Calorie Restriction with Optimum Nutrition
Home • Forum • What's New • What to Eat • Short/Long-Term Benefits of CR • Books • Links, References & Resources
Supplements • 2000 Poll: Graphics • Poll: Statistics • Theories of Aging • CR Mimetics • Science and Research • CRONies

CRON-WEB's Definitive Guide to Supplementation Tier I: Supplementation Necessities

Go To >> Introduction • "Well, it Can’t Hurt, and it Might Help" Mistake • Tier I • Tier II • Tier III • References • Condensed ("Quick-Start") Guide
  • Correct deficiencies (also see UPDATE to this section)
    • 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.[56],[57],[58] Even summer outdoor workers (agriculture, landscaping, etc) do not store up enough D to lat through the winter.[59] 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[60] (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).[61]
      • CR-induced deficiencies: Evidence of increased need for protein, Fe,[62] Cu,[63] Ca[64] during weight loss in ‘CR’ diet – others??
        • OTOH, CR protects against effects of some deficiencies: B1,[65] Mg,[66] Cu.[67]
    • Biochemical individuality: extra folate for MTHFR polymorphism; riboflavin for NQO; other, speculative cases;[68] ‘common’ variance in requirements[69]? 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.
    • UPDATE
  • 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[70],[71],[72],[73],[74] and menatetrenone (MK-4).[75],[76],[77],[78]
    • I3C for cervical dysplasia (carcinoma in situ).[79] (Animal studies report good or bad effects on cancer risk, depending on site[80]).
    • Lipoic acid,[81] benfotiamine[82] for neuropathy.
    • Pantethine, megadose niacin vs. hyperlipidemia
    • 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)?[83]

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 cancer fighter!”
    • Extensive literature (eg. ([84],[85])), but all in vitro.
    • Physiologically irrelevant. All esters removed by GI esterases; appear in plasma as free phenol.[86]
    • 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 instead.[87]
  • 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[88],[89],[90],[91],[92],[93] 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 total phenols in plasma. Consumption of [500 mL] blueberry juice [2589 phenol units/L; ~0 C] had no such effects [my emphasis].”[94] Cf. rodent blueberry studies.
  • “It’s an antioxidant!!”
    • Many in vitro ‘antioxidants’ are not so in vivo;[95] 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.

UPDATE (2006-01-30) to "Correcting deficiencies" (return to original "Correcting deficiencies")

[On recently-introduced or upcoming multi-vitamin/multi-mineral supplements (from that CRONies or health-conscious people may benefit from...]

The first is not yet released, but should be out in Canada soon and in the US a month or 2 after that; it was to be called "3 Squares," but will now be called something else. The supplement facts for 3 caps/day are appended. This is an excellent (IMNSHO) formula of core nutritional supplementation.

The second is Essential Mix. This is a powdered multi, for those who prefer that for whatever reason. I'm not QUITE as happy with this, as it's lacking some of the more sophisticated ingredients (non-beta-carotene carotenoids; lithium and strontium at nutritional dose; vanadium; the putative new vitamin PQQ), contains "excess" (but not psycho) vitamin C (as dictated by customers' preference for the formula that it replaces), and as it is 40 Calories/scoop (daily serving); still, it avoids all the major pitfalls and I'm pretty happy with it.

The third is OrthoCore. It includes all the core stuff in the above, but also some phytochemicals and other nutrients that, while not essential, have health benefits well-justified by good prospective epidemiology *as well as* animal and mechanistic studies, at doses based on that same epidemiology (so, eg, the trans-resveratrol dose is based on amounts in 2-3 glasses of typical red wine, because that's the level of consumption of wine at which the epidemiology points to a net benefit on total mortality. Etc). Of course, doing this is inherently more uncertain than getting DRI- or healthy-diet levels of essential (or like lithium etc, strongly arguably essential) nutrients we don't KNOW that e.g. resveratrol is responsible for the benefits of wine, or indeed even if WINE is responsible for the benefits of wine (could be confounded by other lifestyle factors, etc). I did choose the 'extras' in this formula pretty damned conservatively, and certainly this is not like the idiocy of putting e.g. silymarin into a core multivitamin, but there is inherently a higher level of POTENTIAL for risk (if of nothing else than wasted $ !) with a formula like this -- along with a chance of greater benefit. This is why I've called nutrients like these "Tier 2".

The last is the long-awaited Vegetarian Booster. Vegetarian diets (and to a lesser extent high-vegetable, low-animal-food ones like those many CR folk are on) are commonly deficient in certain nutrients, and also low in, or lack, a variety of nutrients that are not strictly essential but have clear health benefits; the standard dogma is that the latter aren't an issue because of endogenous biosynthesis, but there is evidence of varying strength that not only are vegetarians' levels of them lower than omnivores' (which might of course be harmless), but that supplementing the intake of these nutrients differentially benefits vegetarians, or benefits vegetarians in ways that have not been *reported* in omnivores. This formula is designed to complement a well-designed multi, because the latter will meet MOST folks' needs but will not include, or will not include in proper BALANCE, the nutrients in question.

The two weaknesses with this supplement: it should really have included B6 and lysine, which are commonly insufficient in vegan diets. I have no one to blame for myself but this: it was an unjustified omission made in negligence rather than planning. I have asked for a future iteration to include them.

NB (nota bene) that it does NOT include iron despite the fact that vegans and CR folk are commonly mildly deficient in this; I remain too nervous about the potential cardiovascular and neurological risk of getting too much iron, and don't want to sacrifice the potential ACTIVE BENEFIT of many such folks' low-normal levels of this mineral. But if your ferritin test does indicate that you're low, do definitely get a supplement: they're easy to come by in RDAish levels.

A CRONie said:

> After six years on CR, I belatedly run my food intake against a [dietary] software program. I find I am deficient in thiamine, pantothenic acid, E and iron.

This really needs to be hammered home. If you aren't using nutrition software, you have no damned clue how many Calories you're consuming (cf the recent study posted by CRON4healthyfuture (1) showing using doubly-labeled water that "On average, the women underestimated total energy intake compared to total energy expenditure assessed from DLW by 37% on the [7-day diet record] and 42% on the [food frequency questionnaire]" -- see also (2) which reported similar results) or to what deficiencies or long-term toxicity you are subjecting yourself with your diet. VERY healthy-looking diets can easily fall prey to this (and that, sometimes even WITH the above precaution -- let alone without): my own iodine toxicity and zinc deficiency, and Dean's anemia, are cases in point.

> When I look at what's available in way of supplements for those specific substances, they're all megadoses. If I just want to get them to around 150 % of RDA, I have to go for multi's, and get a lot of stuff that I don't want or need.

In the case of B5 and B1, I think it's harmless to get a few tens of these -- it's WASTEFUL at best, and the evidence on biochemical individuality really does make it make a certain amount of sense to go high on them as actual enzyme cofactors and as water-soluble nutrients.

I'm about to plug several of these, as they fit the bill here: indeed, one of the main things I kept in mind in formulating was to NOT megadose users on stuff either pointlessly (like 50 or 100 mg of all the Bs) or toxically (as in preformed vitamin A (retinol, not carotenoids), which is quite commonly put in at doses (>5000 IU) that roughly double one's long-term fracture risk, per a great deal of published epidemiology).

A CRONie said:

> These nutrients can be bought individually and I would
> simply get a pill cutter and portion them down rather
> than taking a megadose once a week of so.

I've done this for years, and it's a real pain in the ass, especially if like me you also consume a lot of nonessential supps (R-lipoic, ALCAR, pyridoxamine, etc); for a while there I was up around 60 dose units/day ... Still, it's better to do this than to subject the system to most multi's!

Also, folks should not expect ANY multivitamin to perfectly match their individual nutritional needs. Leaving aside the fact that they may disagree with the formulator of a formula of what the optimal dose of a given nutrient is, different peoples' diets will have different weak spots that will necessitate a little extra of this or that. Ironically, especially granted the long-term trend toward megadosing everything in sight, the biggest thing to watch for in a multi is not to OVERDO anything -- if it is well-balanced, you should be able to top up a FEW nutrients in which you're specifically unusually low.

IMO, the *new* RDAs/DRIs are very well-justified by the available evidence as good targets:

Because of biochemical individuality, the multiple cases of impaired nutrient absorption in CR diets, the negative effects of fiber phytate and oxalates on mineral absorption, and the apparently key role of avoiding nutrient deficiency in successful adult-onset CR, I suggest that a good starting point around which to start thinking about sensible nutritional targets for folks on CR who are without specific disease-risk issues CLEARLY amenable to megadoses (prominently, niacin for some forms of dyslipidemia) is something like 5-10 RDAs for water-soluble vitamins, and 1.5 RDA for most other things. Exceptions: do get some PREFORMED vitamin A (retinol), but keep under 2000 IU; and take 800-1000 IU vitamin D3.

However, of course, all of this -- from the RDAs to the targets outlined above -- constitute 'generic' guidelines that does not have, *as a whole*, the backing of clinical trials etc (we certainly have no painstaking, long-term, large-scale dose-response curves on ANY essential nutrient, let alone an entire diet and supplement program), and will need to be customized and even radically revised in individual cases. You will have to make your own judgments on the evidence, get regular blood tests to watch for signs of excess or deficiency, monitor yourself for symptoms of same [see (3) for resources], and involve your personal physician in this as in all health decisions. I am not a doctor or other health care professional, and even if I were, you aren't my patient, I haven't seen your medical history or even a recent panel of blood tests, and have never subjected you to a physical, so I am in no position to give actual ADVICE to YOU.

It's also worth emphasizing that these are targets for a person's ENTIRE INTAKE. It's rather goofy how many people take RDA (or supra-RDA, or indeed any set of targets) intakes of every essential nutrient by popping a FULL DOSE a *generically-formulated* multivitamin, AND then stop there -- all as if their actual DIET didn't exist. Even a SAD (std. American diet) diet will contain most of the RDA for most nutrients; a truly healthy diet, typical of reasonably zealous CRONies, will likely contain the RDA or more of most nutrients. Find out what you're getting from your regular diet by regular use of nutritional software analysis of weighed/measured dietary intake (if you aren't doing this, you're a damned fool -- this includes those damned fools among you out there who I love to pieces :) ) and then TOP UP to the above targets with some fraction of a standard daily dose of a multi, plus a few targeted supplements.

Also be mindful of issues like the RATIO between zinc and copper, which should be held ~10:1; many CR people have such high Cu intake that they will need more Zn than the RDA to prevent an induced deficiency state, whereas in the general population the reverse tendency exists.

A CRONie asked:

> Does anybody know of any supplier of single vitamins with just around one RDA-equivalent in them?

Nope! No one would buy them -- honest. And I don't think you need to be that restrictive in your regimen IAC.

> Or - can one take a mega-dose of those substances say just once a forthnight and get roughly the desired effect?

I wouldn't do that with almost anything, and certainly not with the specific nutrients at issue (thiamine, pantothenic acid, E and iron): the first 2 are water-soluble, so you will want to take them regularly; PROPER E will largely NOT be alpha-tocopherol, and many of the 'other' vitamin Es (the gamma-fractions especially) are rapidly metabolized and excreted, so again they need taken regularly; and taking several RDAs of iron at once is at the very least a recipe for bowel problems, and likely worse.

> Thiamin has a biological half-life in the body of about 15 days so I suppose a forthnight is stretching it for that substance, but say once a week for that one.

This reasoning ultimately won't fly IMO: at RDAish levels, getting down to half-levels means you're deficient, and if you're after higher levels (as you likely should be) it's excreted much more quickly (neither absorption nor excretion are linear to dose).

> As for vitamin E, I've tried to understand the arguments for the mega-doses (assuming all 8 types are included). The strongest evidence ... are of the kind "The subjects with Vitamin E levels in the highest quartile had a risk of cardiovascular events one-sixth those with vitamin E levels in the lowest quartile" and "Men in the highest fifth of the distribution of gamma-tocopherol had one fifth the risk of developing prostate cancer as those in the lowest fifth". Nothing was said of supplements achieving the E-levels, and if it were mainly diet then all one would need ... 10-15 mg per day from food to say 30 mg per day.... But all the stand-alone E:s I can find have a zero attached to the dose needed to get to that level.

The above multi's contain more than this, but only by a few multiples; if you're only taking a half-dose or so, you're quite close, and not in the "megadose" category.

> It's well known that mega-doses of alpha-tocopherol bumps down the gamma-tocopherol and can be negative. I have no scientific background to back it up, but it makes me wonder about the risk of mega-doses of complete 8-type E bumping down something else or throwing a wrench into other processes that we don't even know about now.

This kind of thing always has to be borne in mind, and again, the evidence to support taking true MEGA-doses have to be very carefully weighed over & should not be part of a core multivitamin formula. That said, gamma-E being so rapidly metabolized, I don't think that it is nearly as likely to have negative effects (compare e.g., toxicology of retinol or even vitamin D to that of B vitamins in most people).


1: Mahabir S, Baer DJ, Giffen C, Subar A, Campbell W, Hartman TJ, Clevidence B, Albanes D, Taylor PR.
Calorie intake misreporting by diet record and food frequency questionnaire compared to doubly labeled water among postmenopausal women.
Eur J Clin Nutr. 2005 Dec 14; [Epub ahead of print]
PMID: 16391574 [PubMed - as supplied by publisher]

2. Subar AF, Kipnis V, Troiano RP, Midthune D, Schoeller DA, Bingham S, Sharbaugh CO, Trabulsi J, Runswick S, Ballard-Barbash R, Sunshine J, Schatzkin A.
Using intake biomarkers to evaluate the extent of dietary misreporting in a large sample of adults: the OPEN study. Am J Epidemiol. 2003 Jul 1;158(1):1-13.
PMID: 12835280 [PubMed - indexed for MEDLINE]

3. Unfortunately, I don't know of a REALLY reliable, readily-accessed place to study this. A good source if you will go to the trouble is:

Maurice Shils, MD, ScD; Moshe Shike, MD; James Olson, PhD; A. Catherine Ross, PhD (eds). Modern Nutrition in Health and Disease. 10th Ed. 2005; Lippincott Williams & Wilkins. ISBN: 0-7817-4133-5

More readily-accessible are:

... which is reliable for FRANK and SEVERE deficiency, but is (surprisingly) overly cautious about discussing marginal/sub-clinical deficiency; and this site:
... which is probably a bit too expansive. If you THINK you are suffering one of these, do first check Shils et al (eds), op cit. Then go talk to your doctor.

(return to original "Correcting deficiencies")

Continue on to Tier II...

Top of Page • PREVIOUS: "Well, it Can’t Hurt, and it Might Help" Mistake  • NEXT:  Tier II | References