Calorie Restriction with Optimum Nutrition
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CRON-WEB's Definitive Guide to Supplementation: Introduction

Go To >> Introduction • "Well, it Can’t Hurt, and it Might Help" Mistake • Tier I • Tier II • Tier III • References • Condensed ("Quick-Start") Guide

This guide was written and researched by MR and adapted for the web by CRON-WEB.


MR used to formulate supplements and earn money in the process. MR no longer does so, but still has a relationship with the company ( In addition, I (Khurram) was this company's webmaster in 2004 and 2005. There are some plugs for the company's products in this Guide, but CRON-WEB is not affiliated with AOR in any way.

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.”[1] “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.”[2]

No confirmed evidence for life-extending effects of any drug or supplement in normal, healthy mammals.

Animal Studies

  • ‘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 months 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.”[3]

  • 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 graphs)![4]

  • Deprenyl: data reviewed in ([5]). Only Knoll (inventor has reported increased lifespan for deprenyl; variations by strain, age, etc, in response; no reasonable basis for human dosing.

Human Studies


  • 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.”[6]

  • Hidden vulnerable subpopulations. Eg folate and colon cancer in Nurses' Health Study. Preliminary finding: “Higher … folate intake … was related 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 use was present across all levels of dietary intakes.”[7]

    • 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.”[8]
  • 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),[9] etc).

Randomized, Controlled Trials

Heart disease

  • Alpha-tocopherol
    • 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”.[10]

    • Several other large studies report no effect on any carciovascular outcome.[11],[12],[13],[14]

  • 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).”[15]

    • 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 simvastatin-niacin-plus-antioxidants group.”[16]

    • 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.”[17]


  • 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).”[18] Later reports: no effect on gastric,[19] urinary tract,[20] colorectal,[21] cataract,[22] or maculopathy;[23] no clear effect on pancreatic[24] or colorectal[25] cancers; 50 mg alpha-tocopherol decreased, but synthetic b-c may have increased, clinical prostate cancer incidence and mortality.[26]

  • 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.”[27]

  • 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).[28]
    • Supplementers lost benefit of fruits and veggies![29]

  • 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 those 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 drank 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).”[30] 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.”[31]
    • However…
    • “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]” 31
    • “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).[32] 

  • Linxian Trial: Also successful; also in an intentionally-selected deficient population.[33]

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