synthetic b-c genotoxic in vitro (!), unlike natural.
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.
- 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
suggest that there is a yet-to-be-discovered unique role for
this form of vitamin K that is independent of the currently recognized
- MK-4 has unique effects on bone tissue and cells in vitro, despite similar
gamma-carboxylation coenzymatic activity.
- Dietary MK-4, not phylloquinone, associated
with reduced risk of aortic atherosclerosis.
- 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
5902 mcg/day (older, incomplete database), 11399
and most supplements 25 mg (6937 IU).
- Oxidative metabolites of b-c, if not
detoxified by compensatory C and E, may increase carcinogenesis
smokers; 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
- Too little lycopene: Lots of good epidemiology for tomatoes, tomato paste, dietary
and plasma lycopene vs. various cancers.
- 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) or
tomato paste (22 mg lycopene from target 30 mg
(3/4 C tomato paste) led to lower DNA damage &PSA).
- Earlier epidemiology underestimated lycopene intake
due to incomplete database for tomato products. 29,
- Too little Se? Plenty of good epidemiology for Se intake (not tissue
levels (eg toenail)) vs. cancer.
- 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. Similar
data, but ‘no conclusions can be drawn,’ from IOM;
new DRI, 90 mg/day.
- Plasma levels do not increase at
mg/day when tested 1 x 30 - 4 x 45 mg, but decreasing-returns increases
from 4 x 250 and 4
x 500 mg; plasma
levels essentially plateau at 200 mg w/small increases 500-2500
mg, but tissue saturation (selective active transport into
at ~100 mg/day and excretion of unmetabolized C
jumps at >60 mg/day.
-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,,,,
- 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.’
- Uric acid and other factors may have replaced C in humans.
- B-Vitamin Doses Whacked: Many times greater than food intakes or RDAs with no good evidence of benefit
- Can’t absorb >~8-12
mg thiamin dose. ,,,,,
- PABA of no nutritional value to humans:
needed by bacteria to synthesize folate, but PABA-depleting
harmless to mammalian
cells; ‘it’s an antioxidant!!’
- Why 50 mg of everything?? Strange
‘coincidence:’ purely arbitrary.
- Missing molecules:
- C and ‘E’ for detoxing oxidized b-c
- b-c partly a ‘marker’ for other carotenoids.
- Unknown dietary constituents: eg. new vitamin (?),
- 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,
Strongest associations: vegetables more than
fruits;, 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), limonene (separate epidemiology for citrus peels,).165, 166,
- Major mechanism: altered carcinogen metabolism.
- Phase I detoxification (CytP450/
MFO) polarizes ‘procarcinogens,’ making
them more readily conjugated with eg. acetate,
sulfate by Phase II detoxification.
forms water-soluble: can’t cross cell membranes,
readily excreted in
bile and urine.
“activated” into carcinogens by Phase I enzymes.
in biotransformation enzymes associated with
- Many putative anticarcinogens depress Phase
I (I3C, allyl sulfides) or induce Phase II (sulforaphane, limonene).165,
166, 167, 170, 171,,
Not mentioned in major reviews.
in citrus fruits, cruciferous vegetables.,,,
b-glucuronidase (undoes glucuronidation conjugation;
b-glucuronidase, low D-glucarate,,, poor
glucuronidation associated with cancer/cancer risk.
rarely suggested in reviews, but evidence IMO strong:
in vegetables (esp green vegetables). Would
for green vegetables.
“A close positive relationship between the
vegetable extracts and their
ability to inhibit
the Ames Salmonella system.”
rodent and mechanistic studies (largely using
acts as an “interceptor molecule,”
against real-world carcinogens
(aflatoxin, HCAs, PAH).
efficacy of food chlorophyll, chlorophyll metabolites,
in animal studies. 181,,,
- RCT for reduced aflatoxin-DNA adducts (high-exposure
- 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? – but ubiquitous
and so hard to deconfound. 166
Tier III: Slowing Aging?
Even if we get full lifestyle benefits, so what? Average person's longevity gain
from the eradication of cancer <=3.2 years of life. Ischemic heart disease? <=3.55
years. Both together <= 7.83 years. Both, plus all circulatory diseases
and diabetes:15.3 years. (And, hint: we’re already
living pretty healthily …).
Retarding aging to
extend life span. Logically includes healthspan!
Only one proven intervention: CR [CRON] – and that in rodents!
Hence, warning: maximum speculation follows!!
What factors are associated across mammalian species, and within mammalian spp AL [ad lib] vs CR, with slower aging and extended maximum lifespan?
Only 2 AFAIK [as far as I know]:
- Mitochondrial ROS issues: mtROS production, mtDNA (not nuDNA)
damage, mt membranes oxidative susceptibility
inversely associated with max LS interspecies, and reduced by CR.,
- Antioxidant enzymes inversely associated
with max LS! 187
- Dietary AOs, and prob. AO enzymes, do not reduce
these factors and do not affect aging.
- You must reduce production.
- mtROS production is the great majority of
ROS in vivo.
- Food e- moved to NAD+ (forming NADH) by
glycolysis and then Krebs/Citric Acid/TCA cycle.
- NADH transfers e- to Complex I, passed along
ETS to pump protons, create electrochemical gradient for Complex
hydro dam system, Complex V (ATP synthase) a
- “Fumbling” by CoQ in transferring e- from
Complex I to Complex III allows e- to react with O2, forming
- In CR and longevous spp,
lower mtROS production occurs because of less
reduction of Complex I by NADH. Fewer e- pass thru’ CoQ,
fewer ‘fumblings.’ 188
- Interspp difference genetic by definition;
perhaps Complex I structure?
- de Grey proposes CR redirects NADH to PMRS. Explains
lower ROS production, Complex I location, no reduction in metabolic
- Also (unbeknownst to him) lower peak sprint
speed in CR (seen in rodents and
anecdotally in some humans (eg. me!)) despite
much higher overall activity levels (“CR-induced hyperactivity,”
longer running at any age, continuing running after AL are dead); consistent
w/high NADH levels reported
by Dr. Robert Lord (MetaMetrix) in Society subjects?
- Intervention: R(+)-lipoic acid.
- Hagen and Ames: R(+) reduces mtROS production,
improves mt function, lowers mt damage in normal, healthy aging
rodents (no significant effect in youngsters).,
- Reducing ROS generation or just mopping up afterward? Hagen (personal
communication) and de Grey think the latter most likely. However:
- R(+) specifically reduced to DHLA in mt PDH by NADH, leaving NAD;, , less
NADH means fewer e- transfered to Complex I: lower ROS?
- In cell culture and
in diabetic rodents, NAD:NADH is
indeed increased. (Latter study used racemate; R(+) should mean
higher ratio in mt, lower in cytosol.
- Packer believes that increased NAD:NADH
is responsible for improvements in diabetic neuropathy (corrects
for diabetic hypoxia). 197
- Diabetics overexpress PMRS; consistent
with high NADH:NAD and need for use of PMRS as exit valve.
Consequent cell-surface reductive
stress would explain high oxLDL in NIDDM (mechanism
proposed in MiFRA for how so few cells drive
oxidative stress thru’out the body.).
- Alternatively/additionally, DHLA can quench
ubisemiquinone (CoQ radical which causes fumbling) in membranes
- Even racemate LA reported to reduce
cochlear mtDNA ‘common deletion” in normally-aging
- So why no LS bennies from racemate? Not enough effect,
due to low R(+) content and interference of R(+)
reduction by S(-) 194?
Negative side-effects of S(-) (eg.
thru’ reduced GSH recycling, NADPH?). Dose? (Seidman used 300 mg/kg;
after metabolic scaling (300-400 g rats), human equivalent 17.659
g! LEF studies
used human-equivalent 518 mg. at
standard energy density).
- R(+), not S(-) or racemate,
increased “max LS” in athymic mice (weak evidence: short-lived
strain, increase only based on 2 outliers in small cohort).
- NIA-funded Hagen and Ames LS study with R(+)/ALCAR cocktail.
- Dose: Human-equivalent
612.6 - 1225.2 mg.,,,,, Voodoo:
coincidental equivalence to RCT dosage for racemate in
diabetes, AD. But Seidman et al 203 and LEF LifeSpan studies 4, 203 (using racemate,
NB) might suggest higher dose.
- Intervention 2: Metformin + R(+)
- Roth and Lane: metformin appears “to mimic
some of the bioeffects of [2-deoxyglucose] without
apparent toxicity. Preliminary experiments suggest that [metformin]
can increase median and maximal survival of rats to the same
extent as 30% CR.” Spindler quoted
as claiming ~20% increase in LS.,
- Most assuming works thru’ antidiabetic mechanisms (increased insulin sensitivity and glycolysis inhibition), and perhaps crypto-CR noted by Patrick);
this would likely be irrelevant in normal, healthy folk (basic weight-loss
program (7% weight reduction thru' low-calorie, low-fat diet and moderate
exercise (eg. brisk walking), for at least 150
min/week) more effective than M in preventing the conversion of prediabetics to full fleged NIDDM); “Metformin does
not improve insulin sensitivity nor insulin secretion in obese female patients
with normal glucose tolerance.” But:
- Gene expression changes for wider
range of effects that overlap CR. 213 “These findings
metformin has more
the reduction of blood glucose and insulin, and
that it may be an authentic anti-aging therapy.”
- Much closer overlap than other diabetic
drugs (incl. insulin-sensitizing ’glitazones).
- Metformin inhibits
Complex I in
vitro and ex vivo.
- Associated in vitro with inhibition
of gluconeogenesis from L-lactate 218 – observed in vivo
as dangerous lactic acidosis
- “Because it is established that
[metformin] is not metabolized, these [ex vivo] results
suggest the existence
a new cell-signaling pathway
chain complex I with a persistent effect after
cessation of the signaling process.” 219
- “We conclude that the drug's
pharmacological effects are mediated, at least in part,
through a time-dependent,
of the respiratory chain that restrains hepatic gluconeogenesis
while increasing glucose utilization in peripheral tissues.”
- De Grey was intrigued, even
before Roth’s announcement: “Interesting … I think that
the respiratory chain
bad (at least if the affected cells accumulate),
but partial inhibition may be very different” depending
react to the
inhibition” (per his CR model).
- More evidence for R(+)? In isolated perfused rat
liver, “RLA reduces hepatic glucose release by inhibiting lactate-dependent
glucose production in a concentration-dependent fashion.”
- Previously observed in vitro, and
“antigluconeogenic effects of lipoic acid
in liver can be attributed largely, if not entirely, to sequestration
of intramitochondrial coenzyme A” (??).
- ”When transported into the mitochondrion,
pyruvate [product of glycolysis used by TCA to reduce
NADH] encounters two
enzymes: pyruvate carboxylase (a gluconeogenic enzyme)
and pyruvate dehydrogenase (PDH),
the first enzyme of the PDH complex [requires R(+)
–MR]. With a high cell-energy charge [high NADH:NAD?-MR],
coenzyme A (CoA) is highly acylated … and able
allosterically to activate pyruvate carboxylase,
directing pyruvate toward gluconeogenesis.
When the energy charge is low CoA is not acylated,
pyruvate carboxylase is inactive, and pyruvate is preferentially
the PDH complex and the enzymes of the TCA cycle
to CO2 and H2O. Reduced NADH and FADH2 generated during
to drive ATP synthesis via oxidative phosphorylation.”
- Net effect on safety of metformin/R(+) cocktail??
- In vitro, “Parallel decreases
(30%) in cellular NADH/NAD+ and in lactate/pyruvate ratios
observed in [R(+)-]alpha-lipoate-treated
cells [former should be reflected in latter as re:
glycolytic pathway].” 197
- “Treatment of guinea pigs
(250 g weight) with a-lipoic acid (0.5 mg) for 10 d substantially
the level of lactic
(30% increase with respect to control values), and decreased
the level of citric
acid (60% decrease compared to control). These
have been interpreted as lipoic acid stimulating the
of pyruvic acid to lactic acid, a reaction that
other authors have indicated to occur in both directions.”
- IDDM rodent study: “Gastrocnemius lactic
acid was increased in diabetic rats … and was normal in LA-treated diabetic
- Suicide attempts using 10-40
g racemate have resulted in lactic acidosis. 224
- Human RCT: “lactate and
pyruvate before and after glucose loading were ~45% lower
and obese diabetic
patients after LA treatment.”
- Potential synergism of
inhibited Complex I (metformin) + reduced NADH:NAD (R(+))?
- Dose: PDR,
for diabetics: 500 mg bid, increasing by 500 mg weekly, up
to 2g; or 850 mg, increasing by 850 up to 2550. Combine
with R(+), 600 mg.
- Safety: Lactic acidosis serious and unpredictable.
- Steve Harris: “Metformin's an especially scary drug in this regard, causing liver necrosis
in those susceptible without a lot of warning first, and at doses
which are (or were thought to be) more or less therapeutic. … The
LDH on your liver enzyme panel tells you exactly NOTHING about how well
your liver's lactate processing system is working. Nor really the AST and
ALT – they're simply markers of acute liver cell damage and leakage.” ALT
and AST “won't tell you that you're close to … lactic acidosis … Don't think
of metformin like Jack Daniels or statins,
think of it like digitalis and coumadin. [Cf PDR: “Side effects cannot be anticipated.”] 227 The idea of
skinny nondiabetic calorie restricted laypeople willy nilly using
it as part of a life extension program in the absence of good data
for the pro side, and probably without good lab support in many
cases, scares me. Not a good idea.”
- Per LEF, “According
to the Physician's Desk Reference, clinically significant responses
in Type II diabetics are not seen at doses below 1500 mg a day”. Not
version 227 …
- IMO: Not ready for prime time. This
is a potentially toxic xenobiotic drug, and we’re basing all of this
on a single, unpublished rodent study!! Wait
for repetition (Spindler, Roth).
- Negative Intervention: Avoid
n3 HUFA (EPA/DHA).
- As noted, mt inner membrane (MIM) ‘peroxidizability
index’ (number of double bonds/FA in membrane PL) inversely associated
with max LS; aging increases, and CR reduces, MIM index via lower
HUFA, esp n3 HUFA and esp DHA. Possibly related
to membrane peroxidizability and physical attachment
of MIM to mtDNA (ROS damage to MIM à mtDNA deletions).
- Feeding rodents fish oil increases mt inner
membrane DHA. See details at ().
- In parallel, unusually low desaturase activity
consistently observed in human CR. 191
- Cardio benefits seen equally or more so
with increased ALA intake, per epidemiology and RCTs. 230,,
- No benefit to more than 1-2 fish servings/week in any case,, so
no justification for supplementation.
- Dose: Maximum avoidance. Ensure
adequate intake of n3 with 2-8 g ALA.
- Rate of AGE Accumulation: Inversely
correlated across species; not fully correlated with blood sugar
levels (eg “hyperglycemic” hummingbirds, but
also seen within mammalian class)
and hence evidently genetically regulated. Miller et al zeroing in on such
genes in mice. CR
lowers both blood sugar and AGE, and “markers of skin collagen glycation and glycoxidation rates
can predict early deaths in AL and CR C57BL/6NNia mice.”
- Nearly all “anti-glycation” nutrients have
only ever been tested in vitro, and work at Schiff base formation,
not AGE formation per se: ineffective strategy in vivo (sheer stoichiometry and
vitro conditions extremely misleading in any case. 238
- Includes carnosine
- No in vivo data.
- In vitro, prevents Schiff base formation,
but little effect on AGE.
- Recent LEF ad: “research has shown that metals, predominantly copper, are culprits that promote excess glycation …
A new study concludes
that carnosine not only inhibits glycation earlier than aminoguanidine,
but that it is 625 times more potent at chelating ... the harmful
copper. This new study confirms that carnosine is
the most effective anti-glycating agent.” Misleading – see cited study:
- Looking for mechanisms and to
undo confounding, not clinical utility.
- In vitro, and not
even measuring AGE formation!!
- Physiological concentration already
5 times IC50 for chelation mechanism!
- Chelation of unlikely mechanistic
significance in vivo. 238
- “Earlier” not “better”
- OTOH, in vitro studies suggest alternative
mechanism for in vivo effect via increased proteolysis;, but
physiological relevance still unknown.
- Aminoguanidine does not inhibit AGE formation
in areas distal from the circulation (skin and tail collagen), is
quite toxic (antinuclear antibodies (sign of autoimmunity)
and flulike symptoms) and of no clear benefit in diabetic humans
was of no benefit in the LEF LifeSpan studies. 4
- Intervention 1: Pyridoxamine
- Post-Amadori AGE inhibitor. 238,
- Extensive animal evidence:
lowers AGE (&ALE) accumulation,
including in skin and tail collagen;,,, prevents
or treats nephropathy in insulin-resistant hyperlipidemia,
246 NIDDM and
IDDM, 249 with
stronger effects than aminoguanidine; reduces
atherosclerosis in hyperlipidemia; 246 reduces
retinopathy in IDDM. 247
- Human Phase II Studies:
Well-tolerated at doses which create plasma levels similar
to those in rodent studies;
12 patients with diabetic nephropathy, “The average decrease
from baseline in 24 hour urinary albumin excretion was 32% at day
45 ... Three
receiving Pyridorin had also converted from macroalbuminuria
mg albumin excretion/24h] to microalbuminuria [<300
mg/24h] by the end of the treatment period.”
- “Should” primarily work on extracellular
proteins (connective tissue, some parts of glomeruli,
retina), as phosphorylated upon (regulated) intracellular
- Dose: 500 mg PM dihydrochloride (~300 mg
“elemental” PM) used in Phase II study, yields similar plasma
levels to 2 g/L
used in rodent studies.
- Possible neuropathic side-effects: observed
with pyridoxine: cutoff dose controversial. LOAEL 500 mg pyridoxine; NOAEL 200 mg. No increase
in pyridoxine seen with PM, 253, but in vitro, pyridoxine and pyridoxamine of equal neurotoxicity.
- Unusual B6 metabolism in CR rodents and
possibly humans. 191
- Intervention 2: Benfotiamine
- Lipophilic thiamin derivative: higher bioavailability
and cellular uptake (thiamin absorption at both levels very limited:
GI can’t absorb more than ~8-12 mg thiamin at a time, 155,
156, 157, 158, 160 vs. dose-proportional passive diffusion
of Benfotiamin). ,,,,
- Benfotiamin much more potently
elevates thiamin pyrophosphate (thiamin coenzyme) and activates
thiamin-dependent enzyme). 256, 257, 258, 259, 260
- Mechanisms: TPP itself a post-Amadori
AGE inhibitor (weaker than PM); 245 key
mechanism pentose phosphate shunt:
- Neurons, glomeruli, retinal
capillaries’ glucose uptake is not insulin-dependent, but follows
blood levels. Hence, high blood sugar (postprandial
state, insulin resistance, (N)IDDM) causes intracellular
- Hyperglycemia overloads glycolytic
pathway, and leads to increased mtROS, which deactivates
key glycolytic enzymes.
- Causes buildup of triosephosphate
intermediates (reactive dicarbonyls): causes intracellular
- High levels of transketolase
activity allow for “shunting” into pentose phosphate pathway.260, ,
- Benfotiamine proven to reduce AGE burden in diabetic humans and
animals. 260, 
- Benfotiamine proven to prevent and treat diabetic
complications (neuropathy in RCTs, ,,,, ,,, retinopathy260 and nephropathy in
animal studies). Megadose thiamin less effective in animal studies, 264,
273 ineffective in preliminary data from ( 264)  and
in head-to-head human trial. 269
- Much less
likely important in normals or CR folk, in whom hyperglycemia
(?): postprandial period).
320-400 mg first month, 120-160 mg thereafter in diabetic
- Intervention 3: Interprandial arginine
- Carbonyl scavenger. 238 Reduces
AGE accumulation in diabetic rodent kidneys,, and
in humans inconsistent.,
- Dose: 2g/day, taken ~40 min before meals to address postprandial dicarbonyl surge.
- Alternate (even more speculative!) CR-Mimetic
- SIR2, PNC1 Gene Silencing  ,
- Free NAD+ or NAD:NADH ratio prevents inhibition
- Yeast. Mammals do not form rDNA circles;
“aging” in yeast entirely replicative (relevance to mammals questionable: postreplicative brain,
heart, muscle tissues). If Guarente correct
on mechanism (CR in yeast causes reduced glycolytic flux,
hence higher NAD:NADH), possibly irrelevant (mammals apparently show
no reduced metabolism in response to CR). If Anderson correct (PNC1 converts nicotinamide to nicotinic
acid), greater potential relevance.
- Intervention: R(+)-lipoic acid.
- See above: lowers cytosolic and mt NADH:NAD.
- Insulin/IGF1 Signaling 
- ”Reduced signaling of insulin-like peptides
increases the [max] life-span of nematodes, flies, and rodents.”
- CR lowers insulin and IGF-1
- Anti-mitotic (anti-cancer; preserves immune
reserve and prevents autoimmunity (CR)?)
- Reduced mtROS seen in Ames dwarf mice.
- Reduced IGF-1 signalling in mammals does not
fully reproduce CR effects.,,
- Intervention: Benfotiamin?
- Monnier: Activation of PPP by B might reduce glycolytic
flux, reduce deleterious insulin-related signaling.
- I don’t buy it.
- Benfotiamin effective during intracellular
hyperglycemia in cells whose uptake of glucose (via GLUT1)
is not insulin-mediated.
- Likely little reduction in glycolysis
per se, esp in normoglycemic folk.
- Irrelevant to heart, skeletal muscle.
- Negative intervention: Avoid
GH-boosting supplements, hGH injections, etc.
- PMRS Modulation
- See mt discussion above. De Grey’s e- shunt
through PMRS 189 would
create mild REDOX stress. Lawen et al suggest
‘rescue’ of bioenergetically deficient cells by taking e- at
PMRS; could make PMRS e- less toxic, extend CR LS bennies
- Intervention: CoQ10?
- Tissue uptake negligible outside of liver and spleen, so
cardio effects not due to mt enrichment. Lawen et al 291 show
that CoQ unloads e- from PMRS; proposed as mechanism.
- Several LS Studies Negative:
- Favorable, but not definitive, result from Bliznakov: injects
50 mcg/week/mouse, beginning at ~510 days (~51 human years);
av’g LS increased to ~728 from ~650 days (12% increase); max LS either
or 1084 days. Promising, but
no clear effect vs. optimally-cared-for rodents; pharmacokinetic
- Null effect from 10 mg/kg/day oral CoQ in
rats (scales to 213 mg). Older
(16 mo) dams of experimental populations supplemented during pregnancy;
complications? (Not teratogenic; did not
affect litter size; no difference in BW thru’out lifespan).
- Another null effect from Lonnrot et al mice: prob.
Scales to ~100 mg/day.
- Null effect, or even slightly unfavorable, LEF
LifeSpan studies, alone or in combination; 4 dose 86 mg.
- Steve Harris unpublished
LS study at human-equivalent 500-750 mg/day: robust 23%
curve-squaring. Video suggests v. healthy.
- Extended LS from CoQ-free diet
in Clk-KO flatworms irrelevant
to mammals: mutant strain probably CoQ-deficient,
so CoQ-free diet causes halt in respiratory chain.
- Most studies (but
report lower tissue CoQ with CR; not relevant
to present mechanism or pharmacokinetics of CoQ itself,
and could be a limiting factor rather than a mechanism.
750 mg/day, per Harris study; 100 insufficient, per Lonnrot, and >200 mg normally required to achieve therapeutic levels in human
heart failure (>2.0 mcg/L), w/ highly variable bioavailability. , 1200
mg needed for clear-cut effect in Parkinson’s; responders
in prostate cancer case series all achieved > 3.0 mcg/L, nonresponders all < 2.0 mcg/L, at 600 mg/day. Use softgels or
dissolve in oil; take with fat-containing meal.
- Reverses cellular senescence
- In vitro!!
- -Role of
cellular senescence in aging debatable; possible indirect effects thru’
- Selective inhibition of cancer cell growth: no effect on normal or
embryonic stem cells.
- In vitro!!
- In SAM-P mice, increases mean LS by 20%, reduces some
‘aging’ phenotypes (hair fullness and color, skin ulcers, periopthalmic lesions, spinal curvature) and normalizes binding
of NMDA receptors, MAOb, Na/K-ATPase.
- SAM-P mice are fuckups; still much shorter LS
than normal mice.
- No effect on max LS.
- SAM-P mice have ‘naturally’ low carnosine levels.
- Painfully speculative: zero data
on normal, healthy organisms, no epidemiology, nada. But intriguing …
- 100 mg/kg used in SAM-P 312 and
in studies on ischemic assaults.,, Human-equivalent
rodent studies, human-equivalent 500 mg/day does not elevate brain or muscle
levels ,, and do
not protect rodent vascular system from fructose-rich diets. Human-equivalent
doses of ~945 mg a day raise tissue levels 317, 320 and
protect vascular system.
- However, carnosinase enzyme degrades carnosine to beta-alanine + histidine. Rodents only
have a nonspecific dipeptidase with carnosinase activity by default.
Humans have an additional, specific serum carnosinase;
than proportional scaled doses will be required.
- Strangely, oral supplementation leads to increased
urinary C, yet no increase in plasma levels, in humans;, “it
seems that absorbed carnosine may be very rapidly
cleared from the plasma and sequestered in some compartment
before it is excreted by the kidneys.” 324 Alternately,
hydrolyzed and resynthesized?
- IAS claims
lower doses reduce urinary MDA; MDA
is a bad marker of oxidative stress, and in any case
also seen in rodent studies using TBARS, despite a
tissue levels (associated
with conserved vitamin E in liver). 318 Uncontrolled,
unpublished trial by unpublished ‘researcher.’
- Dose Conclusion:
Substantially > 1
g will be required; 1500 mg?
- High-protein diet leads to higher C
diets reduce absorption. Prob due
to density or activity of dipeptide transporters.
- Various dipeptides (eg glycyl-L-proline,
alanine) compete with C for transporters, inhibit absorption: take
on an empty stomach.
- ALCAR issues. Human RCTs for
Alzheimer’s disease; also
seems effective for spatial learning in healthy young subjects.
- Improves various aspects of mt structure and
function in rodents;,, supplementation
in middle-aged (16 mo) rats had mixed effects on pathology but improves
survival to 22 mo (38/45 vs. 29/45 survivors). But Hagen and Ames reported increased mtROS production in old
supplemented rodents. Yikes!
- Only observed in old rodents.
- Observed at v. high dose: 1.5%
in drinking water, scales to 12.9 g.
dose-ranging studies, “lower concentrations of ALCAR (0.15% and
especially 0.5% [scales to 1.29 to 4.3 g]) ameliorated the
age-associated decline in ambulatory activity (TABLE 2) and
loss in the dentate gyrus of the hippocampus (FIG.
12) more effectively [MR's emphasis] than
the 1.5% dose. The lower doses had no effect on protein oxidation,
in contrast to the 1.5% dose, which caused an increase in protein
carbonyls in the
brain. Furthermore, lower doses (0.15%) also reduced the age-dependent
increase in malondialdehyde … more effectively than the 1.5%
dose”. 332 Likewise, “Lower doses of ALCAR, that is, below
in the drinking water did not increase hepatocellular oxidative
- Tissue-specific effects: In
heart, even high dose (1.5% in drinking water,
= 12.9 g) caused “no alterations in oxidant production in
isolated cardiac myocytes ... Furthermore, myocardial levels of ascorbic
(P < 0.02) with age (FIG. 5) did not exhibit a further ALCAR-induced
decline”. 333 (Cf. tissue-specific effects
of aging and CR on mt function,).
- ALCAR reduces mtDNA deletions in
cochlea per Seidman at massive dose (17.7 g, scaled); 202 again, tissue-specific
(local bioavailability eg)?
- mt structural improvements (retarded
loss of cristae) 332 at lower
doses argue for direct benefit, in addition to metal chelation,
improved bioenergetics, and other antioxidant mechanisms.
- R(+) corrects ALCAR-induced mtROS even
at high dose; 334, 336 as
argued above, likely a real, primary effect
- Dose: 1.29 to 4.3
g – again, suggestive coincidence, as this is the standard
therapeutic range for AD. 330
Conservatives might lean lower than lower end, but not clinically