Antioxidants: A Research Review

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Antioxidants: A Research Review

 

Antioxidants in Health and Disease: The Big Picture

E. Cheraskin, MD, DMD

 

(Reprinted with permission of the author and the

Journal of Orthomolecular Medicine 10: #2, 89-96,

Second Quarter, 1995.)

 

Abstract

In December 1993, four reports appeared describing the

ecology of macular degeneration (MD). (1-4) It was

generally agreed that the environmental contribution

includes sunlight. It was suggested that the

antioxidants serve to counter the oxidative damage. In

any case, the articles prompted a letter to the editor

entitled, " Now That We Have All The Pieces... Why Is

There Still A Puzzle?” (5) This was intended to

indicate that we still have very little opportunity to

slow and/or stop the degenerative process. We have

even less knowledge about how to reverse and/or

prevent MD.

 

This report is intended to cast additional light on

the subject It is suggested that, viewed in the bigger

picture, the total body concept, significant changes

in macular degeneration and other diseases may occur

when larger-than-recommended amounts of the

antioxidants are supplied. Additionally, it is

proposed that the therapy be instituted for longer

periods of time and begun earlier in life. It is hoped

that this report will continue more action in the

pursuit of this approach to macular degeneration.

 

Introduction

The literature is replete with information which

suggests that a common denominator in the aging

process and in the major diseases associated with

aging is oxidative damage. This has led to an interest

in the use of antioxidants in the prevention and

treatment of such problems. There are hundreds, if not

thousands, of articles on this subject. Some are

retrospective; other prospective. They deal with large

and small samples of short and long duration. They

range from the womb to the tomb. Most of them are of

an epidemiologic (correlational) nature. However, many

are concerned with intervention and possibly provide

causal data.

 

This report will outline evidence to show that the

antioxidants are necessary, singly, in combinations,

in larger amounts than generally held, and must be

started much earlier in life. Hence, we will attempt

to emphasize the relationship of antioxidants to

common disorders such as heart disease, cancer,

diabetes, arthritis, cataracts, and macular

degeneration as well as other syndromes through an

examination of 40 representative studies in the

English language literature.

 

Vitamin A Studies

Included (Table 1) are five representative studies of

vitamin A consumption in health and disease. (6-10)

According to the Subcommittee on Foods and Nutrition

of the National Research Council, the daily

recommended requirements (RDA) for vitamin A are 5,000

and 4,000 IU respectively for men and women. (11) It

is clear from Table 1 that much larger amounts than

proposed for healthy people in the RDA are needed.

Additionally, the evidence from these studies suggest

that there were no side effects.

 

It is generally recognized that vitamin A blood levels

below 10 mcg% are considered evidence of obvious

deficiency. (12) Olson contends that the normal range

is 20 to 50 mcg% and therefore anything above 50 is

high.

 

Table 2 summarizes the studies on vitamin A in the

blood in health and sickness. You will note that the

reports shown suggest that what Olson call high levels

are probably the desired amounts.

 

Vitamin C Studies

According to the Recommended Dietary Allowances, 60 mg

of vitamin C is the suggested normal requirement.

(11)Table 3 features studies which underscore the

desirability of larger-than-recommended amounts.

(18-22) It will be noted that amounts as large as

three grams per dose provide remarkable consequences.

 

Back in the '40s, the Interdepartmental Committee on

Nutrition for National Defense (ICNND) began to set

the standards for optimal plasma vitamin C.

Originally, acceptability was anything above 0.1 mg%.

Through the '40s, the figures were changed to 0.2 and

then 0.4 mg%. Most of the literature today considers

0.4 mg% as being a satisfactory blood vitamin C level.

In this connection, Block points out that 15% of white

men, 65-74 years of age, in the U.S. today have blood

ascorbate levels below 0.4 mg%.(23) Chandra views 0.5

to 2.0 mg% as the acceptable range. (24) It is clear

from Table 4 that the best clinical results parallel

plasma levels above 1.0 mg%. (17, 25-28)

 

Vitamin E Studies

According to the RDA, 30 mg of vitamin E or 10 mg of

alpha tocopherol is considered the recommendation for

healthy man.(11) It will be noted (Table 5) that

amounts ranging from 400 to 3200 mgs contribute to the

solution of many classical problems. (29-33)

 

There is not much in the literature regarding the

optimal blood vitamin E levels. MachIm, in his book

(34) indicates that anything less than 0.7 mg% is

deficient, levels between 0.7 and 0.9 are low, and

values above 0.9 mg% are acceptable. Simonoff adds the

fact that the blood levels of vitamin E are different

in the sexes and at different ages. (35) For example,

in the young adult, the values should be 1.6 to 1.9

mg% and decrease with age to 0.9 to 1.1 mg% in the

elderly. In the light of these so-called norms, it is

interesting (Table 6) that salutary effects seem to

parallel higher blood vitamin E levels. (14, 36-39)

 

 

Other Antioxidants

While vitamins A, C, and E have been recognized for a

long time for their antioxidant properties, there are

others such as zinc, selenium, and bioflavinoids which

directly or indirectly serve as free radical

scavengers. Perhaps the one receiving the most

attention at the moment is the carotenoids and

particularly beta carotene. Since beta carotene serves

as a provitamin A, there are suggestions as to its

daily requirement. (11) However, beta carotene also

serves an independent function as an antioxidant. The

requirement in this regard is not very clear.

 

Table 7 outlines the relationship of dietary beta

carotene to some of our major problems. (40-44) There

seems to be no question but that beta carotene in

larger-than-generally recommended amounts exert

salutary effects.

 

In line with our earlier format, Table 8 outlines the

blood carotene levels. (14, 45-48) In general, the

levels in health are considerably larger than those

with illness.

 

The Antioxidant Index

Perhaps more importantly is the observation that the

relationship between various antioxidants in health

and disease are sharpened when they are viewed as an

antioxidant index. For example, macular degeneration,

(26) colorectal adenomas, (49) rheumatoid arthritis,

(50) cancer, (51) and cardiovascular disease, (52)

become even more meaningful when viewed in terms of

conditions of antioxidants rather than single ones.

 

Comments

We have been trying to answer the question of the role

of antioxidants in the aging process and in

age-related diseases. We think that we have some of

the answers. It would seem, from what has transpired,

that the antioxidants are important in the prevention

and treatment of these problems. However, there are

still unanswered questions. We still do not know all

of the antioxidants. We are still not sure of the

dosages except that they are larger than usually

recommended. We have little information about the

amounts for different diseases. For example, are the

dosages larger for macular degeneration than heart

disease? Or, are the amounts more a function of the

oxidative damage? And, perhaps more importantly, we do

not have the time frame period.

 

Since the disturbances associated with aging and these

age-related diseases are characterized by a long

incubation period and an insidious clinical course,

the question of when one should institute an

antioxidant program is still unresolved. The one thing

we know for sure is starting when the disease appears

is too late.

 

Summary and Conclusions

In the final analysis, how we fare is a function of

two sets of interdependent factors. On the one hand,

we are at the mercy of numerous environmental threats,

such as physical, chemical, microbial, thermic,

actinic, and psychologic. For macular degeneration,

the dominant one is solar radiation; for lung cancer,

it is tobacco consumption. However, how we fare is

also a function of how well we tolerate these

environmental challenges. These protective systems are

collectively referred to as resistance/susceptibility,

constitution, predisposition, immunocompetence,

homeostasis and/or harmony. The antioxidants serve as

an important ingredient in building resistance and

reducing susceptibility and largely because of its

free radical scavenging action. However, how much,

when and for how long are still the burning questions.

At the moment, in the light of these 40 representative

studies, macular degeneration and cataracts enjoy

positions like heart disease and cancer.

 

(Table 1 in the original paper contains Dietary

Vitamin A Levels)

 

Reference # 6/ Precancer

In a study of oral leukoplakia, patients were given

200,000 IU of vitamin A per week for six months versus

placebo capsules. Fifty-seven per cent of vitamin A

supplemented patients had complete remission and,

during that time, no new lesions appeared.

 

#7/HIV

A study was done with 25 HIV patients with CD4+ T cell

counts less than 800. Thirty-two per cent of the

subjects had retinol levels less than 30 mcg%.

Subjects taking a daily multivitamin containing modest

amounts of vitamin A (1500-2100 mcg) had higher serum

retinol levels than those taking no supplements (72

versus 42 mcg%). These observations suggest that even

modest doses of vitamin A can have significant impact

on serum retinol levels in advanced HIV patients.

 

#8/ Cancer

A case control study conducted among a cohort of

chemical manufacturing employees provided an

opportunity to test the hypothesis that lung cancer

risk is inversely related to dietary intake of vitamin

A. Subjects in the lowest tercile of vitamin A intake

(less than 62,000 lU/week) had approximately twice the

risk of lung cancer as those in the highest (greater

than 100,000 IUI week).

 

#9/Respiratory Tract Infections

Preschool-age children (157) with a history of

frequent respiratory illness were randomized into

vitamin A supplemented (450 mcg/day) and placebo

groups. Respiratory symptoms were recorded on a daily

basis over a period of 11 months. The children who

received the supplement experienced 19% fewer episodes

of respiratory symptomatology than their placebo

counterparts.

 

#10/Mortality

Mortality of Sumatran children randomized to receive a

200,000 IU vitamin A capsule (n=9776) was compared

with those who did not (n=2447). During the four

months after completion of the first distribution,

mortality among the recipients was 75 per cent less

than the nonrecipients. One capsule every six months

may provide adequate protection for the vast majority

of children.

 

(Table 2 in the original paper contains Blood Vitamin

A Levels)

 

Reference # 13/Measles

In a study of children in Long Beach, California, the

blood levels in youngsters with measles was 24 mcg%;

in those with nonmeasles 26 mcg%; and in the well kids

40 mcg%.

 

#14/ Alzheimer's Disease

Elderly people with Alzheimer's Disease

post-infarct-dementia and controls were examined. The

average vitamin A levels were 45 mcg% in Alzheimer's

Disease compared to an average 61 mcg% in the control

group.

 

#15/ Cancer

The vitamin A blood levels of patients with pulmonary

cancer, non-cancer pulmonary disease, and controls

were compared. The levels were 45.6 mcg% (range 20.2

to 79.5) for the pulmonary cancer subjects; 64.3 mcg%

(range 43.6 to 80.8) for the patients with noncancer

pulmonary disease; and 68.4 mcg% (range 52.6 to 101.2)

in the controls.

 

#16/ Bronchopulmonary Disease

This study showed that low vitamin A levels (less than

10 mcg%) observed in infants with bronchopulmonary

dysplasia (BPD), and implies that therapeutic

administration of vitamin A may help prevent and treat

BPD.

 

#17/ Cardiovascular Disease

There is data from the cross-cultural European

comparisons of the Edinburgh Aging Control Study and

of the Basel Prospective Study. They show, for the

first time with fair probability, that vitamin A

concentrations needed to decrease ischemic heart

disease risk are 63 to 80 mcg%.

 

(Table 3 in the original paper contains Dietary

Vitamin C Levels)

 

Reference #18/Infertility

One gram of ascorbic acid per day for 60 days was

provided to 20 clearly-diagnosed infertile, but

otherwise healthy, men. A separate control group of 20

men were placebo-supplemented. At the end of these two

months, conception occurred unanimously only in the

vitamin C supplemented couples!

 

#19/Diabetes

A study of the small blood vessels of the skin and

retina was carried out in 24 normal subjects and 12

diabetics. The experiment revealed very clearly that

the capillary strength of both the eye and skin of all

diabetics improved during the vitamin C treatment (one

gram/day) and worsened when it was discontinued.

 

#20/Mental Illness

The manic/depressive state was assessed in 24 subjects

who completed two generally accepted psychometric

tests. Each patient was provided with either a three

gram ascorbic acid effervescent tablet or a placebo.

In the vitamin C treated group, the severity of the

bipolar state was reduced within the first hour and

then declined even more rapidly between the second and

fourth hours. No change occurred in the placebo

subset.

 

#21/Life Expectancy

In a reexamination of a large federal government

study, it was discovered that those men who consumed

300 to 400 mgs of vitamin C daily compared with those

who consumed less than 50 mgs showed art overall

mortality reduction of 42% principally due to a

decline in heart disease and cancer. This translates

into living approximately six years longer!

 

#22/ Cardiovascular Disease

A 1000 mg ascorbic acid tablet or a placebo was

supplemented daily to 20 adults for two six-week

periods in a randomized, crossover design. Under these

conditions, vitamin C supplementation reduced the

systolic pressure.

 

(Table 4 in the original paper contains Blood Vitamin

C Levels)

 

Reference #25/Periodontal Disease

In a study of 24 adult volunteers with initially low

and partially even deficient plasma vitamin C values,

the hydroxyproline and proline content was measured

before and after supplementation. There was a

statistically significant rise but not before the

plasma ascorbate level was above 0.9 mg%. The optimal

plasma vitamin C level which was associated with the

highest hydroxyproline and proline content in

periodontal tissue ranged between 1.0 and 1.3 mg%.

 

#17/Heart Disease

The most recent work on risk factors in ischemic heart

disease (IHD) is available from several cross-cultural

epidemiologic studies. They all suggest, for the first

time with fair probability, that protection against

IHD is paralleled by vitamin C levels in the range of

0.7 to 0.9 mg%.

 

#26/ Macular Degeneration

From the Eye Disease Case Control Study Group, there

is evidence that blood levels of vitamin C in the 0.7

to 1.6 mg% range have a risk of one third to one half

that in blood levels below 0.7 mg% for macular

degeneration.

 

#27/ Hypertension

In a study of 685 patients without known hypertension,

it was discovered that the higher the plasma vitamin C

level, the lower the systolic and diastolic pressure.

Specifically, with plasma ascorbic acid (PAA) of 0.7

mg%, the blood pressure was 147/83 mm Hg; with PAA of

1.4 mg%, the pressure was 139/78 mm Hg.

 

#28/ Cataracts

A classification was designed of three blood ascorbate

levels; less than 0.7 mg%, greater than 1.6 mg%, and a

group with plasma levels at intermediate range.

Persons with the lowest ascorbate intake status had

11-fold the risk of developing cataracts in the

posterior region of the lens as individuals with the

highest ascorbate levels.

 

(Table 5 in the original paper contains Dietary

Vitamin E Levels)

 

Reference #29/ Cardiovascular Disease

One of the major signs of peripheral arterial disease

(PAD) is intermittent claudication. In a double-blind

study, 1600 mgs of alpha tocopherol a day

significantly reduced (66%) this important sign of

cardiovascular disease.

 

#30/Parkinson's Disease

A comparison was made of the clinical picture of

Parkinson's Disease as measured by a Unified

Parkinson's Disease Scale, in patients taking vitamin

E in dosages from 400 to 3200 IU per day versus those

not taking vitamin E. The overall and individual

performance, mentation, activities of daily living,

motor examination, and complications of daily living

improved only in the supplemented group.

 

#31/Rheumatoid Arthritis

The use of 1200 mg per day of vitamin E was studied in

rheumatoid arthritis patients in Austria. The evidence

suggests a strong relationship between the consumption

of vitamin E and a reduction in pain and stiffness.

 

#32/ Cataracts

A case control group of 175 cataract patients, 55

years of age or older, were matched with a like number

of cataract-free subjects. The incidence of cataracts

was shown to be half in those consuming more than 400

IU of vitamin E per day.

 

#33/Immune Response

The effect of daily vitamin E supplementation (800 IU

alpha tocopherol for 30 days) on immune responses of

32 healthy subjects (60+ years old) was examined in a

placebo-controlled, double-blind trial in a metabolic

research unit. The data suggest that vitamin E

supplementation improves immune responsiveness in

healthy elderly.

 

(Table 6 in the original paper contains Blood Vitamin

E Levels)

 

Reference #36/ Immune Response

In a metabolic unit, using a double blind protocol,

immune response was studied in a group receiving

vitamin E (8OOmg per day) versus placebo. The

increased immunocompetence was matched by blood

vitamin E levels which jumped from 1.1 to 3.1 mg%. No

such change in blood vitamin E occurred in the control

group (1.1 to 1.0 mg%).

 

#14/Alzheimer's Disease

A comparison of vitamin E blood levels in Alzheimer's

Disease (0.8 mg%), infarct-dementia (0.7 mg%) and in a

group of controls (1.3 mg%) indicates that the vitamin

F levels in the healthy subjects are approximately

double that in the sick people.

 

#37/ Cataracts

In the Baltimore Longitudinal Study on Aging; using a

case control design, the prediction of cataracts

correlated with serum vitamin E. Specifically, those

with the lowest blood levels (0.8 mg%) had an odds

ratio of almost double those in the upper terciles

(1.3 mg%).

 

#38/ Macular Degeneration

In the Baltimore Longitudinal Study, it was shown that

those with macular degeneration (MD) have alpha

tocopherol levels of 0.8 versus 1.3 mg% in the

quartile free of MD. Hence, macular degeneration

occurs twice as often in patients with low levels.

 

#39/Diabetes

Blood levels following supplementation of 2000 IU of

vitamin F daily for two weeks was studied. The average

serum tocopherol increased from 1.48 to 5.06 mg/g.

This is the first time levels over 5 mg/g in the blood

have been reported.

 

(Table 7 in the original paper contains Dietary Beta

Carotene Levels)

 

Reference #40/ Cardiovascular Disease

In the Nurses' Health Study in which a cohort of

121,000 US female nurses ages 30-55 were followed,

those who consumed more than 15-20 mg/day of beta

carotene had 40% lower risk of stroke and 22% lower

risk of heart attack, compared to women who reported

eating less than 6 mg/day.

 

#41/ Cancer

At the moment, this is the largest study of dietary

factors and lung cancer in nonsmokers. The evidence

suggests that dietary beta carotene and raw fruits and

vegetables reduce the risk of lung cancer in

nonsmoking men and women.

 

#42/ Immune Response

Immune system response to short-term, high-dose beta

carotene supplementation was examined. Supplements of

180 mg of beta carotene per day for two weeks

increased the number of T4 lymphocytes (helper cells)

and did not effect the T8 lymphocytes (suppressor

cells).

 

#43/ Precancer

In a study of 24 people with oral leukoplakia, given

30 mg/day of beta carotene for 3 to 6 months, there

was a 71% response rate. Of particular importance was

the fact that no clinically significant toxicity was

observed during this trial that could be attributable

to beta carotene.

 

#44/Mortality

A study was conducted regarding the association

between consumption of vegetables high in beta

carotene and cardiovascular mortality in a prospective

cohort of 1299 elderly Massachusetts residents. Those

consuming the greatest amount (in the upper quartile)

of beta carotene rich foods had one half the risk of

cardiovascular mortality as those in the lowest

quartile.

 

(Table 8 in the original paper contains Blood

Carotenoid Levels)

 

Reference #14/ Alzheimer's Disease

The blood carotene levels were 7 to 23 mcg% in

Alzheimer's Disease; 7 to 16 mcg% in multi-infarct

dementia patients versus 7 to 82 mcg% in controls.

 

#45/ Precancer

In oral and pharyngeal cancer, the blood carotene

levels were 39.5 in cases versus 61.5 mcg% in control

patients.

 

#46/Measles

Beta carotene levels were 35.0 mcg% in children with

measles and kerotomalacia versus 39.0 mcg% in kids

with measles without kerotomalacia as compared with

64.0 mcg % in health controls.

 

#47/ Macular Degeneration

The Eye Disease Case Control Study Group discovered

that the chances of having macular degeneration is

reduced about half in those demonstrating the larger

amounts of carotenoids in the blood (greater than 69

mcg%).

 

#48/ Cardiovascular Disease

A 12-year follow-up of cardiovascular mortality in the

Basel Prospective Study revealed a significantly

increased relative risk of ischemic heart disease and

stroke of a magnitude of two-fold at initially low

plasma levels of carotene (less than 12 mcg%)

independent of the classical cardiovascular risk

factors.

 

 

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