(Circulation. 1997;96:37-43.)
© 1997 American Heart Association, Inc.
Articles |
From the Department of Family and Preventive Medicine, University of California, San Diego, School of Medicine (La Jolla).
| Abstract |
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Methods and Results A community-based sample of 1041 men
and 1303 women aged 50 to 93 years was studied cross-sectionally in
1984 to 1987, with follow-up of 372 men and 545 women 8 years later. In
the cross-sectional study, levels of total cholesterol (TC)
and LDL cholesterol (LDL-C) decreased and levels of HDL
cholesterol (HDLC) increased with age in men (all
P<.001) but not in women. In the prospective study, TC,
LDL-C, and HDL-C levels all decreased in both men and women, in all age
groups (50 to 64 years, 65 to 74 years, and
75 years) and in all
weight change groups (>2.5-kg loss, change within 2.5 kg, and >2.5-kg
gain) and in all waist girth change groups, for an overall decrement of
1% per year. In multiple linear regression models, change in weight
was the most important independent and consistent predictor of
changes in TC, LDL-C, and HDL-C. Similar results were obtained in
analyses excluding subjects taking lipid-lowering drugs or
estrogen and in analyses adjusted for changes in cigarette
smoking, alcohol intake, physical activity, medication use, and
incident myocardial infarction, cancer, or diabetes.
Conclusions Cross-sectional decrements in TC and LDL-C with age in men are not explained by survivor bias because they are also observed prospectively. Although weight change was the most important explanatory variable, TC, LDL-C, and HDL-C levels also decreased in those who lost or gained weight. Age was not an independent predictor of change. Other prospective studies are recommended to better define the causes and consequences of cholesterol and lipoprotein changes in old age.
Key Words: aging population studies lipids weight change
| Introduction |
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65 years of age have reported that total and
LDL cholesterol levels decrease with age. Although HDL
cholesterol levels do not vary with age in most
cross-sectional studies,1 3 14 15 16 17 18 22 levels decreased with
age in both men and women in the majority of the prospective studies
(of largely middle-aged subjects).5 6 8 9 10 12 22 Few studies have examined lipid and lipoprotein levels prospectively in elderly subjects,12 21 22 23 and none have examined both behavior and medical causes for the observed changes. The purpose of this report was to examine the association of total cholesterol and lipoproteins with age, both cross-sectionally and longitudinally over 8 years of follow-up, and to determine the relative contribution of age, weight change, behavior change, medication use, disease, and mortality to these changes in older community-dwelling adults.
| Methods |
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8 years after the baseline visit,
between May 1992 and December 1994, all surviving participants were
invited to a follow-up clinic visit; 372 men (35.6%) and 545 women
(41.8%) were reexamined, 343 men (32.8%) and 553 women (42.0%) are
awaiting reexamination, and 330 men (31.6%) and 213 women (16.2%)
have died. At both clinic visits, venous samples were drawn in the morning from seated subjects after a requested 12-hour fast. Lipids and lipoproteins at baseline and follow-up visits were measured in the same Centers for Disease Control and Preventioncertified La Jolla Lipid Research Clinic Laboratory. Total plasma cholesterol was measured by enzymatic techniques using an ABA-200 biochromatic analyzer (Abbott Laboratories). HDL cholesterol was measured by precipitating the other lipoproteins with heparin and manganese chloride according to the standardized procedures of the Lipid Research Clinics protocol.25 LDL cholesterol was estimated according to the Friedewald formula.26
Height and weight were measured with subjects wearing light clothing and without shoes; body mass index (BMI) was calculated as weight (kg)/height (m2) and used as a measure of overall obesity. Waist circumference was measured at the bending point, and hip circumference was measured at the iliac crest; the waist-to-hip ratio (WHR) was calculated and used as a measure of central obesity. (These ratios were highly correlated [r=.97] with ratios based on measurements of smallest waist and largest hip circumferences.)
At both clinic visits, demographic data, personal history of current cigarette smoking (yes/no), alcohol consumption (two or more drinks per week), physical activity (three or more times per week), and medication use were determined with a standardized questionnaire. Medications were validated by examination of prescriptions or pills brought to the clinic for that purpose. Participants were asked about physician-diagnosed myocardial infarction, diabetes mellitus, and cancer with onset during the follow-up interval.
After excluding 17 subjects who had fasted for <12 hours, there were 1041 men and 1303 women who were seen at the 1984-to-1987 baseline visit and who form the basis of the cross-sectional analysis. From this cohort, 372 men and 545 women who were examined again between 1992 and 1994 (mean follow-up, 8 years) form the basis of the longitudinal analysis.
Statistical Analysis
Change variables were defined as follow-up values minus
baseline values. Sex-specific mean differences between follow-up and
baseline visits were tested by paired t test before and
after stratifying for age or by ANCOVA when mean differences were
adjusted for age in analyses stratified for weight change
(>2.5-kg loss, change within 2.5 kg, and >2.5-kg gain) or waist girth
change groups. Waist girth change groups were defined by 1 SD of the
sex-specific mean change in waist girth. A change of >±1 SD from the
mean change was considered to be increased or decreased. The percent
lipid and lipoprotein changes per year were calculated. Regression to
the mean for repeated measurements was calculated according to the
method of Mee and Chua.27
Multiple linear regression of lipid change and lipoprotein change on age and BMI at baseline and changes in age, weight, behaviors (smoking, alcohol consumption, physical activity), medication use (lipid-lowering drugs, thiazides, thyroid hormones, estrogens), and morbidity (myocardial infarction, diabetes mellitus, cancer) were computed separately for men and women. Analyses were repeated after separately excluding all subjects who died within 1 year of the follow-up visit, all those taking lipid-lowering drugs, and all women using estrogen replacement therapy.
The Statistical Analysis System28 was used for all analyses. All probabilities are for two-tailed tests, with statistical significance defined as P<.05.
| Results |
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Table 1
shows sex- and age-specific cross-sectional mean
levels of total cholesterol and lipoproteins. Among men,
total and LDL cholesterol decreased significantly with
increasing age, and HDL cholesterol increased significantly
with age. Among women, total cholesterol and lipoprotein
levels were not associated with age before (Table 1
) or after
stratification for estrogen replacement therapy (data not shown).
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Longitudinal Analysis
The 372 men and 545 women aged 58 to 96 years who were seen at the
follow-up visit had a mean age of 75±8 and 76±9 years, respectively.
Participation rates for survivors who were 50 to 69 years at baseline
were 60% for men and 58% for women; for those 70 years and older at
baseline, rates were 44% in men and 42% in women. Participants were
on average 10 years younger than those who died during the 8 years of
follow-up. Men who came to the follow-up visit did not differ from
those who had appointments pending (n=343) or who had died (n=330) with
regard to baseline total, LDL, or HDL cholesterol levels.
Women who came to the follow-up visit did not differ significantly from
those who were pending or dead with regard to LDL
cholesterol levels, but they did have significantly higher
total and HDL cholesterol levels than women whose
appointments were pending (n=553) or who had died (n=213). Similar
results were obtained after adjustment for estrogen replacement therapy
(data not shown).
Table 2
shows the sex-specific mean total and
lipoprotein cholesterol levels, mean changes, and percent
change per year. In both men and women, total, LDL, and HDL
cholesterol levels decreased
1% per year (all
P<.001). Fig 1
shows that the decrease in
total, LDL, and HDL cholesterol levels was similar and
statistically significant in men and women in all age groups.
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Fig 2
shows that weight loss began around age 65 to 74
in both men and women and was characteristic of men and women aged
75. Significant weight gain was observed only in women aged 50 to 65.
Increasing weight loss with increasing age was significant in both men
and women (all P linear regression <.001). Weight loss only
partially explained the cholesterol changes with age,
however. As shown in Fig 3
, mean total, LDL, and HDL
cholesterol levels decreased in men and women who lost,
gained or did not change weight; all decrements were statistically
significant except decreases in total and LDL cholesterol
in women who gained weight.
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Similar results were obtained in analyses in which change in waist girth was used instead of weight change. During the 8-year follow-up, waist girth significantly increased in both men and women (mean change, 1.8 cm in men and 2.5 cm in women; all P<.001); the degree of increase in waist girth decreased with increasing age (P linear regression, .02 in men and <.001 in women). Waist girth change was also concordant with weight change, increasing in those who maintained or gained weight and decreasing in those who lost weight (standardized ß=.772 and .684 in men and women, respectively). In age-adjusted analyses in which men and women were stratified by sex-specific changes in waist girth, total, LDL, and HDL cholesterol decreased in all waist girth change groups (data not shown). In age-adjusted linear regression models, change in waist girth was a significant independent predictor of change in total and LDL cholesterol in men (ß=.110 and .115, respectively; P<.001) and women (ß=.162 and .152, respectively; P<.001). In men, change in waist girth was not associated with change in HDL cholesterol (ß=-.066; P=.2) but was weakly associated in women (ß=-.087; P=.05).
None of the above results were changed in analyses that excluded the 36 men and 56 women who were using lipid-lowering drugs or the 253 women who were using estrogen at either visit (data not shown).
Among participants in the 8-year follow-up evaluation, 29% of
men and 33% of women reported a myocardial infarction, 19% of men and
13% of women reported cancer, and 5% of men and 3% of women reported
newly diagnosed diabetes. Except for a decrease in physical activity,
there were relatively few changes in behaviors or medications that
could affect lipid levels during the 8-year interval, as shown in Table 3
.
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Table 4
shows the results of multiple linear regression
used to determine the independent contribution of age, change in
weight, behaviors, medication (lipid-lowering drug, thiazide, thyroid
hormone, or estrogen), and diseases to changes in total
cholesterol and lipoproteins over 8 years. In both sexes,
change in body weight was the most consistent and significant
predictor of change in total cholesterol and lipoproteins.
This effect was independent of age and BMI at baseline and of changes
in behaviors, medication use, and morbidity. During the 8-year
follow-up, total and LDL cholesterol levels decreased more
and HDL cholesterol levels decreased less in persons with
weight loss. Change in waist girth was less important than change in
weight, based on a comparison of standardized ß coefficients. (We did
not use weight change and waist girth change in the same model because
they were highly correlated; r=.66 for men and
r=.59 for women.)
|
Cessation of cigarette smoking or alcohol ingestion were each
significantly and independently associated with changes in HDL
cholesterol levels (Table 4
). HDL cholesterol
levels decreased less in the 15 men and 36 women who quit smoking; HDL
cholesterol levels also decreased in the 25 men and 54
women who quit drinking alcohol (P=.05 for men and
P=.06 for women). Table 4
shows that medication changes also
were significant and independent predictors of changes in total
cholesterol and lipoproteins. Total and LDL
cholesterol levels decreased more and HDL
cholesterol levels decreased less in 34 men and 51 women
who started receiving lipid-lowering drugs. Total and LDL
cholesterol levels also decreased more in the 15 men and 47
women who started receiving thyroid hormones. Women who started
estrogen replacement therapy (n=57) showed a significant decrease in
total and LDL cholesterol levels, and their HDL
cholesterol levels decreased less with age (Table 4
).
Incident diseases such as myocardial infarction, diabetes, and cancer
were not associated with changes in total cholesterol and
lipoproteins. None of the results of multiple linear regression were
changed in analyses that excluded those who were using
lipid-lowering drugs or estrogen at either visit (data not shown).
Similar decreases in total cholesterol and lipoprotein
levels were observed after exclusion of the 42 follow-up visit
participants who died within the first year of follow-up (possible
evidence of occult disease at reexamination) (data not shown).
In additional calculations according to the method of Mee and Chua,27 regression to the mean accounted for <8% of any of the observed changes in total, LDL, or HDL cholesterol (data not shown).
| Discussion |
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These cross-sectional results are concordant with other cross-sectional
studies reporting that total and LDL cholesterol levels in
adults increased progressively to age
65 in men and
75 in women,
after which concentrations appeared to fall.1 2 3 4 13 14 15 16 17 18 19 20 Most
cross-sectional studies have not found HDL cholesterol
levels to vary with age,1 3 14 15 16 17 21 but a recent
cross-sectional report from the Cardiovascular Health
Study18 found that HDL cholesterol levels
appeared to increase with age in men but not in women, which is similar
to the results reported here.
Longitudinal studies are necessary to show true age-related changes. In this cohort, neither selective mortality nor selective participation accounted for the prospectively observed changes in cholesterol and lipoprotein levels in men. Among women, participation bias was suggested only for changes in HDL cholesterol levels, because women who died or had appointments pending had significantly lower HDL cholesterol levels than did women who were examined at follow-up.
A cohort effect is unlikely to explain the observed changes in total, LDL, and HDL cholesterol levels because changes were similar in all age groups. Laboratory drift in the total cholesterol measurements is an unlikely explanation because the total cholesterol levels reported here (measured in the Lipid Research Clinic laboratory) were also measured as part of a routine diagnostic chemistry panel by an independent clinical laboratory with highly concordant results (r=.957 and r=.983 for baseline and follow-up total cholesterol measurements), and the direction of change and statistical significance were unchanged. Finally, regression to the mean account for <8% of changes in total, LDL, and HDL cholesterol in both men and women.
The decrease in total, LDL, and HDL cholesterol levels with age in the Rancho Bernardo cohort is similar to results in two12 22 but partially discordant with two other21 23 prospective studies of the elderly. In a recent study of elderly Dutch men,23 total cholesterol decreased by 0.04 mmol/L per year with age, which is similar to the decrement in cholesterol observed among Rancho Bernardo men and women, but HDL cholesterol did not change with age. Women were not studied in the Dutch cohort.
In the present study, weight loss was the most important factor associated with lipid change, which is consistent with results from clinical trials,29 30 31 32 but it did not completely explain the observed decrements. Total and LDL cholesterol levels also decreased with age in men and women who gained weight, whereas HDL cholesterol also decreased in men and women who lost weight. These results are concordant with results from a prospective study of older women and men from the Framingham study.12 Decline in HDL cholesterol levels in men and women who lose or maintain weight may be accounted for by a concomitant decline in lean body mass, increase in body fat, or change in fat distribution with age.33 34
Rancho Bernardo men and women who lost weight showed a decrease in waist girth, and change in waist girth was only marginally associated with change in HDL cholesterol and only in women. Change in waist girth, although predictive of change in total and LDL cholesterol, was less important than change in weight. These results are concordant with results from clinical trials in which the degree of weight loss was more important in predicting change in cholesterol and lipoproteins than was weight lossinduced changes in WHR or waist girth.31 32
Few studies have examined behavior change among the elderly.35 36 To our knowledge, this is the first study to determine whether changes in behaviors, medications, or morbidity predict changes in lipids and lipoproteins in community-dwelling elders. The majority of this relatively healthy cohort did not change behaviors or medications known to affect the lipid profile. One exception was cigarette smoking, which, although uncommon, was stopped by approximately half of those who were smokers at baseline (15 of 34 men and 36 of 70 women). Despite the small numbers (and the association between quitting smoking and weight gain), there was a significant independent and favorable effect of smoking cessation on HDL cholesterol levels, similar to that previously reported in younger subjects.8 9 10 37 38 Consistent with previous studies conducted in middle-aged or young adults7 8 9 37 starting alcohol use during the 8-year interval was associated with a marginally significant increase in HDL cholesterol levels. Changes in physical activity were not related to changes in HDL cholesterol levels. These results are concordant with an absent effect of exercise on lipoproteins reported in middle-aged and elderly men32 but inconsistent with the beneficial effects of exercise on lipoprotein levels reported in younger adults.9 39 40 Differences may reflect the difficulty in assessing physical activity by self-report or the infrequency of strenuous activity in the elderly.
Change in dietary habits, an important determinant of lipid and
lipoprotein levels,41 could not be directly examined
because not all subjects had the same diet assessment at both visits.
However, younger individuals (aged 50 to 69 years) from this population
were much more likely to report having decreased their dietary fat
intake than were persons
70 years old,36 whereas
cholesterol and lipoprotein changes were greatest in oldest
subjects, making it less likely that the observed decreases in total
and LDL cholesterol levels reflect reduction in fat
intake.
Lower cholesterol levels are frequently observed in association with clinical and subclinical diseases.42 43 44 In the present study, decreases in total and lipoprotein cholesterol levels were independent of chronic diseases and use of medications known to affect lipid levels in both multivariate and stratified analyses. Subclinical illness was unlikely to account for the decline in cholesterol levels in Rancho Bernardo because similar changes were observed after excluding participants who died within 1 year of the follow-up visit.
The observed decline in cholesterol levels might reflect inflammatory responses to infections, which increase with age,42 or age-related reduced cholesterol absorption from the intestine.45 Other prospective studies are needed to investigate these and other possible explanatory factors. Regardless of the mechanism, the late life decrease in total cholesterol could explain why high plasma cholesterol levels are less predictive of heart disease in the elderly than in younger persons.46 47 48 49 50 The reduced association between cholesterol levels and ischemic heart disease in old age may also be a consequence of an illness associated with a decline in cholesterol levels, in which ischemic heart disease is the cause of death.48 51 52 On the other hand, the observation that HDL cholesterol levels worsen with age may explain why low HDL cholesterol levels represent an independent risk factor for coronary heart disease in elderly men and women.48 49
Because cholesterol levels decrease in old age and do not reflect lifetime levels, it does not necessarily follow that lowering cholesterol levels is without value in the elderly. Recent primary and secondary prevention trials53 54 have shown that medications that lower LDL and raise HDL levels can significantly reduce the risk of cardiovascular disease and total mortality in older men and women. The results of the present study also indicate that in addition to starting lipid-lowering drugs, weight reduction, quitting smoking, and starting estrogen replacement therapy predicted a favorable change in total, LDL, and HDL cholesterol levels in elderly men and women.
| Acknowledgments |
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| Footnotes |
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Dr Ferrara is currently at the Division of Research, Kaiser Permanente, Oakland, Calif.
Received October 9, 1996; revision received January 16, 1997; accepted January 23, 1997.
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