J. Amer. Aging Assoc., Vol.

23, 25-31, 2000

ANTIOXIDANT SUPPLEMENTS:
EFFECTS ON DISEASE AND AGING IN THE UNITED STATES POPULATION
Denham Harman
University of Nebraska College of Medicine
Department of Medicine
984635 Nebraska Medical Center
Omaha, Nebraska 68198-4635
Phone: (402) 559-4416
Fax: (402) 559-7330

ABSTRACT Aging is the accumulation of diverse deleterious

changes in the cells and tissues that increase the risk of
Ingestion of antioxidant supplements by the United
disease and death (1,2). Aging changes can be attrib-
States (US) population has increased steadily since
uted to developmental and genetic defects, the environ-
the mid-1950's. This review tried to determine if the
ment, disease processes, and an inherent process,
supplements have contributed significantly to ben-
referred to as "the aging process". The chance of death
eficial changes in the US during this period. Experi-
of an individual of a given age in a population - readily
mental animal studies have demonstrated that anti-
available from vital statistics d a t a - serves as a measure
oxidant supplements lower the incidence of a wide
of: 1) the average number of adverse changes, i.e.,
variety of diseases and increase life span. Anti-
aging changes, accumulated by persons of that age, and
oxidants are associated with similar changes in
2) physiologic age, i.e., "true age", in contrast to chrono-
man. Changes since the mid-1950's in the US popu-
logical age. The chances for death in a population
lation include: 1) ingestion of antioxidant supple-
determine the ALE-B.
ments has increased from one percent, or less, to
Conventional means (CM) of increasing the ALE-B of
40-50 percent today. Cost: now 4-5 billion dollars per
a population by decreasing the chances for death th rough
year, 2) disproportionate increases in the percent-
improvements in general living conditions, e.g., better
age of older individuals as average life expectancy
nutrition, housing, medical care, are becoming increas-
at birth (ALE-B) rose, 3) declining chronic disability
ingly futile (1,2). This is illustrated in Figure 1 by the
in the elderly since 1982, 4) declining cancer mortal-
curves of the logarithm of the chance of death versus
ity since 1991, and 5) the decline in the rate of
age for Swedish females for various periods from 1751
reported cardiovascular disease beginning in the
to 1992 (3,4); a straight line represents exponential
1950's which significantly increased further in 1965.
increases with age. The chances for death in the devel-
The last four changes suggest that the rate of in-
oped countries are now near limiting values while ALE-
crease in physiological age with time has been
B's approach plateau values of around 76 years for
slowed. This can be attributed to decreases in the
males and 82 years for females.
rate of accumulation of free radical-induced aging
Thus, as living conditions in a population approach the
changes by the joint action of antioxidant supple-
optimum, and premature deaths a minimum, the loga-
ments/dietary measures, and improvements in con-
rithmic curve of the chance of death versus age shifts
ventional measures (CM) which increase ALE-B,
towards a limit determined by the sum of: 1) the irreduc-
e.g., better medical care, nutrition, housing, acci-
ible contributions to the chance of death by aging changes
dent prevention. The contribution by antioxidants to
decreases in physiological age is seemingly small that can be prevented to varying degrees by CM, e.g.,
compared to that of CM. However, it will grow rela- those due to the environment and disease, and 2)
contributions that can be influenced little, if at all, by CM,
tive to CM as the amount and duration of supple-
ment use increases and improvements in CM raise i.e, those due to the inherent aging process. The now
near limiting chances for death rise almost exponentially
ALE-B closer to 85 years, the age associated with
optimal living conditions. after about age 28. Only 1-2 per cent of a cohort die
before this age.
INTRODUCTION The inherent aging process is the major risk factor for
disease and death in the developed countries after age
Past efforts to increase average life expectancy at birth 28 (1,2). It limits average life expectancy at birth to about
(ALE-B) have been restricted to improving general living 85 years and the maximum life span to around 122
conditions, e.g., nutrition, medical care, public health years. This inherent process is caused by chemical
facilities, and accident prevention (1,2). ALE-B's in the reactions that arise in the course of normal metabolism
developed countries now range from 76-79 years, 6-9 which, collectively, produce aging changes that expo-
years less than the limit of about 85 years imposed by nentially increase the chance of death with advancing
aging (1,2). Future efforts to increase ALE-B will be age even under optimal living conditions.
based increasingly on an understanding of aging.

25
 5OO
100
O
O creased the senescence periods (11,12) as there was
10
t~
(D
a ing changes with age by the inherent aging process
0.5
U 25 50 75 100
Years
Figure 1. Age-specific death rates of Swedish females in
various periods from 1751 to 1950 (adapted from HR Jones3)
and for 19924.
Many theories (1,2) have been advanced to account
for aging. No theory is generally accepted. The Free
Radical Theory of Aging (FRTA) (2,5,6) shows promise;
the subsequent discussion is based on the assumption
that it is correct. It, and the simultaneous discovery of the
important, ubiquitous involvement of free radicals in
endogenous metabolic reactions, was proposed in 1954
(5,6). The theory arose from a consideration of aging
phenomena from the premise that a single common
process, modifiable by genetic and environmental fac-
tors, was responsible for the aging and death of all living
things. The FRTA postulates that the common process
is the initiation of free radical reactions. These reactions,
however initiated, could be responsible for the progres-
sive deterioration of biological systems over time due to
their inherent ability to produce random change. The
theory was extended in 1972 (7,8) with the suggestions
that: 1) most free radical reactions were initiated by the
mitochondria at an increasing rate with age, and 2) the
life span is determined by the rate of free radical damage
to the mitochondria. Collectively, the free radical reac-
tions initiated by the mitochondria constitute the inherent
aging process.
The FRTA suggests the possibility that measures to
decrease the rates of initiation and/or chain lengths of
free radical reactions may decrease aging changes,
even under optimal living conditions, and in turn the rate
of aging and of disease pathogenesis. Many studies now
support this possibility (2,9,10). Most animal studies
have used dietary antioxidant supplements to decrease
chain lengths; these augment the natural defenses
26
against free radical reaction damage. For example,
addition of one percent by weight of 2-mercapto-
ethylamine hydrochloride to the diet of male LAF1 mice,
started shortly after weaning, increased ALE-B by 30
percent (11 ); the maximum life span was increased little,
if at all. When 0.5 percent of ethoxyquin was added to the
diet of male and female C3H mice, the increase in ALE-
B was 20 percent for both groups with no change in the
maximum life spans (12).
Thus, antioxidant supplements in mice increased the
percentage of older animals in the studies and de-
little, if any, effect on the maximum life spans. The latter
because the exponentially increasing production of ag-
progressively nullity the beneficial effects of the antioxi-
dants, keeping increases in maximum life span minimal.
The FRTA further suggests that improvements in CM
which increase ALE-B, decrease the chances for death
in a population (Fig. 1) by decreasing the rate of accumu-
lation of aging changes associated with suboptimal
living conditions. For example, a) better nutrition pro-
vides more compounds, e.g., vitamins C and E, and 13-
carotene, to decrease free radical damage, b) housing
improvements may decrease the amount of food me-
tabolized - and hence free radical production, needed to
maintain body temperature, c) in the case of diseases,
free radical reactions are widely involved (2,9,10) so that
measures to improve prevention and treatment would
be expected to have beneficial effects on life span, d)
tissue injury causes free radical formation, thus better
accident prevention measures should reduce the accu-
mulation of aging changes.
The growing awareness since the late 1950's of the
beneficial effects produced by dietary antioxidant supple-
ments on the life span and disease incidence of animals
prompted an increasing number of individuals to ingest
antioxidants. The collective effect of this 40 year plus
effort to slow aging in man may be reflected in measur-
able changes in the US population as a whole. The
purpose of this review was to determine if this has
occurred.
METHODS
Literature survey of:
A, Changes since the mid 1950's in: 1) use of antioxi-
dant supplements and consumption of fruits and
vegetables, 2) age structure of the United States
population, 3) incidence of chronic disability in the
elderly, 4) incidence of cancer, and 5) incidence of
cardiovascular disease.
B. Epidemiological studies on the effect of antioxidant
supplements, and of fruits and vegetables, on dis-
ease incidence and life span.
RESULTS
A. Changes in the U. S. population since the 1950's
include:
1) The percentage of the United States population
that take antioxidant/mineral supplements has Table 1. Changes in Age Composition of the U. S. Population,
1960-1990. Numbers in thousands.+
grown since the mid-1950's from probably less
than a fraction of one percent to forty to fifty per 1960 1990 Percentincrease
cent today (13-17). Most individuals who take Population 179,323 248,710 38.7
antioxidant supplements (13-17) do so on an
irregular basis; around 4 percent take vitamin E 65 plus 16,560 (9.2)* 31,079 (12.5)* 86.7
daily (usually 100 IU or more) and 8 percent take 85 plus 929 (0.5)* 3,021 (1.2)* 225.2
vitamin C (frequently 500mg). Multiple vitamin-
* Percentage of the total U.S. population.
mineral supplements are taken by around 20 + From Reference 29, page 2-3.
percent of the population. If the multivitamin in-
cludes vitamin E it is usually 30mg or less, while Percent of Population
vitamin C is generally 60mg (18). The latest A. 65 years and older 12.9%
antioxidant supplements now being used are Co- . Oo

enzyme Qlo (19,20), melatonin (21), lipoic acid 10.0% 9.2% ~

6.8%
(22), and the polyphenols (23).
Antioxidant supplements are readily available
and generally inexpensive, particularly vitamins C 0% 9
1900 1920 1940 1960 1980 2000
and E. Sales of antioxidant supplements are now ..85 ars a~ ,8~

t0
4-5 billion dollars a year (24,25). Thus, the aver-
1.o%J
age person spends about $40 per year on antioxi-
dants, more than enough to purchase a year's
supply of the three most common antioxidants 2% 0.2% = /
= ;
supplements - vitamins C and E, and ~3-carotene.
1~ 1~o l&O 1~ 14o
This assumes that 40 per cent of a U.S. population YEAR
of 250 million spend 4 billion dollars per year for Figure 2. Percentage of the United States population from
antioxidant supplements. 1900 to 20003~that are: A. Aged 65 and older, and B. Aged 85
Consumption of fruits and vegetables has ap- and older.
parently remained almost constant over time
Chronically D i s a b l e d ( m i l l i o n s )
(26,27). They are the major dietary sources of 13-
carotene and vitamins C and E (28). Although the ~ Projected
A 8" A 9 Actual
amount of these compounds in the diet is small,
they have a beneficial effect on disease and s=
longevity (28). Increasing these benefits by di-
etary means is limited by practical considerations.
For example, an individual would need to ingest
about six cups of peanuts to obtain the amount of 9

vitamin E present in one 4001U tablet. Hence o w i

1 982 1989 1994

antioxidant supplements are generally used to
augment the free radical defenses provided by
diet.
2) The ALE-B rose from 69.7 years in 1960 to 75.4
years in 1990 and 76.1 years in 1996 (29). As
shown in Table 1, the 5.7 year increase in ALE-B
between 1960 and 1990 was associated with a
38.7 percent increase in the total population and
disproportionate increases in the number of older
persons. The 65+ group (the elderly) grew by 86.7
percent and the 85+ group (the oldest-old) by
225.2 percent (30,31). The changes in these two
age groups since 1900 are shown in Figures 2A
and 2B (30). In 1990 (30) about 12.5 percent of the
total population were 65 years of age and over,
while the corresponding figure for the 85 plus
group was 1.2 percent. In 1960 the figures (30)
were 9.2 percent and 0.5 percent, respectively.
3) The number of chronically disabled individuals
aged 65 and over in the United States is not
increasing as fast as anticipated from 1982 and
~
Year
Population Aged 65 and Over ( m i l l i o n s )
_._.,.__-.------.
2O
o~
<[
1982 1989 1 94
Year
Figure 3. Chronic disability in the United States population
aged 65 and older (millions), 1982-1994.32 A. Actual and
projected numbers of chronically disabled. B. United States
population aged 65 and over.
1984 National Long Term Care surveys (Figure 3)
(32,33). In 1994 there were 33.7 million persons
over age 65; of these 7.1 were chronically dis-
abled - 1.2 million fewer than had been predicted
(32).
4) Cancer incidence and mortality has been de-
creasing since 1991 for the first time since national
record keeping was instituted in the 1930's (34-
36). Figure 4A (29) shows the cancer death rate

27
 Age-adjusted Death Rates per 100, 0 0 0 U . S . Standard Population
500.0
A. Heart Disease arid Cancer 1950 - 1996
300 0 HeartDisease
~ 9 i v i i ! =
0 1950 1955 1960 1965 1970 1975
Year
B. Cancer, 1979 -1997.
135 -
134-
m 133
n-
.==
132
O
i
O
131
130
125
1970 1980 1990
War
Figure 4. Age-adjuste(/death rates per 100,000 United States
s t a n d a r d population (1940). A. Heart d i s e a s e an(/ cancer,
1950-1996. 29 B. Cancer, 1979-1997. 29.ae
for 1950-1996 and the start of the decline in 1991 ;
the latter is shown in detail in Figure 4B.
5) Heart disease has continued to decline since the
1950's (29) (Figure 4A) after emphasis was placed
on controlling risk factors. The rate of decline
began to significantly increase further around
1965 (29).
B. Epidemiological studies include those which demon-
strate that: 1) antioxidant and/or mineral supple-
ments are associated with beneficial effects on car-
diovascular disease (18,37-39), cancer (40-42), and
life span (43-45), and 2) fruits and vegetables are
associated with decreases in both cancer (28,46,47)
and cardiovascular disease (48-50).
Examples of the above studies include:
1) Men and women who took at least lOOmg per day
of vitamin E for two years or more reduced their
risk of coronary disease by 40 percent (18,37).
2) Male smokers, age 50-69 years, receiving 50 mg
of vitamin E per day for 6 years had a 32 percent
decrease in the incidence of clinical prostate can-
cer while mortality from prostate cancer was de-
creased by 41 percent (40).
3) The Epidemiologic Fotlowup Study of the First
National Health and Nutrition Examination Survey
(NHANES I) was analyzed for the effect of vitamin
C consumption on mortality rates in men and
women (44). Comparing men and women con-
suming about 30mg or around 300mg of vitamin C
per day, the standardized mortality ratio (SMR)
values were 10 to 48 percent lower among the
high intake groups. These differences in SMR's
correspond to differences in longevity of about 5-
7 years for men and about 1-3 years for women at
age 35.
DISCUSSION
i i i i
1980 1985 1990 1996 Changes in the U. S. population since the mid 1950's
include: 1) the growing use of antioxidant supplements,
2) disproportionate increases in the percentage of older
individuals in the population, 3) declining chronic disabil-
ity in the elderly since 1982, 4) declining cancer mortality
beginning in 1991, and 5) a decline in the rate of reported
cardiovascular disease beginning in the 1950's which
increased further significantly in 1965.
Taken together the last above four changes suggest
that since the 1950's the rate of increase in physiological
age of individuals in the population with time has been
slowed. This can be attributed to decreases in the rate of
accumulation of free radical-induced aging changes by
the joint action of: 1) continuing improvements in the
effectiveness of CM, and 2) increasing use of antioxidant
! supplements and, possibly, of fruits and vegetables.
2000
Enhancements in CM during the past 40 years include
improvements in: 1) antibiotics, 2) surgical procedures,
and 3) the prevention and treatment of diseases, e.g.,
cancer and cardiovascular diseases. In addition, the
advent of Medicaid and Medicare in 1965, facilitated
preventive medicine resulting in early diagnosis and
treatment.
Superimposed on the CM improvements were at-
tempts by a growing number of individuals to further
reduce their chances for death by taking antioxidants to
reduce the chain lengths of free radical reactions. This
effort is decreased with age and becomes essentially
futile at around age 85, as with CM, owing to the
increasing rate of initiation of free radical reactions with
age by the mitochondria (2).
The above individuals now comprise 40-50 per cent of
the U. S. population. On the average they are physiologi-
cally younger than their counterparts in the population,
i.e., they have accumulated fewer free radical-induced
aging changes, hence they are likely to have less
disease, live longer, and have shorter senescence peri-
ods.
Together, the above efforts since the 1950's have
seemingly reduced the rate of increase in physiological
age of the US population as a whole - it is younger. This
provides the most parsimonious explanation of the four
population trends described above. Thus, reductions in
physiological age cause: 1) concomitant increases in
average life expectancy. This results in progressive
disproportionate increases in the percentages of older
persons in the population (Figure 2), because the rapidly
increasing chance of death in the older groups (Figure 1)
ensures that few will exceed 100 years. 2) reductions in
the probability of developing age-associated disorders:
a) chronic disability in the elderly began to fall for the first
time in 1982 (Figure 3), b) that for cancer in 1991 (Figure
4A, B), and c) the continuing modest decline in heart
28
Antioxidant supplements: Effects in U.S.
disease since the 1950's was significantly increased
around 1965 (Figure 4A).
Assessment of the relative contributions of CM and of
supplement/dietary measures to the above trends in the
US is confounded by many factors (32,33,51), e.g., the
advent of Medicaid and Medicare. Both measures low-
ered free radical reaction damage thereby decreasing
physiological age and increasing the ALE-B. The rela-
tive contributions of the two measures can be inferred
from their effects on ALE-B.
ALE-B is a reflection of the ability of CM and antioxi-
dants to counteract the accumulation of free radical
damage with age due to the sum of those: 1) associated
with suboptimal living conditions, and 2) formed at an
exponentially increasing rate by the innate aging pro-
cess. Improvements in CM in the United States and
other developed countries have raised ALE-B's to within
6-9 years of the potential maximum value of about 85
years (1,2), and concomitantly lowered formation of
aging changes associated with suboptimal living condi-
tions.
On the average in these countries, initiation of free
radical reactions by mitochondria in individuals is high
and progressively increasing. Antioxidant supplements
under these conditions may make only a modest contri-
bution to increases in the ALE-B, and essentially none to
the MLE, because the decreases in formation of aging
changes produced by them would be expected to be a
small, and progressively so as ALE-B increases, fraction
of those formed by the innate aging process.
In contrast, as populations come to live under near-
optimal living conditions throughout life, as with the mice
discussed above, the rate of accumulation of aging
changes will be small during the early part of life, and
depressed further by antioxidant supplements. The an-
tioxidants will delay, depending on the amounts in-
gested, the eventual normal exponential rise in the rate
of accumulation of aging changes and thus raise the
ALE-B's, but without significant increases in maximum
life span.
ALE-B rose rapidly from 47.3 years in 1900 to 69.7 in
1956. Increases since have been slower, particularly
between 1956 and 1972 when ALE-B reached 71.2
years (1,2,52) (Figure 5). The slower increases in ALE-
B since 1956 reflect to some degree the growing use of
antioxidant supplements. The antioxidant contribution is
undoubtedly small compared to that of CM as the
increases in ALE-B are about those to be expected from
the improvements in CM.
Failure to find a definite impact of antioxidant supple-
ment use on the ALE-B of the US population is because
the decreases in free radical damage produced by the
supplements is significantly less than the formation of
free radical-induced aging changes by the innate aging
process and those associated with the US suboptimal
living conditions. The US ALE-B is about nine years less
than the potential value of around 85 years associated
with optimal living conditions (1,2).
29
Average Life Expectancy at Birth
United States 1900-1996
lOO
96
92
~ 69
'~ 7 6
68
64
.,,52
48
44
40
1960 1908 1916 1924 1932 1940 1948 1956 1964 1972 1980 1988 1996
Figure 5. Average life expectancy at birth for the United States
population, 1900-1996.
The contributions of antioxidant supplements to in-
creases in ALE-B, and to the four US population changes
discussed above, may become apparent with time as: 1)
the number of supplement takers and the quantity and
duration of supplement use increases, and 2) living
conditions throughout life approach closer to optimal
because of continued improvements in CM.
The "chain length" aspect of the FRTA has been
reduced to practice. Efforts (53) have been started to
implement the "free radical initiation" aspect of the
FRTA, primarily by decreasing the rate of mitochondrial
superoxide formation, in order to increase the maximum
life span while living a normal life.
REFERENCES
1. Harman, D. Aging: phenomena and theories. Ann
NY Acad Sci. 1998;850:1-7.
2. Harman, D. Aging: prospects for further increases
in the functional life span. Age 1994;17:119-46.
3. Jones HR. The relation of human health to age,
place and time. In: Birren JE, ed. Handbook of
Aging and the Individual. Chicago: Chicago Univer-
sity Press, 1995: 333-63.
4. Sveriges Officiella Statistik. Befolknings
forandringar. Livslangstabeller, 1951-1993.
Statistiska centralbyran, Stockholm, Sweden, 1993:
114-15.
5. Harman D. Aging; a theory based on free radical
and radiation chemistry. J Geronto11956;11:298-
00.
6. Harman D. Free radical theory of aging: history. In:
Emerit I, Chance B, eds. Free Radicals and Aging.
Basel: Birkhauser, 1992:1-10.
7. Harman D. The biological clock: the mitochondria?
J Am Geriatr Soc 1972;20:145-47.
8. Harman D. Free radical theory of aging: conse-
quences of mitochondrial aging. Age 1983;6:86-94.
9. Harman D. Free radical theory of aging: the "free
radical" diseases. Age 1984;7:111-31.
10. Halliwell B, Gutteridge JMC. Free Radicals in Biol-
ogy and Medicine. 2nd ed. Oxford: Clarendon
Press;1989.
11. Harman D. Free radical theory of aging: effect of
free radical inhibitors on the mortality rate of male
LAF 1 mice. J Gerontol 1968;23:476-82.
12. Comfort A. Effect of ethoxyquin on the longevity of
C3H mice. Nature 1971;229:254-55.
13. Koplan, JP, Annest JL, Layde PM, Rubin LL. Nutri-
ent intake and supplementation in the United States
(NHANES II). Am J Public Health 1986;76:287-89.
14. Stewart M J, McDonald JT, Schucker RE, Henderson
DP. Vitamin/mineral supplement use: a telephone
survey of adults in the United States. J Am Dietetic
Assoc 1985;85:1585-90.
15. Subar AF, Block G. Use of vitamin and mineral
supplements: demographics and amounts of nutri-
ents consumed. Am J Epidemol 1990;132:1091-
01.
16. Slesinski M J, Subar AF, Kahle LL. Trends in use of
vitamin and mineral supplements in the United
States: the 1987 and 1992 National Health Inter-
view Surveys. J Am Dietetic Assoc 1995;95:921-
23.
17. Meyers DG, Maloley PA, Weeks D. Safety of anti-
oxidant vitamins. Arch Intern Med 1996;156:925-
35.
18. Stampfer M J, Hennekens CH, Mason JE, Colitz
GA, Rosner B, Willett WC. Vitamin E consumption
and the risk of coronary disease in women. N Engl
J Med 1993;328:1444-49.
19. Greenberg S. Co-enzyme Q10: a new drug for car-
diovascular disease. J Clin Pharmaco11990;30:596-
08.
20. Ernster L, Dallner G. Biochemical, physiological
and medical aspectsof ubiquinonefunction. Biochim
Biophys Acta 1995; 1271:195-04.
21. Reiter RJ. The Pineal Gland and Melatonin: Regu-
lation and Role in Oxidative Defense, Cancer and
Aging. Boca Raton, FI, CRC Press, 1994
22. Packer L, Witt EH, Tritshler EH. Alpha-lipoic acid as
a biological antioxidant. Free Rad Biol Med
1995;19;227-50.
23. Rice-Evans CA, Miller NJ, Paganga G. Structure-
antioxidant activity relationships of flavonoids and
phenolic acids. Free Rad Biol Med 1996;20:933-56.
24. 1992 Overview of the Nutritional Supplement Mar-
ket. Washington, DC: Council for Responsible Nu-
trition;1993.
25. Nutrition Business Journal. San Diego, CA: Nutri-
tion Business International: 1997;3,No.9:4-5.
30
26. Norris J, Harnack L, Carmichael S, Pouane T,
Wakimoto P, Block G. US trends in nutrient intake:
the 1987 and 1992 National Health Interview Sur-
veys. Am J Public Health 1997;87:740-46.
27. Patterson BH, Block G, Rosenberger WF, Pee D,
Kahle LL. Fruit and vegetables in the American diet:
data from the NHANES II survey. Am J Public
Health 1990;80:1443-49.
28. Block B, Patterson B, Subar A. Fruit, vegetables,
and cancer prevention: a review of the epidemio-
logical evidence. Nutr Cancer 1992; 18:1-29.
29. Peters KD, Kochanek KD, Murphy SL. Deaths:
Final Data for 1996. National vital statistics reports;
vol 45 no 9. Hyattsville, Maryland: National Center
for Health Statistics. 1998.
30. Hobbs FB, Damon BL. U.S. Bureau of the Census.
Current population reports, Special Studies, P23-
190, Sixty-five plus in the United States. U.S. Gov-
ernment Printing Office, Washington DC, 1996.
31. Campion EW. The oldest old. N Engl J Med
1994;330:1819-20.
32. Manton KG, Corder L, and Stallard E. Chronic
disability trends in elderly United States popula-
tions: 1982-1984. Proc Natl Acad Sci USA
1997;94:2593-98.
33. Freedman VA, Martin LG Understanding trends in
functiona~ limitations among older Americans. Am
J Public Health 1998;88:1457-62.
34. Cole P, Rodu B. Declining cancer mortality in the
United States. Cancer 1996;78:2045-48.
35. Kramer BS, Klausner RD. Grappling with cancer -
defeatism versus the reality of progress. N Engl J
Med 1997;337:931-34.
36. Anderson RN, Rosenberg HM. Age standardization
of death rates: implementation of the Year 2000
Standard. National vital statistics reports: vo147 no
3. Hyattsville, Maryland: National Center for Health
Statistics. 1998.
37. Rimm EB, Stampfer M J, Ascherio A, Giovannucci
E, Colditz GA, Willett WC. Vitamin E consumption
and the risk of coronary heart disease in men. N
Engl J Med 1993;328:1450-56.
38. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and
vitamin C supplement use and risk of all-cause and
coronary heart disease mortality in older persons:
the Established Populations for EpidemiologJcStud-
ies of the Elderly. Am J Clin Nutr 1996;64:190-6.
39. Hathcock JN. Vitamins and minerals: efficacy and
safety. Am J Clin Nutr 1997;66:427-37.
40. Heinonen OP, Albanes D, Virtamo J, et al. Prostate
cancer and supplementation with o~-tocopherol and
13-carotene: incidence and mortality in a controlled
trial. J Natl Cancer Inst 1998;90:440-46.
Antioxidant supplements: Effects in U.S.

41. Yoshizawa K, Willett, WC, Morris J, Stampfer MJ,

Rim EB, Giovannucci E. Study of prediagnostic
selenium level in toenails and the risk of advanced
prostate cancer. J Natl Cancer Inst 1998;90:1219-
24.
42. Clark CC, Combs GF, Turnbull BW. Effects of
selenium supplementation for cancer prevention in
patients with carcinoma of the skin. JAMA
1996;276:1957-63.
43. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake
and mortality among a sample of the United States
population. Epidemiol 1992;3:194-02.
44. Enstrom JE. Counterviewpoint: Vitamin C and mor-
tality. Nutrition Today 1993;28(May-June):39-42.
45. Block G. Vitamin C and reduced mortality. Epidemiol
1992;3:189-91.
46. Byers T, Perry G. Dietary carotenes, vitamin C, and
vitamin E as protective antioxidants in human can-
cers. Annu Rev Nutr 1992;12:139-59.
47. Chen J, Geissler C, Parpia B, Li J, Campell TC.
Antioxidant status and cancer mortality in China.
Intern J Epidemiol 1992;21:625-35.
48. Riemersma RA, Wood DA, Macintyre CCA, Elton
RA, Gey KF, Oliver MF: Risk of angina pectoris and
plasma concentrations of vitamins A, C, and E and
carotene. Lancet 1991 ;337:1-5.
49. Hertog MGL, Feskens EJM, Hollman PCH, Katan
MB, Kromhout D: Dietary antioxidant flavonoids
and risk of coronary heart disease: the Zutphen
Elderly Study. Lancet 1993;342:1007-11.
50. Gey KF: Vitamin E and other essential antioxidants
regarding coronary heart disease: risk assessment
studies. Epidemiological basis of the antioxidant
hypothesis of cardiovascular disease. In: Packer L,
Fuchs J, eds. Vitamin E in Health and Disease. New
York, NY: Marcel Dekker, Inc.; 1996:589-33.
51. Manton KG, Corder LS, Stallard E. Estimates of
change in chronic disability and institutional inci-
dence and prevalence rates in the U. S. elderly
population from the 1982, 1984, and 1989 National
Long Term Care Survey. J Gerontol 1993;48:$153-
$66.
52. National Center for Health Statistics. Vital statistics
of the United States, 1991, vol. II, mortalilty, part A.
Washington: Public Health Service. 1996.
53. Harman D. Aging: Minimizing free radical damage.
J Anti-Aging Med 1999;2:15-36.

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