ANTIOXIDANTS and CARDIOVASCULAR DISEASES - A GLOBAL ANALYSIS
Abstract: The separate antioxidant contributions of Beta Carotene, Vitamin C, Vitamin E and Selenium from both foods and diet supplements are combined into a single function to both total and limit amounts of and duplication of their contribution to reducing risk of cardiovascular disease. The reduction in risk of antioxidants also depends on duration of their use. Life Ahead now recognizes up to a 50% reduction in risk of cardiovascular diseases for any amount or combination of these antioxidants used for long durations. But this benefit can only be achieved via use of dietary supplements. A maximum likely benefit from antioxidants in foods in practical diets may be a reduction in risk of less than 20%. This analysis shows that the theory that "All needed antioxidants can be obtained from foods" must be false. A new picture on how antioxidants in foods and supplements develops reduced risk of disease over time is proposed.
BACKGROUND: A large amount of research on how antioxidants affect the risks of both cardiovascular diseases (CVD) and cancer has been published during the past two decades. The process of atherosclerosis that produces CV diseases depends in substantial part on the oxidation state of LDL cholesterol in the blood. A pro-oxidative state of LDL cholesterol increases a rate of atherosclerosis, and a less oxidized state of the cholesterol slows atherosclerosis. This in turn can substantially increase or decrease the risk of cardiovascular diseases and especially of coronary heart disease at a given level of cholesterol. Although less well understood but now well confirmed, antioxidants also appear to slow the progress of most types of cancer. and from death from all causes.
Hundreds of studies have suggested that a wide variety of biochemical agents that affect cardiovascular diseases are related to their pro or antioxidant capability. Cigarette smoking is noted as creating a pro-oxidant environment. Agents particularly noted for antioxidant behavior included Vitamin A and Beta carotene, Vitamin C, Vitamin E and Selenium. Vitamin E has the most potent antioxidant capability of these nutrients. But other agents including estrogen, polyunsaturated fats and other vitamins and minerals also have antioxidant capability. Individual foods all have a varying antioxidant capability depending on their content of these and perhaps other included nutrients.
THE ANTIOXIDANT MODEL: Life Ahead now identifies the so-called antioxidant capability of Vitamins A, C, and E and Selenium by their ability to reduce risk of CVD disease. The Global Model for relating antioxidant risks to CVD diseases developed herein for Life Ahead thus includes a combined effect on risk of Beta carotene (for Vitamin A), Vitamin C, Vitamin E, and Selenium. The 140 key population study valuations found of these nutrients that were used in developing risks of cardiovascular diseases and cancer and more than 20 additional studies for death from all causes for these antioxidants are included in the Health Research Library via these and related links.
More recent research has identified the actual chemical antioxidant potency of a wide variety of foods and other nutrients. Called the Oxygen Radical Absorbance Capacity, or ORAC, this new valuation probably identifies a more specific level of true antioxidant potential than that obtained from risks of disease. A vast variety of nutrients have widely varying measured ORAC values. Ideally it would be desirable to use more specific values of food and nutrient antioxidants such as ORAC in the Life Ahead analysis. Unfortunately, a brief exploration of this possibility found that there was no evident relationship between the ORAC values and their probable effect on the major diseases as now developed. ORAC is a test tube type chemical valuation, and the actual bioavailability of various nutrients may differ much from their actual chemical values. Also, although called antioxidants, the four above antioxidants also may protect against diseases by mechanisms other than anti-oxidation per se. Hopefully, as more is learned on this the present Life Ahead antioxidant model can be expanded and improved.
Conventional health models usually multiply risks of various factors. This is incorrect because there is duplication of benefits among various factors such as different antioxidants. A multiplication of maximum potential benefits of the above four nutrients would produce reductions in risks in the order of 80% that are not now verified. As will be discussed, such a large risk reduction would be implausible from biochemistry. Rather, the extent to which any amount of all so-called antioxidants can slow atherosclerosis probably will reach some limit. Life Ahead thus combines the indicated antioxidant effects of these four nutrients and imposes a limit on their total potential benefit. This limit is set as that level of benefit now reasonably well verified by research.
THE FORMULA and ITS CONFIRMATION: A summary of risk benefits for cardiovascular diseases for each of these four antioxidants follows. Detail on the research and analysis used in obtaining these valuations is provided via separate discussions on each factor in the Health Library. Averaged risk ratios were obtained from the identified amounts of antioxidants for a duration of use estimated at about 10 years.
For Nutrient Vitamin E Beta-carotene Vitamin C Selenium
Avg Amount in Research 200IU 15,000IU 400mg 100mcg
Avg Research Risk Ratio 0.67 0.76 0.75 0.60
Formula Value 0.67 0.76 0.75 0.75
Risk Ratio per Year of Use 0.961 0.973 0.972 0.973
No Research Risk Ratios from
Population studies included 23 10 9 8
Life Ahead formula that sums benefits from all of these nutrients in food plus supplements on the risk of cardiovascular disease is:
(1) CVD risk = Exp(-0.002 * (Vitamin E, IU-8) - 0.000018 * (Betacarotene,IU -6000) - 0.00072 *( Vitamin C,mg - 250) - 0.0027 *( Selenium, mcg - 90)
Risk is based on differences in the amounts of these antioxidants from assumed average population values to compute a risk as a ratio to that for the average population. The above formula reproduces for the first 3 antioxidants their actual average risk at their average value found from research. The value accepted for selenium was reduced somewhat for conservatism vs. the average of research because of the higher margin of error of a number of the included population studies of this mineral, and because biochemical research suggests its antioxidant effect will be less than that of Vitamin E. Because antioxidants should from both biochemical engineering and actual research reduce risk as a function of their duration of exposure, the reduction in risk ratio per year of their use also is noted above.
This formula produces a risk factor for antioxidants of 1.0 or unity if all antioxidants have their average US population values in foods and no supplements are used. Diets low in antioxidants will have a risk factor above 1.0, those high in antioxidants will have risk factors below 1.0. Most of the risk benefits for antioxidants in the tables provided herein were obtained from the addition of dietary supplements to actual diets of foods eaten by the wide variety of differing populations included in the research.
The usual margins of error of individual studies usually were inadequate for each study to confirm a consistent benefit from null at the 95% level of probability for risk factors in the above 0.67 to 0.76 range. Yet 44 of the 50 above comparisons did show a benefit vs null for the antioxidant studied. The probable actual risk ratio for Vitamin E is established with the likely limits of 0.67 (5%-95%, 0.59-0.75) and averaged risk factors for the other three antioxidants are are established at adequate significance. Life Ahead now limits amounts accepted of supplements of these antioxidants to maximum values of 300 IU for Vitamin E, 400 mg for Vitamin C, 12,000 IU for Beta carotene, and 100 mg for Selenium. Life Ahead now also imposes a maximum computed benefit of a 50% reduction in risk of cardiovascular disease as potential for use of any combination, amount and duration of then multiple use of these four antioxidants. This level of benefit appears highly likely from the research results now obtained and probably is conservative. For example 300 mg per day of Vitamin E alone should produce close to the maximum benefit now accepted for maximum amounts of all four of these nutrients. It remains possible and even likely that larger benefits than the maximum of 50% risk reduction now accepted in Life ahead can be achieved from use of multiple antioxidants, but this remains to be confirmed adequately by research . Amounts larger than these suggestions should not be used. There are indications the use of beta carotene in amounts above 15,000 IU may actually be harmful, and no benefit is now noted for amounts of Vitamin E above about 300 IU. Because a diet probably will included at least 300 IU of beta carotene from food, the maximum accepted for a beta carotene and vitamin A supplement is 12,000 IU and 4000 IU respectively. Note these average values all are modified for user weight and gender. Thus higher values are required for equivalent benefits for large men than are needed for small women.
BENEFITS from ANTIOXIDANTS in FOODS are LIMITED: This new model provides an interesting new perspective on the potential value of antioxidants in foods vs those in supplements. First consider that combinations of added antioxidants from supplements probable can reduce risk of cardiovascular diseases by at least 50%. A next question becomes: "Can we develop practical diets of foods that will include enough additional antioxidant to produce this reduction in risk of 50% that appears to be a conservative potential benefit from combinations of supplements?"
A review of 8 quite different diets provided in an earlier Life Ahead demo shows the variation of nutrients found in foods as: For Vitamin E, 7 to 11 IU; for Beta carotene 2100 to 8000 IU; for Vitamin C, 120 to 340 IU; and for Selenium 55 to 120 mg. Roughly similar variations in the nutrients of population diets have been noted in diets included in various research studies. But those diets having the highest value of one of these nutrients did not include highest values of others. The computed overall antioxidant risk of these 8 diets used for 10 years ranged from a high of 1.085 to a low of 0.86. These 8 diets included an average one, one high in fruits, fish and elements considered 'good'; one 'bad' with very high in fats and low in fruits and vegetables, and 5 different daily diets recommended by various proponents including one from Pritikin and one from Atkins. These various diets produced differences in estimated Well-Days of life of more than 8 years. Yet in this group the most favorable dietary antioxidant risk vs average obtained from the total of the four included food nutrients now recognized as antioxidants was only a rather modest risk ratio of 0.86 or a reduction in risk of only 14%.
In contrast to this mediocre benefit from food antioxidants, each of the above supplement antioxidants used only in the average amounts studied in research produced quite significant risk average reductions in risk of 25% to 33%. And this same research suggests that combinations of supplements and/or use of vitamin E in larger amounts should produce a risk reduction of at least 50% . These are far larger benefits than those obtainable from the total amounts of the same four antioxidants included in these practical diets.
The actual research on risks associated with antioxidants in foods and vs those in supplements although limited shows a similar picture. A large study of (Kushi, New Engl J Med 1996:334:1156) failed to find useful effects of food content of Vitamins A and C, the antioxidants included in substantial amounts in foods. In fact the above benefits of food antioxidants are far too small to be usefully identified by practical population studies within their usual margins of error. Antioxidants in foods also are so heavily inter-correlated with each other and with other factors that their identification via the population research study method probably will not be feasible. Useful quantified benefits for individual antioxidants probably only can be obtained by analysis of multiple study results on supplements and Global Analysis as has been done above.
It is theoretically possible to develop a diet that contains adequate antioxidant benefits from foods by including very large if impractical amounts of specific fruits. Yet the above comparison shows that it is extremely unlikely that practical diets used by most people in our population will achieve more than a small fraction of the antioxidant benefit in reducing risk of cardiovascular disease obtainable from even any one of the above dietary supplements. Claims in diet books that individuals can obtain all needed healthful antioxidants from diets proposed have never been verified and must be false. Further, the amount of both Vitamin E and Folate in unfortified foods is far below that needed for best health benefit. More about other benefits of nutrients in foods and supplements is included elsewhere in this Library.
The computation that amounts of antioxidant vitamins and minerals in most diets are far short of the amounts that independent research on supplements shows produce lowest risk of major disease hardly requires rocket science. Yet this writer could find no record of this essentially required computation being done by those making claims about vitamin sufficiency. Uncounted millions of lives of our populations probably could have been and still could be extended and improved by the simple long term use of appropriate amounts of antioxidant supplements.
ANTIOXIDANTS in FOODS and SUPPLEMENTS can have DIFFERING BENEFITS: The antioxidant model computes values for foods and supplements separately. This is required because duration of antioxidant use is a key factor that affects atherosclerosis and risk of disease. The years of use of supplements is asked by Life Ahead of users, and benefits of supplements start at this entered age and build up gradually. For example at a 1st year of 400 mg of Vitamin C use, only a 0.972 benefit for coronary disease is computed. At 5 years use the benefit becomes about 0.87, and at 10 years use benefit becomes a factor of 0.75. As will be discussed, Life Ahead usually imposes arbitrarily for conservatism a limit of 20 years for including a benefit for any duration related nutrient factor.
This same effect of duration of use also must apply to the benefits of antioxidants in foods. A measured duration of a person's actual dietary foods over long time periods rarely will be available. Life Ahead now assumes that usual dietary foods of program users have been fairly consistent over time. Thus an assumption now made is that food antioxidants in recent diets probably have been fairly consistent for the full accepted 20 years prior to present age. This provides food antioxidants with their maximum potential computed value at present age for those beyond age about 40. In contrast, the benefits of diet supplements are computed at present age only for the years they have been used as entered into the program. Thus for this reason benefits from antioxidants in foods and in supplements can have quite differing contributing benefits at a given point in time. Because antioxidants in foods will have been present for a longer duration than dietary supplements started just a few years previous, population studies should measure somewhat higher benefits for antioxidants in foods than from supplements. Yet even with this inherent advantage, measured risks of antioxidants in foods have been marginal at best. But over the longer and lifetime term - and for the Well-Days computation - the effective durations of antioxidants in foods and supplement will become similar for most people if they are used in these proportions for the rest of life.
A MAXIMUM ASSUMED BENEFIT for ANTIOXIDANTS: The likely major mechanism by which antioxidants reduce risk of CVD diseases is by reducing the rate of atherosclerosis. The risk of coronary disease increases about 11% each year in an average male population from age 30 to 70, and about 13% per year for women. Life Ahead now imposes four assumed limits on antioxidant benefit from both food and supplements. First, and as above, a limit is imposed on the amount of each antioxidant that is considered useful for its estimates. These limits for an average individual are for Vitamin E, 300 IU; for Beta-carotene, 15,000 IU; for Vitamin C, 750 mg. and for Selenium, diet plus 100 mg of supplement. These limits are adjusted further for gender and body weight. Second, risks are computed for an assumed duration of food and supplement use during each year of life, and this duration is taken as no longer than 20 years. Note that in the Global Analysis of Diabetes, risks continued to expand for 30 years of duration.
Third, a maximum rate of benefit is taken as an annual risk reduction of 0.95 or 5%. Thus the maximum accepted benefit for antioxidants in Life Ahead is a reduction in the future age related increase in heart diseases for men of from 11% to about 6% per year. This is only modestly above the 0.96 or 4% per year benefit noted above for 200 mg of Vitamin E. Fourth, a maximum risk factor benefit for 20 years use of any individual amount of any combination of multiple antioxidants is now set in Life Ahead at 0.50. This as noted previously is a benefit much below that computed from multiplying the benefits of combined antioxidants. These assumptions may result in a substantial undervaluation of the potential benefits for antioxidants, but adequate direct verification of much larger benefits is not now available.
Another interesting finding of the Life Ahead analysis is that antioxidants also can reduce the population incidence of cancer by as much as they reduce CVD diseases. The Global antioxidant analysis of cancer is based on the large majority of about 90 different research study comparisons, more than those found for cardiovascular diseases.
BENEFITS of ANTIOXIDANT SUPPLEMENT USE to HEALTH and LIFE: Even with the above conservative limits on benefits, Life Ahead forecasts that use of optimum antioxidant supplements with an average diet can increase the future Well-Days of life of average 50 year old men and women by about 7 years. The available data confirm their expected benefits on death from all causes. This and estimates following assume no other health actions will accompany this use of supplements. After 20 years of use, incidence of both CVD diseases and cancer will be reduced in half. Use of 200-400 IU of Vitamin E alone should increase Well-Days by 6 years, and individual use of each of the other supplements should increase Well-Days by 4 to 5 years. Maximum presently computed benefits should be obtainable by use of any two supplements in the above indicated amounts. But health interested persons should consider using all four supplements individually in not more than full or at least half of the above suggested maximum amounts in part because each may contribute somewhat different benefits, and because the present assumptions of maximum benefit may be too conservative. Some antioxidants are water soluble and some are fat soluble, and each may provide unique contributions to long range health. Life Ahead can compute the probable benefits for any duration of use for any combination of antioxidants that are present in dietary supplements. Test of a typical modest level supplement, Beta carotene 5000 IU; Vit C 90 mg; Vit E 30 mg; Selenium 70 mcg, suggests 4.0 years of Well-Days benefit. A much more potent supplement produced a near maximum computed benefit. Benefits in Well-Days for those of high Cardiofitness and/or low serum cholesterol will be lower, and benefits for those having high cholesterol or family history risk will be higher.
An important caution is that benefits of dietary supplements that occur by changing rates of progress of a disease cannot be measured usefully by a practical randomized clinical study. Life ahead now successfully forecasts and explains the results of most available clinical studies on antioxidants and can forecast a likely result for any such clinical study. It can take 20 years of duration of a clinical study for a 10 year average duration to disease to be measured. It is felt here that Global Analysis identifies now a probable result from 160 study comparisons that should be much more accurate than can achieved by any feasible direct population study. It thus is potentially important to the future health of our population that this type of Global Analysis becomes more widely understood, used, accepted and improved.
OTHER ANTIOXIDANTS: Dozens - and perhaps even hundreds of different chemical nutrients have antioxidant properties. Promoters of longevity point to small research studies about antioxidant properties of many different proposed diet supplements as justifying their potentially costly daily use. The problem with such research is that it usually identifies a result on each chemical nutrient individually. The real question is: Starting with the now well confirmed benefits of herein recommended and powerful combinations of inexpensive Vitamins A, C, E and selenium, will the addition of some other added chemical nutrient accomplish any further benefit? Unless this question can be answered as yes from direct measurement, it seems unlikely that any further antioxidant nutrient will produce any further benefit to health.
FUTURE IMPROVEMENTS: The present antioxidant model provides a useful start toward the practical valuation of health benefits of individual and multiple antioxidants. But there is a serious need for more focused research data on antioxidant properties of a widest variety of nutrients and other factors on a consistent basis. We need a clearer relation between specific measures of antioxidants and risk of disease that is not now available. The present model focuses on CVD disease risk as a measure of antioxidant benefit. There also is much information relating to bio-availability of these chemicals and their possible interactions with other factors. The limiting value for antioxidants also should depend on the level of serum or LDL cholesterol present. And more data is needed for large differences in antioxidant dose or amount and for any possible negative benefits they may show for large amounts. No adequate data on this were found except for the indication that large amounts of beta carotene might be harmful.
Factors other than the four nutrients considered here probably should be part of the antioxidant model. Estrogen probably is of major importance. The analysis for cancer suggest that antioxidants may not reduce cancer risk during women's pre-menopausal years during which estrogen may replace the effect of antioxidants. Polyunsaturated fat may produce benefits via this mechanism rather than via the present cholesterol-related mechanism now used and perhaps should be a part of this antioxidant Global model. We need better information on the risks of combinations of these four antioxidants and of their use of these combinations in larger effective amounts.