Published in medi.philica.com
The validation of a scientific theory requires that it encompasses predictability for future experimentation or observations. Failure to do so, invalidates or falsifies the proposed theory. Harman’s free radical theory has repeatedly failed to demonstrate scientific predictability for over a half a century. The myriad of diseases, supposedly caused by electronically modified oxygen derivatives (EMODs), have now reached pandemic proportions, in spite of the widespread use of antioxidants. Many experiments demonstrate the harmful potential of the antioxidant vitamins. Thus, we have witnessed a significant lack of predictability for the free radical theory and its consequent probable downfall.
A scientific theory is a proposed description, explanation, or model of the manner of interaction of a set of natural phenomena, capable of predicting future occurrences or observations of the same kind, and capable of being tested through experiment or otherwise falsified through empirical observation. The free radical theory lacks predictability and has been repeatedly invalidated via numerous experiments and through empirical observations. Yet, it enjoys widespread support from the global medico-scientific community.
I have written extensively on this subject and have performed a selective review of the world's literature on oxygen metabolism 1-5.
In the 1950s, Denham Harman 6 proposed the "free radical theory," postulating that damage to cellular macromolecules via free radical production in aerobic organisms is a major determinant of life span. Subsequently, these alleged damaging derivatives of oxygen, which were formerly termed "reactive oxygen species (ROS)", were defined as being deleterious and harmful. The investigators' approach was as simple as one, two and three:
- 1. Electronically modified oxygen derivatives (EMODs) were believed to be harmful and they were accused of causing over 100 pathophysiologies.
- 2. Antioxidants would therefore nullify or negate the effects of these deleterious EMODs.
- 3. Based on Harman's free radical theory, diseases, such as cancer, atherosclerosis and diabetes and also including aging, would be reversed, prevented or cured by the judicious use of antioxidants.
Over half of a century later, the predictions based on the free radical theory have repeatedly failed to support the free radical theory 1-5. Briefly, the theory states that the aging process results from the "stochastic" accumulated damage caused by so-called reactive oxygen species (ROS), alleged highly reactive molecules that, among other sources, are normal by-products of cellular metabolism 7-9.
Similarly, the free radical theory of aging assumes oxygen free radical reactions cause damage and thus constitute the bulk of deleterious events that lead to aging 7, 8, 10-14.
It now appears that, contrary to most formulations of the free radical theory of aging, which argue EMODs are uncontrolled and thus cause damage that accumulates with age, EMODs are under strict metabolic control. In fact, a compartmentalization of oxidative events appears to exist in terms of physiological stimuli, signaling mechanisms, and functional consequences 15, 16, clearly arguing in favor of seeing EMODs as crucial and constructively functional in aerobic cells.
Negative results from the feeding of antioxidants have been rationalized by arguing that many of the antioxidants fed to mammals interfere with mitochondrial respiration, and so the failure of antioxidant trials to extend lifespan may have been due to their toxicity 17.
In the studies testing the validity of the free radical theory, paradoxes are pervasive in the literature and authors are seemingly reluctant to accept experimental results which are contrary to the dogma of the free radical theory. However, assuming the invalidity of the free radical theory eliminates many of these paradoxes and offers a level of understanding that was hitherto unavailable. I discuss in great detail the essential nature of EMODs for the normal functioning of aerobic cells and their crucial role as secondary cellular messengers in my e-books 1-5, which are available at www.thepundit.com.
Not only have antioxidants failed to stop or reverse disease and aging but they also appear to cause harm and in some studies they may increase overall mortality. A 2005 nutrition and supplement review in JAMA bolsters my position 18.
The glowing predictions for vitamin E alone or in combination with vitamin C and beta carotene have been muffled by a compelling body of clinical trial evidence and by the association of certain adverse effects with antioxidant vitamin usage. The following antioxidant studies and clinical trials have been conducted on over 600,000 humans and have failed to lend credence to the free radical theory and they serve to effectively invalidate it.
Alpha_Tocopherol/Beta-Carotene Prevention Study (ATBC) (1994)19: 29,133 (pooled) finnish male smokers found an 18% excess of lung cancer in participants reveiving beta-carotene after 6 years and it cncreased the incidence of cardiac death, hemorrhagic stroke and the risk for major coronary events. this trial was stopped early.
Polyp Prevention Study Group (1994)20: 751 completed the four-year clinical trial. Neither beta carotene or vitamins C and E reduced the incidence of adenomas nor prevented any subtype of polyp.
The Beta-Carotene and Retinol Efficacy Trial (CARET) (1996)21: 18,314 smokers, former smokers, and workers exposed to asbestos, were given β-carotene and vitamin A for 4.0 years, and they had a 28% increase in lung cancer incidence. The trial was stopped 21 months early.
Physicians' Health Study I (PHS I) (1996)22: β-carotene, in 22,071 US male physicians, showed no differences in the incidence of malignant neoplasms, stroke or cardiovascular disease or in overall mortality after 12 years of supplementation.
ATBC Sub-Study Shows Increased CVD Deaths (1997)23: 1,862 men, with prior myocardial infarction, took α-tocopherol and β-carotene for 5.3 years. There were no significant differences in major coronary events but significantly more deaths from fatal coronary heart disease.
Antioxidant Vitamin Effect on Traditional CVD Risk Factors (1997)24: In 297 retired teachers, after 2-4 months of supplementation the combined antioxidant supplement had no significant effect on the systolic and diastolic blood pressures, fasting serum lipids (total Cholesterol, high-density lipoprotein cholesterol, and LDL cholesterol) and fasting glucose.
The Nurses' Health Study (1998) and Folic Acid and Colon Cancer (1998)25: 88,756 women taking vitamin C and B-carotene, for 8 years, did not have any reduction in heart disease risk. Multivitamins containing folic acid had no benefit with respect to colon cancer after 4 years of use and had no significant risk reductions after 5 to 9 or 10 to 14 years of use. Long-term use of over 15 years of multivitamins may substantially reduce risk for colon cancer, perhaps due to folic acid.
The Women's Health Study (1999)26: In 39,876 healthy women aged 45 years or older, there was no benefit from β-carotene, after 4.1 years, on the incidence of cancer, cardiovascular disease or death totals.
The GISSI Trial (1999)27: 11,324 patients with recent heart attacks, showed no benefit from vitamin E supplements for up to 2 years. Results indicated that n-3 PUFA supplements, but not synthetic vitamin E, reduced long-term complications of myocardial infarction. The fish oil group had 15% decreased risk of death, nonfatal MI, and stroke.
The Health Professionals Follow-Up Study (1999)28: 43,738 men were followed for 8 years. Vitamin E and C supplements and specific carotenoids did not reduce risk for stroke.
Meta-Analysis of Vitamin E in CVD, Ischemic Heart Disease (IHD) and Mortality (2000)29: Four randomized trails on 51,000 participants taking vitamin E or placebo for 1.4 to 6 years, did not demonstrate a reduction in cardiovascular and IHD (ischemic heart disease) mortality or nonfatal myocardial infarction.
The Heart Outcomes Prevention Evaluation Study Investigators (HOPE) (2000)30: 9,541 patients, at high risk for cardiovascular events or diabetes, were treated with vitamin E for 4.5 years and had no effect on cardiovascular outcomes or stroke.
Age-Related Eye Disease Study Research Group (AREDS) (2001)31: 4,757 participants, taking β-carotene, vitamin C and E, had no effect on the 7-year risk of development or progression of age-related lens opacities or visual acuity loss.
HDL Atherosclerosis Treatment study (HATS) (2001)32: in a three-year, double-blind trial, 160 patients with coronary disease subjects were randomized to simvastatin (lipid-lowering) plus niacin treatment, or antioxidants (vitamin C, α-TOH, β-carotene, and selenium) or a combination of both. Antioxidant supplementation alone had no significant effect on clinical end points but, notably, when used in combination with simvastatin/niacin, antioxidants negated the benefit of the latter on plasma lipid profile and stenosis progression.
MRC/BHF Heart Protection Study (2002)33: studied antioxidant vitamin supplementation in 20,536 high-risk individuals in a randomized placebo-controlled trial. It found no benefit from a combination of vitamins E and C, and β-carotene, for heart disease, cancer, and several other conditions. It also found that vitamin E, vitamin C, and β-carotene supplementation resulted in small but significant increases in serum total cholesterol, low density lipoprotein-cholesterol, and triglyceride concentrations.
Antioxidant Vitamins and US Physician CVD Mortality (2002)34: 83,639 male U.S.A. physicians taking vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD or CHD mortality.
The Women"s Angiographic Vitamin and Estrogen (WAVE) Trial (2002)35: 423 postmenopausal women, with at least one 15% to 75% coronary stenosis, showed that neither hormone replacement therapy nor antioxidant vitamin supplements (vitamins C & E) provided any cardiovascular benefit. Instead, a potential for harm was suggested.
Antioxidant vitamins for the prevention of cardiovascular disease meta-analysis (2003)36: In 7 trials with 82,000 patients, vitamin E supplements provided no benefit for cardiovascular mortality.
High dosage vitamin E supplementation meta-analysis (2005)37: In a 2004 meta-analysis, including more than 135,000 subjects, it was concluded that high doses of vitamin E increased mortality.
Heart Outcomes Prevention Evaluation (HOPE) investigators report a 2.5-year extension of HOPE (HOPE-TOO) (2005)38: 3994 of the 7030 original study enrollees elected to continue the randomized vitamin E/placebo drug assignment. After a mean of 7.2 years of follow-up, vitamin E did not significantly reduce the relative risk (RR) of total cancer incidence, of cancer death, or a composite of cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and stroke, or of individual components of this composite end point. These findings of lack of benefit from vitamin E (natural source, 400 IU -tocopheryl acetate) during the extended study are consistent with the original HOPE report and with recent meta-analyses of Vivekananthan 36 and Miller 37. Another subgroup finding in HOPE-TOO was a vitamin E-associated increased risk of heart failure incidence that appeared in a secondary end point analysis in the 4.5-year report and persisted in the 7-year extended follow-up, as did the risk of hospitalization for heart failure. The National Cancer Institute (NCI) issued a statement following the HOPE-TOO study as follows: "NCI has never recommended that people take vitamin E outside a clinical trial for the prevention of cancer."
HOPE Study and MICRO-HOPE Substudy (2002)39: 3,654 people with diabetes in a randomized clinical trial with a 2 x 2 factorial design, which evaluated the effects of vitamin E and of ramipril in patients at high risk for CV events. The daily administration of 400 IU vitamin E for an average of 4.5 years to middle-aged and elderly people with diabetes and CV disease and/or additional coronary risk factor(s) has no effect on CV outcomes or nephropathy.
Prospective, randomized, placebo-controlled clinical trials and meta analysis of various trials, (such as HOPE 30, GISSI 27, ATBC 19, Hennekens study 22, Omenn's study 21, Brown's study 32, MRC/BHF 33, Vivekananthan's meta-study 36, Miller's meta-study 37), testing the effect of vitamin E and other antioxidant vitamins or their combinations on clinical manifestations of cardiovascular disease, cancer and diabetes, have consistently shown that commonly used antioxidant vitamin regimens (vitamins E, C, beta carotene, or a combination thereof) do not significantly reduce overall cardiovascular events, diabetes or cancer. Additionally, the antioxidant vitamins may have significant adverse effects or may increase mortality.
Judging the overall data objectively, these studies and many others cited in "The Howes Selective World Library of Oxygen Metabolism (available at www.thepundit.com)" demonstrate the repeated failed predictions and consequent downfall of the free radical theory.
1. Howes, R. M. © 2004. U.T.O.P.I.A. - Unified Theory of Oxygen Participation in Aerobiosis. Free Radical Publishing Co. Kentwood, LA.
2. Howes, R.M. © 2005. The Medical and Scientific Significance of Oxygen Free Radical Metabolism. Free Radical Publishing Co. Kentwood, LA.
3. Hydrogen Peroxide Monograph 1: Scientific, Medical and Biochemical Overview & Antioxidant Vitamins A, C, & E Monograph 2: Equivocal Scientific Studies, © 2006. Free Radical Publishing Co. Kentwood, LA.
4. Cardiovascular Disease and Oxygen Free Radical Mythology. © 2006. Free Radical Publishing Co. Kentwood, LA.)
5. Diabetes and Oxygen Free Radical Sophistry. © 2006. Free Radical Publishing Co. Kentwood, LA.
6. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298-300, 1956.
7. Harman, D., 1981. The aging process. Proc. Natl Acad. Sci. USA 78, 7124-7128.
8. Beckman, K.B., Ames, B.N., 1998. The free radical theory of aging matures. Physiol. Rev. 78, 547-581) (Finkel, T., Holbrook, N.J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature 408, 239-247.
9. Balaban, R.S., Nemoto, S., Finkel, T., 2005. Mitochondria, oxidants, and aging. Cell 120, 483-495.
10. Weindruch, R., 1996. The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol. Pathol. 24, 742-745.
11. Cadenas, E., Davies, K.J., 2000. Mitochondrial free radical generation, oxidative stress, and aging. Free Radic. Biol. Med. 29, 222-230.
12. Harman D. Aging: overview. Ann NY Acad Sci 928: 1-21, 2001.
13. Barja, G., 2002. Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Ageing Res. Rev. 1, 397-411.
14. Harman D. The free radical theory of aging. Antioxid Redox Signal 5: 557-561, 2003.
15. Pani, G., Bedogni, B., Colavitti, R., Anzevino, R., Borrello, S., Galeotti, T., 2001. Cell compartmentalization in redox signaling. IUBMB Life 52, 7-16.
16. Soberman, R.J., 2003. The expanding network of redox signaling: new observations, complexities, and perspectives. J. Clin. Invest. 111, 571-574.
17. Harman, D. H.. Free radical theory of aging: effects of antioxidants on mitochondrial function. Age 10: 58-61, 1987.
18. Lichtenstein, A.H. & R.M. Russell. 2005. Essential nutrients: Food or supplements? JAMA. 294:351-358.
19. Heinonen, O.P., J.K. Huttunen, D. Albanes & ATBC cancer prevention study group. 1994. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N. Engl. J. Med. 330:1029-1035.
20. Greenberg, E.R., J.A. Baron & T.D. Tosteson. 1994. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. N. Engl. J. Med. 331:141-147.
21. Omenn, G.S., G.E. Goodman, M.D. Thornquist, et al. 1996. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334(18):1150-1155.
22. Hennekens, C.H., J.E. Buring, J.E. Manson, et al. 1996. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N. Engl. J. Med. 334(18):1145-1149.
23. Rapola, J.M., J. Virtamo, S. Ripatti, J.K. Huttunen, D. Albanes, P.R. Taylor & O. P. Heinonen. 1997. Randomized trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 349(9067):1715-1720.
24. Miller, E.R. 3rd, L.J. Appel, O.A. Levander & D.M. Levine. 1997. The effect of antioxidant vitamin supplementation on traditional cardiovascular risk factors. J. Cardiovasc. Risk. 4(1):19-24.
25. Giovannucci, E., M.J. Stampfer, G.A. Colditz, D.J. Hunter, C. Fuchs, B.A. Rosner, F.E. Speizer & W.C. Willett. 1998. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann. Intern. Med. 129(7):517-524.
26. Lee, I.M., N.R. Cook & J.E. Manson. 1999. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: Women's Health Study. J. Natl. Cancer Inst. 91:2102-2106.
27. Dietary supplement with n-3 polyunsaturated acids and vitamin E after myocardial infarction: results of the GISSI-Prevention trial. Gruppo, Italiano per lo Studio Sopravvivenza nell'Infarto miocardico. 1999. Lancet. 354: 447-455.
28. Ascherio, A., E.B. Rimm, M.A. Hernan, E. Giovannucci, I. Kawachi, M.J. Stampfer & W.C. Willett. 1999. Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann. Intern. Med. 130(12):963-970.
29. Dagenais, G.R., R. Marchioli, S. Yusuf & G. Tognoni. 2000. Beta-carotene, vitamin C, and vitamin E and cardiovascular diseases. Curr. Cardiol. Rep. 2(4):293-299.
30. Yusuf, S., G. Dagenais, J. Pogue, et al. 2000. Vitamin E supplementation and cardiovascular events in high risk patients: The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 342:154-160.
31. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. 2001. Arch. Ophthalmol. 119(10):1439-1452.
32. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, and Albers JJ. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345: 1583-1592, 2001.
33. Collins, R., J. Armitage, S. Parish, P. Sleight & R. Peto. 2002. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: A randomized placebo-controlled trial. Lancet. 360(9326):23-33.
34. Muntwyler, J., C.H. Hennekens, J.E. Manson, J.E. Buring & J.M. Gaziano. 2002. Vitamin supplement use in a low-risk population of US male physicians and subsequent cardiovascular mortality. Arch. Intern. Med. 62(13):1472-1476.
35. Waters, D.D., E.L. Alderman, J. Hsia, B.V. Howard, F.R. Cobb, W.J. Rogers, P. Ouyang, P. Thompson, J.C. Tardif, L. Higginson, V. Bittner, M. Steffes, D.J. Gordon, M. Proschan, N. Younes & J.I. Verter. 2002. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 88(19):2432-2440.
36. Vivekananthan, D.P., et al. 2003. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet. 361:2017-2023.
37. Miller, E.R., R. Pastor-Barriuso, D. Dalal, et al. 2005. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann. Intern. Med. 142(1):37-46.
38. The HOPE and HOPE-TOO Trial Investigators. Effects of Long-term Vitamin E Supplementation on Cardiovascular Events and Cancer. A Randomized Controlled Trial. JAMA. 2005;293:1338-1347.
39. Eva Lonn et al. Effects of Vitamin E on Cardiovascular and Microvascular Outcomes in High-Risk Patients With Diabetes. Results of the HOPE Study and MICRO-HOPE Substudy. Diabetes Care 25:1919-1927, 2002.
Prof. Hon. Randolph M. Howes, M.D., Ph.D.
Adjunct Assistant Professor of Plastic Surgery, The Johns Hopkins Hospital, Baltimore, Md., U.S.A. and Espaldon Professor of Plastic and Reconstructive Surgery, University of Santo Tomas, Manila, Philippines.
Address for communication: 27439 Highway 441, Kentwood, Louisiana 70444-8152, USA. Email: firstname.lastname@example.org
Information about this Article
Peer-review ratings (from 1 review, where a score of 100 represents the ‘average’ level):
Originality = 125.00, importance = 150.00, overall quality = 125.00
This Article was published on 22nd January, 2007 at 16:17:06 and has been viewed 10394 times.
This work is licensed under a Creative Commons Attribution 2.5 License.
The full citation for this Article is:|
Howes M.D., PhD., R. (2007). The Consequent Downfall of the Free Radical Theory. PHILICA.COM Article number 75.
1 Peer review [reviewer #47336] added 25th August, 2011 at 07:42:05
A well-documented review of various studies related to the topic approached in this article. It seems, however, that there are still many authors that would not agree with the point of view so strongly put forward in this article, as well as in several previously published books (mostly by the same publisher). Interestingly, even several Nobel Laureates have disagreed-at least in part- with the author of this article about the free radical theory in biology and medicine. However, one cannot judge from only this fact that the author’s conclusions are either valid or invalid. Moreover, the author correctly points out the vast amount of NIH resources that were spent on studies that have not resulted in positive effects of huge vitamin supplementation tests, etc. The originality of this viewpoint is somewhat in question because similar, high-quality review articles that were peer-reviewed, and were also written earlier, by other authors are not cited or even referred to without citation in this interesting summary of some of the evidence against the often claimed positive effects of mega-dose vitamin supplementation over the last decades. It would have been interesting to read the author’s point of view about mild supplementation effects of the diets with vitamin E in attempts to prevent Alzheimer’s disease suggested by some other authors. As in previous articles, the standard recommended style of Philica.com has not been followed exactly, hence the corrsponding rating regarding the overall quality of the article.
Originality: 5, Importance: 6, Overall quality: 5