Overweight, Obesity, and Mortality in a Large Prospective Cohort of Persons 50 to 71 Years Old
http://www.100md.com
《新英格兰医药杂志》
ABSTRACT
Background Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned.
Methods We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health–AARP cohort who were 50 to 71 years old at enrollment in 1995–1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status.
Results During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated.
Conclusions Excess body weight during midlife, including overweight, is associated with an increased risk of death.
Substantial epidemiologic evidence indicates that obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death.1 However, whether overweight (defined by a BMI of 25.0 to 29.9) increases the risk of death has not been established.2 A substantial proportion of the U.S. adult population is overweight but not obese3; any association between overweight and mortality might have important clinical and public health implications.
Reverse causation owing to preexisting chronic disease and inadequate control for smoking status can distort the true relation between body weight and the risk of death, because chronic illness and smoking are associated with both decreased BMI and an increased risk of death.4 Possible approaches to addressing these potential biases include disregarding deaths occurring in the initial period of follow-up and restricting the analysis to persons without preexisting disease or those who have never smoked. Another approach is to evaluate BMI earlier in life,5 when it reflects typical adult weight largely unaffected by the onset of chronic disease. We examined the association between BMI and the risk of death in the National Institutes of Health (NIH)–AARP Diet and Health Study,6 which is based on a cohort of more than half a million people who were 50 to 71 years old at baseline. At baseline this cohort was large enough to permit the use of restriction to minimize potential bias caused by preexisting disease and smoking. In addition, because information was available on subjects' weight at the age of 50 years, we were able to analyze the relation between BMI in midlife and the subsequent risk of death.
Methods
Study Population
The NIH–AARP Diet and Health Study was established in 1995–1996 when 567,169 questionnaires eliciting information on demographic and anthropometric characteristics, dietary intake, and numerous health-related behavioral patterns were returned by 18 percent of AARP members who were 50 to 71 years old and resided in six U.S. states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and two metropolitan areas (Atlanta and Detroit).6 We excluded records from 179 persons with duplicate representation in our database; 321 persons who moved out of the study area; 261 persons who died before their questionnaires were received; 15,760 persons whose questionnaires were completed by a spouse or other surrogate respondent; 16,649, 4648, and 2085 persons with missing or extreme values for current height or weight, energy intake, or alcohol consumption, respectively; and 1 person who withdrew from the study. We analyzed the data from the remaining 527,265 participants (313,047 men and 214,218 women).
Follow-up
The vital status of cohort members was determined from 1995–1996 through December 31, 2005. Vital status was ascertained by annual linkage of the cohort to the Social Security Administration Death Master File on deaths in the United States,7 with the most recent update on January 15, 2006. The design and maintenance of this cohort have been described elsewhere.6,8 The NIH–AARP Diet and Health Study was approved by the Special Studies Institutional Review Board of the National Cancer Institute. All participants provided written informed consent. All authors vouch for the accuracy of the data and concur with the interpretation of the results.
Assessment of Height, Weight, and Other Potential Risk Factors
Information on current height and weight, disease history, smoking habits, race or ethnic group, physical activity, and diet was collected by means of a self-administered, mailed questionnaire. The height and weight were used to calculate the BMI, which we divided into 10 categories (16.0 to 18.4, 18.5 to 20.9, 21.0 to 23.4, 23.5 to 24.9, 25.0 to 26.4, 26.5 to 27.9, 28.0 to 29.9, 30.0 to 34.9, 35.0 to 39.9, and 40.0 or more) that incorporated the definitions of underweight (less than 18.5), normal weight (18.5 to 24.9), overweight (25.0 to 29.9), and obesity (30.0 or more) proposed by the World Health Organization classification.9 In a subanalysis, we calculated BMI in the cohort at the age of 50 years on the basis of recalled weight at that age from a supplementary questionnaire mailed to the entire cohort six months after baseline (rate of response, 60 percent).6
Statistical Analysis
Age-adjusted mortality rates were calculated by direct standardization10 with the use of five-year age categories. Age-adjusted and multivariate relative risks were estimated by Cox regression analysis with age as the underlying time metric.11 Multivariate models were adjusted for race or ethnic group, level of education, smoking status, physical activity, and alcohol consumption. We performed stratified analyses to assess whether the association between BMI and the risk of death varied according to race or ethnic group, age group, smoking status, presence or absence of chronic disease, and duration of follow-up. We also evaluated the relations between body-mass index and the risk of death according to sex and smoking status with nonparametric regression curves that used restricted cubic spline12 graphs.
We calculated the population attributable risk,13 which is an estimate of the percentage of premature deaths in the cohort that would not have occurred if all persons had been of normal weight at the age of 50 years, given the assumption of a causal association between weight and the risk of death. Because the relation of BMI to the risk of death differed between current or former smokers and those who had never smoked, we calculated the population attributable risk according to sex both for the entire cohort and for the subgroup of subjects who had never smoked. The analysis was adjusted for confounding factors and modification of effects according to age.
Results
During a maximum follow-up of 10 years (4,821,757 person-years), 42,173 men and 19,144 women died. As compared with men and women in the reference group (BMI, 23.5 to 24.9), overweight and obese men and women had a lower percentage of current smokers, a lower level of education, and were less physically active (Table 1).
Table 1. Baseline Characteristics of 527,265 Men and Women According to BMI.
Among all men (Table 2 and Figure 1A) and women (Table 3 and Figure 2A), including smokers and those with preexisting disease, there was a U-shaped relation between current BMI and the risk of death, with the highest risk in the lowest and the highest categories of BMI. Overweight was not associated with an increased risk of death among men but was weakly associated with an increased risk of death among women. The associations between obesity and the risk of death were slightly stronger among Hispanic men and women and among Asian, Pacific Islander, or Native American men and women than among white or black men and women. The elevated risks associated with both extremely high and extremely low values of BMI declined slightly with increasing age in both men and women (Table 2 and Table 3 and Figure 1B and Figure 2B). In analyses stratified according to smoking status, we observed stronger associations between obesity and an increased risk of death among those who had never smoked than among former and current smokers. Underweight was most strongly associated with an increased risk of death among former and current smokers (Table 2 and Table 3 and Figure 1C and Figure 2C).
Table 2. Mortality Rates and Relative Risks of Death in Relation to BMI for All Men and for Selected Subgroups of Men.
Figure 1. Multivariate Relative Risks of Death in Relation to BMI among Men.
In each panel, the lines are natural cubic splines showing the shape of the dose–response curve for mortality according to BMI on a continuous basis. Relative risks are indicated by solid lines, and 95 percent confidence intervals by dashed lines. Panels A, B, and C are based on current BMI values, whereas Panel D represents BMI at the age of 50 years. The reference point is the midpoint of the reference group (BMI, 23.5 to 24.9) for categorical analyses, with knots placed at the 5th, 25th, 75th, and 95th percentiles of the BMI distribution among all men. The graphic display is truncated at 1 percent and 99 percent of BMI on the basis of the distribution of baseline (current) BMI among all men (Panels A, B, and C) and BMI at the age of 50 years among men who had never smoked (Panel D). All models are adjusted for age, race or ethnic group, level of education, alcohol consumption, and physical activity. The model for all men is adjusted for smoking status and the number of cigarettes smoked per day. The models for men who were former or current smokers are adjusted for the number of cigarettes smoked per day; men for whom information on the number of cigarettes smoked per day was missing were excluded.
Table 3. Mortality Rates and Relative Risks of Death in Relation to BMI for All Women and for Selected Subgroups of Women.
Figure 2. Multivariate Relative Risks of Death in Relation to BMI among Women.
In each panel, the lines are natural cubic splines showing the shape of the dose–response curve for mortality according to BMI on a continuous basis. Relative risks are indicated by solid lines, and 95 percent confidence intervals by dashed lines. Panels A, B, and C are based on current BMI, whereas Panel D represents BMI at the age of 50 years. The reference point is the midpoint of the reference group (BMI, 23.5 to 24.9) for categorical analyses, with knots placed at the 5th, 25th, 75th, and 95th percentiles of the BMI distribution among all women. The graphic display is truncated at 1 percent and 99 percent of BMI on the basis of the distribution of baseline (current) BMI among all women (Panels A, B, and C) and BMI at the age of 50 years among women who had never smoked (Panel D). All models are adjusted for age, race or ethnic group, level of education, alcohol consumption, and physical activity. The model for all women is adjusted for smoking status and the number of cigarettes smoked per day. The models for women who were former or current smokers are adjusted for the number of cigarettes smoked per day; women for whom information on the number of cigarettes smoked per day was missing were excluded.
To address the potential effect of bias owing to preexisting disease and disease-related weight loss, we conducted separate analyses for participants with and those without preexisting chronic conditions at enrollment (Table 2 and Table 3). We also divided the follow-up into earlier and later periods. In both men and women, the relation of obesity to the risk of death was consistently stronger among participants without preexisting chronic disease than among those with preexisting chronic disease. In separate analyses of the first five years of follow-up and the subsequent five years of follow-up, the association between obesity and the risk of death was stronger in the second than in the first follow-up period.
We also examined relations between BMI and the risk of death within racial or ethnic groups and age categories after restricting the analysis to those without preexisting disease who had never smoked. These relations within each age group were similar to those from the age-stratified analyses in the full cohort (data not shown). The number of deaths among nonwhites was insufficient to allow firm conclusions to be drawn about the relations between BMI and the risk of death among those who had never smoked and were free of preexisting disease.
The prevalence of chronic conditions increased markedly with age: the percentages of participants who reported physician-diagnosed heart disease, emphysema, stroke, end-stage renal disease, or cancer were 13.9 percent among men and women who were 50 to 55 years of age at enrollment, 19.2 percent among those 56 to 60 years of age, 26.2 percent among those 61 to 65 years of age, and 33.1 percent among those 66 to 71 years of age. Among both men and women 65 years of age or older, weight loss after the age of 50 years was more strongly associated with the risk of death than was weight gain (data not shown).
We attempted to correct for potential bias from disease-related weight loss by using participants' recalled weight at the age of 50 years to examine the relation of BMI to the risk of death, after confirming that the association between current BMI and the risk of death in the subcohort of respondents to the supplemental questionnaire was consistent with that for the entire cohort (data not shown). In addition, we confirmed that persons classified as overweight or obese at baseline who died by the end of the follow-up period were as likely to respond to the supplemental questionnaire as their counterparts of normal weight (the response rates were 54.5 percent and 55.9 percent, respectively).
We observed a J-shaped relation between BMI at the age of 50 years and the risk of death in both men and women, with a trend toward increased risk across the entire range of overweight and obese categories (Table 4). In contrast, the relation of underweight to the risk of death on the basis of BMI at the age of 50 years was weaker in both men and women than that noted in analyses based on current BMI.
Table 4. Relative Risk of Death in Relation to BMI at the Age of 50 Years among Men and Women.
When we further restricted the analysis of BMI at the age of 50 years to participants who had never smoked, we observed significant increases in the risk of death throughout the range of above-normal categories of BMI in both men and women (Table 4 and Figure 1D and Figure 2D). As compared with men with a BMI of 23.5 to 24.9 at the age of 50 years, morbidly obese men (BMI of 40.0 or more) had a multivariate relative risk of death of 3.82 (95 percent confidence interval, 2.87 to 5.08). The corresponding relative risk among women was 3.79 (95 percent confidence interval, 3.06 to 4.70). The increased risk of death among underweight participants remained but was diminished and not significant, with only 18 underweight men and 32 underweight women who died (Table 4).
Excess weight accounted for approximately 7.7 percent of all premature deaths among men and 11.7 percent of all premature deaths among women in the overall cohort. It accounted for 18.1 percent of all premature deaths among men who had never smoked and 18.7 percent of all premature deaths among women who had never smoked.
Discussion
In this large prospective study, obesity was strongly associated with the risk of death in both men and women in all racial and ethnic groups and at all ages. After we accounted for potential bias owing to preexisting disease and residual confounding by smoking status by using midlife BMI values and restricting the analysis to participants who had never smoked, we found that even moderate elevations in BMI conferred an increased risk of death. The risk among participants who were overweight at the age of 50 years was 20 to 40 percent higher than that among participants who had a BMI of 23.5 to 24.9 at that age. The risk among obese subjects was two to at least three times that of participants with a BMI of 23.5 to 24.9. The risk of death among underweight participants was attenuated.
Excess body fat has long been recognized as a harbinger of disease and early death.14 Nearly a half-century ago, insurance records showed that life expectancy was diminished in obese persons.15 Epidemiologic studies subsequently confirmed the link between obesity and an increased risk of death.1 Several studies showed that after smokers and those who died in the early years of follow-up were excluded, above-normal weight (BMI greater than 25.0), including overweight, was associated with an increased risk of death from any cause.16,17,18,19,20,21,22,23,24
However, whether moderate elevations in BMI (i.e., overweight) truly increase the risk of death is controversial.2 Several studies reported no increase in the risk of death among overweight subjects even after those who died during the initial years of follow-up were excluded or subjects were stratified according to smoking status.25,26,27,28,29 Recently, Flegal et al. reported that overweight was not associated with an excess risk of death in the nationally representative samples of U.S. adults drawn from the National Health and Nutrition Examination Survey.29 They speculated that possible causes for their finding might be improved medical management of obesity-related chronic disease or differences between the U.S. general population and populations in other studies.29 Others have suggested that inadequate control for the combined effects of smoking and chronic illnesses could be the explanation.30 Smoking is associated with both a lower BMI and an increased risk of death and can therefore distort the relation between BMI and the risk of death. Statistical adjustment for smoking status does not fully address the problem; the adjusted findings represent a potentially complex combination of the associations between BMI and the risk of death among current smokers, former smokers, and those who have never smoked. Restriction of analyses to persons who have never smoked is a powerful tool for addressing this potential bias. Our cohort included more than 186,000 men and women who had never smoked. When we restricted our analyses to these persons, the relation of obesity to the risk of death was substantially strengthened, and significant increases emerged in the risk of death, even among overweight participants.
Preexisting disease is linked to both decreased weight and an increased risk of death. Bias related to preexisting disease can be circumvented by restricting the analysis to healthy subjects and excluding those who died during the first years of follow-up (when deaths are more likely to reflect preexisting disease). In our data, the association between overweight or obesity and the risk of death among both men and women was strengthened by the use of these techniques.
An alternative approach to addressing bias related to preexisting disease is to examine weight at an earlier age (50 years in our study), a time of life reflecting typical adult weight and largely unaffected by the onset of diagnosed disease. When we analyzed BMI at the age of 50 years in relation to the risk of death, the results were stronger than those based on the current BMI after the exclusion of participants who died during the early years of follow-up. This suggests that within the 10-year time frame of our study, using weight at a younger age was more effective in accounting for preexisting disease than using current BMI and excluding participants who died during the initial years of follow-up. Finally, we observed the strongest associations between BMI and the risk of death when we combined analytic techniques for addressing bias from both preexisting disease and smoking by examining the relation of adiposity to the risk of death using BMI at the age of 50 years among those who had never smoked.
Large prospective studies are especially valuable for determining a more precise dose–response gradient for the connection between BMI and the risk of death. Our large cohort enabled us to estimate risks of death according to narrow categories of BMI with great precision and to discern not only an elevated risk for most categories of overweight but also substantially enhanced risk among the obese.
Although we did not compare our participants' assessments of height and weight with directly measured values, self-reported height and weight are generally known to be accurate. The correlation between BMI based on self-reported height and weight and that based on measured height and weight is typically greater than 0.9,31 and weight recalled from 28 years previously by elderly people has been reported to have a correlation of more than 0.8 with measured weight at that time.32 Some evidence suggests that obese persons are more likely to underestimate their weight than are persons of normal weight.33 This bias may be offset if underweight persons at higher risk for death report normal weight and are thus misclassified in the reference group. On balance, and given the strong correlation between self-reported and measured weight, including weight at the age of 50 years, the combined effect of random and systematic reporting error on the observed association between BMI and the risk of death is probably minimal.
We adjusted for several variables, including level of education, race or ethnic group, alcohol consumption, and physical activity, which allowed us to minimize the potential for confounding by these factors. Because we cannot rule out the possibility that unmeasured or unknown confounding factors accounted for the associations observed in our study, we cannot conclude with complete certainty that the relation between adiposity and the risk of death is causal.
The biomedical foundation for an association between excess body fat and the risk of death is well established. Medical complications of adiposity include hypertension, type 2 diabetes mellitus, cardiovascular disease, pulmonary disease, and cancer.34 Pathophysiologic processes that could plausibly mediate the connection between BMI and the risk of death include insulin resistance, lipid abnormalities, hormonal alterations, and chronic inflammation.35,36
The NIH–AARP Diet and Health Study is a contemporary investigation with vital status ascertained from 1995–1996 through the end of 2005. Many of the participants, who were 50 to 71 years old at baseline, are from the baby-boomer generation. Much has been written recently about the rise in obesity — and its medical consequences — in this segment of the population.37,38 Even against the background of advances in the management of obesity-related chronic diseases in the past few decades, our findings suggest that adiposity, including overweight, is associated with an increased risk of death.
Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
No potential conflict of interest relevant to this article was reported.
The views expressed are those of the authors.
We are indebted to the participants in the NIH–AARP Diet and Health Study for their outstanding cooperation, to Dr. Anne Thiebaut for statistical advice, and to Leslie Carroll and David Campbell at Information Management Services and Tawanda Roy at the Nutritional Epidemiology Branch for research assistance.
Source Information
From the Nutritional Epidemiology Branch (K.F.A., A.S., T.M., M.F.L.), Division of Cancer Epidemiology and Genetics and the Biometry Research Group (V.K.), Division of Cancer Prevention, and the Division of Cancer Control and Population Sciences (R.B.-B.), National Cancer Institute, and the Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging (T.B.H.), the National Institutes of Health, Bethesda, Md.; and the AARP, Washington, D.C. (A.H.).
Address reprint requests to Dr. Adams at the Nutritional Epidemiology Branch, 6120 Executive Blvd., Suite 320, Rockville, MD 20852, or at adamske@mail.nih.gov.
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Background Obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death, but the relation between overweight (a BMI of 25.0 to 29.9) and the risk of death has been questioned.
Methods We prospectively examined BMI in relation to the risk of death from any cause in 527,265 U.S. men and women in the National Institutes of Health–AARP cohort who were 50 to 71 years old at enrollment in 1995–1996. BMI was calculated from self-reported weight and height. Relative risks and 95 percent confidence intervals were adjusted for age, race or ethnic group, level of education, smoking status, physical activity, and alcohol intake. We also conducted alternative analyses to address potential biases related to preexisting chronic disease and smoking status.
Results During a maximum follow-up of 10 years through 2005, 61,317 participants (42,173 men and 19,144 women) died. Initial analyses showed an increased risk of death for the highest and lowest categories of BMI among both men and women, in all racial or ethnic groups, and at all ages. When the analysis was restricted to healthy people who had never smoked, the risk of death was associated with both overweight and obesity among men and women. In analyses of BMI during midlife (age of 50 years) among those who had never smoked, the associations became stronger, with the risk of death increasing by 20 to 40 percent among overweight persons and by two to at least three times among obese persons; the risk of death among underweight persons was attenuated.
Conclusions Excess body weight during midlife, including overweight, is associated with an increased risk of death.
Substantial epidemiologic evidence indicates that obesity, defined by a body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters) of 30.0 or more, is associated with an increased risk of death.1 However, whether overweight (defined by a BMI of 25.0 to 29.9) increases the risk of death has not been established.2 A substantial proportion of the U.S. adult population is overweight but not obese3; any association between overweight and mortality might have important clinical and public health implications.
Reverse causation owing to preexisting chronic disease and inadequate control for smoking status can distort the true relation between body weight and the risk of death, because chronic illness and smoking are associated with both decreased BMI and an increased risk of death.4 Possible approaches to addressing these potential biases include disregarding deaths occurring in the initial period of follow-up and restricting the analysis to persons without preexisting disease or those who have never smoked. Another approach is to evaluate BMI earlier in life,5 when it reflects typical adult weight largely unaffected by the onset of chronic disease. We examined the association between BMI and the risk of death in the National Institutes of Health (NIH)–AARP Diet and Health Study,6 which is based on a cohort of more than half a million people who were 50 to 71 years old at baseline. At baseline this cohort was large enough to permit the use of restriction to minimize potential bias caused by preexisting disease and smoking. In addition, because information was available on subjects' weight at the age of 50 years, we were able to analyze the relation between BMI in midlife and the subsequent risk of death.
Methods
Study Population
The NIH–AARP Diet and Health Study was established in 1995–1996 when 567,169 questionnaires eliciting information on demographic and anthropometric characteristics, dietary intake, and numerous health-related behavioral patterns were returned by 18 percent of AARP members who were 50 to 71 years old and resided in six U.S. states (California, Florida, Louisiana, New Jersey, North Carolina, and Pennsylvania) and two metropolitan areas (Atlanta and Detroit).6 We excluded records from 179 persons with duplicate representation in our database; 321 persons who moved out of the study area; 261 persons who died before their questionnaires were received; 15,760 persons whose questionnaires were completed by a spouse or other surrogate respondent; 16,649, 4648, and 2085 persons with missing or extreme values for current height or weight, energy intake, or alcohol consumption, respectively; and 1 person who withdrew from the study. We analyzed the data from the remaining 527,265 participants (313,047 men and 214,218 women).
Follow-up
The vital status of cohort members was determined from 1995–1996 through December 31, 2005. Vital status was ascertained by annual linkage of the cohort to the Social Security Administration Death Master File on deaths in the United States,7 with the most recent update on January 15, 2006. The design and maintenance of this cohort have been described elsewhere.6,8 The NIH–AARP Diet and Health Study was approved by the Special Studies Institutional Review Board of the National Cancer Institute. All participants provided written informed consent. All authors vouch for the accuracy of the data and concur with the interpretation of the results.
Assessment of Height, Weight, and Other Potential Risk Factors
Information on current height and weight, disease history, smoking habits, race or ethnic group, physical activity, and diet was collected by means of a self-administered, mailed questionnaire. The height and weight were used to calculate the BMI, which we divided into 10 categories (16.0 to 18.4, 18.5 to 20.9, 21.0 to 23.4, 23.5 to 24.9, 25.0 to 26.4, 26.5 to 27.9, 28.0 to 29.9, 30.0 to 34.9, 35.0 to 39.9, and 40.0 or more) that incorporated the definitions of underweight (less than 18.5), normal weight (18.5 to 24.9), overweight (25.0 to 29.9), and obesity (30.0 or more) proposed by the World Health Organization classification.9 In a subanalysis, we calculated BMI in the cohort at the age of 50 years on the basis of recalled weight at that age from a supplementary questionnaire mailed to the entire cohort six months after baseline (rate of response, 60 percent).6
Statistical Analysis
Age-adjusted mortality rates were calculated by direct standardization10 with the use of five-year age categories. Age-adjusted and multivariate relative risks were estimated by Cox regression analysis with age as the underlying time metric.11 Multivariate models were adjusted for race or ethnic group, level of education, smoking status, physical activity, and alcohol consumption. We performed stratified analyses to assess whether the association between BMI and the risk of death varied according to race or ethnic group, age group, smoking status, presence or absence of chronic disease, and duration of follow-up. We also evaluated the relations between body-mass index and the risk of death according to sex and smoking status with nonparametric regression curves that used restricted cubic spline12 graphs.
We calculated the population attributable risk,13 which is an estimate of the percentage of premature deaths in the cohort that would not have occurred if all persons had been of normal weight at the age of 50 years, given the assumption of a causal association between weight and the risk of death. Because the relation of BMI to the risk of death differed between current or former smokers and those who had never smoked, we calculated the population attributable risk according to sex both for the entire cohort and for the subgroup of subjects who had never smoked. The analysis was adjusted for confounding factors and modification of effects according to age.
Results
During a maximum follow-up of 10 years (4,821,757 person-years), 42,173 men and 19,144 women died. As compared with men and women in the reference group (BMI, 23.5 to 24.9), overweight and obese men and women had a lower percentage of current smokers, a lower level of education, and were less physically active (Table 1).
Table 1. Baseline Characteristics of 527,265 Men and Women According to BMI.
Among all men (Table 2 and Figure 1A) and women (Table 3 and Figure 2A), including smokers and those with preexisting disease, there was a U-shaped relation between current BMI and the risk of death, with the highest risk in the lowest and the highest categories of BMI. Overweight was not associated with an increased risk of death among men but was weakly associated with an increased risk of death among women. The associations between obesity and the risk of death were slightly stronger among Hispanic men and women and among Asian, Pacific Islander, or Native American men and women than among white or black men and women. The elevated risks associated with both extremely high and extremely low values of BMI declined slightly with increasing age in both men and women (Table 2 and Table 3 and Figure 1B and Figure 2B). In analyses stratified according to smoking status, we observed stronger associations between obesity and an increased risk of death among those who had never smoked than among former and current smokers. Underweight was most strongly associated with an increased risk of death among former and current smokers (Table 2 and Table 3 and Figure 1C and Figure 2C).
Table 2. Mortality Rates and Relative Risks of Death in Relation to BMI for All Men and for Selected Subgroups of Men.
Figure 1. Multivariate Relative Risks of Death in Relation to BMI among Men.
In each panel, the lines are natural cubic splines showing the shape of the dose–response curve for mortality according to BMI on a continuous basis. Relative risks are indicated by solid lines, and 95 percent confidence intervals by dashed lines. Panels A, B, and C are based on current BMI values, whereas Panel D represents BMI at the age of 50 years. The reference point is the midpoint of the reference group (BMI, 23.5 to 24.9) for categorical analyses, with knots placed at the 5th, 25th, 75th, and 95th percentiles of the BMI distribution among all men. The graphic display is truncated at 1 percent and 99 percent of BMI on the basis of the distribution of baseline (current) BMI among all men (Panels A, B, and C) and BMI at the age of 50 years among men who had never smoked (Panel D). All models are adjusted for age, race or ethnic group, level of education, alcohol consumption, and physical activity. The model for all men is adjusted for smoking status and the number of cigarettes smoked per day. The models for men who were former or current smokers are adjusted for the number of cigarettes smoked per day; men for whom information on the number of cigarettes smoked per day was missing were excluded.
Table 3. Mortality Rates and Relative Risks of Death in Relation to BMI for All Women and for Selected Subgroups of Women.
Figure 2. Multivariate Relative Risks of Death in Relation to BMI among Women.
In each panel, the lines are natural cubic splines showing the shape of the dose–response curve for mortality according to BMI on a continuous basis. Relative risks are indicated by solid lines, and 95 percent confidence intervals by dashed lines. Panels A, B, and C are based on current BMI, whereas Panel D represents BMI at the age of 50 years. The reference point is the midpoint of the reference group (BMI, 23.5 to 24.9) for categorical analyses, with knots placed at the 5th, 25th, 75th, and 95th percentiles of the BMI distribution among all women. The graphic display is truncated at 1 percent and 99 percent of BMI on the basis of the distribution of baseline (current) BMI among all women (Panels A, B, and C) and BMI at the age of 50 years among women who had never smoked (Panel D). All models are adjusted for age, race or ethnic group, level of education, alcohol consumption, and physical activity. The model for all women is adjusted for smoking status and the number of cigarettes smoked per day. The models for women who were former or current smokers are adjusted for the number of cigarettes smoked per day; women for whom information on the number of cigarettes smoked per day was missing were excluded.
To address the potential effect of bias owing to preexisting disease and disease-related weight loss, we conducted separate analyses for participants with and those without preexisting chronic conditions at enrollment (Table 2 and Table 3). We also divided the follow-up into earlier and later periods. In both men and women, the relation of obesity to the risk of death was consistently stronger among participants without preexisting chronic disease than among those with preexisting chronic disease. In separate analyses of the first five years of follow-up and the subsequent five years of follow-up, the association between obesity and the risk of death was stronger in the second than in the first follow-up period.
We also examined relations between BMI and the risk of death within racial or ethnic groups and age categories after restricting the analysis to those without preexisting disease who had never smoked. These relations within each age group were similar to those from the age-stratified analyses in the full cohort (data not shown). The number of deaths among nonwhites was insufficient to allow firm conclusions to be drawn about the relations between BMI and the risk of death among those who had never smoked and were free of preexisting disease.
The prevalence of chronic conditions increased markedly with age: the percentages of participants who reported physician-diagnosed heart disease, emphysema, stroke, end-stage renal disease, or cancer were 13.9 percent among men and women who were 50 to 55 years of age at enrollment, 19.2 percent among those 56 to 60 years of age, 26.2 percent among those 61 to 65 years of age, and 33.1 percent among those 66 to 71 years of age. Among both men and women 65 years of age or older, weight loss after the age of 50 years was more strongly associated with the risk of death than was weight gain (data not shown).
We attempted to correct for potential bias from disease-related weight loss by using participants' recalled weight at the age of 50 years to examine the relation of BMI to the risk of death, after confirming that the association between current BMI and the risk of death in the subcohort of respondents to the supplemental questionnaire was consistent with that for the entire cohort (data not shown). In addition, we confirmed that persons classified as overweight or obese at baseline who died by the end of the follow-up period were as likely to respond to the supplemental questionnaire as their counterparts of normal weight (the response rates were 54.5 percent and 55.9 percent, respectively).
We observed a J-shaped relation between BMI at the age of 50 years and the risk of death in both men and women, with a trend toward increased risk across the entire range of overweight and obese categories (Table 4). In contrast, the relation of underweight to the risk of death on the basis of BMI at the age of 50 years was weaker in both men and women than that noted in analyses based on current BMI.
Table 4. Relative Risk of Death in Relation to BMI at the Age of 50 Years among Men and Women.
When we further restricted the analysis of BMI at the age of 50 years to participants who had never smoked, we observed significant increases in the risk of death throughout the range of above-normal categories of BMI in both men and women (Table 4 and Figure 1D and Figure 2D). As compared with men with a BMI of 23.5 to 24.9 at the age of 50 years, morbidly obese men (BMI of 40.0 or more) had a multivariate relative risk of death of 3.82 (95 percent confidence interval, 2.87 to 5.08). The corresponding relative risk among women was 3.79 (95 percent confidence interval, 3.06 to 4.70). The increased risk of death among underweight participants remained but was diminished and not significant, with only 18 underweight men and 32 underweight women who died (Table 4).
Excess weight accounted for approximately 7.7 percent of all premature deaths among men and 11.7 percent of all premature deaths among women in the overall cohort. It accounted for 18.1 percent of all premature deaths among men who had never smoked and 18.7 percent of all premature deaths among women who had never smoked.
Discussion
In this large prospective study, obesity was strongly associated with the risk of death in both men and women in all racial and ethnic groups and at all ages. After we accounted for potential bias owing to preexisting disease and residual confounding by smoking status by using midlife BMI values and restricting the analysis to participants who had never smoked, we found that even moderate elevations in BMI conferred an increased risk of death. The risk among participants who were overweight at the age of 50 years was 20 to 40 percent higher than that among participants who had a BMI of 23.5 to 24.9 at that age. The risk among obese subjects was two to at least three times that of participants with a BMI of 23.5 to 24.9. The risk of death among underweight participants was attenuated.
Excess body fat has long been recognized as a harbinger of disease and early death.14 Nearly a half-century ago, insurance records showed that life expectancy was diminished in obese persons.15 Epidemiologic studies subsequently confirmed the link between obesity and an increased risk of death.1 Several studies showed that after smokers and those who died in the early years of follow-up were excluded, above-normal weight (BMI greater than 25.0), including overweight, was associated with an increased risk of death from any cause.16,17,18,19,20,21,22,23,24
However, whether moderate elevations in BMI (i.e., overweight) truly increase the risk of death is controversial.2 Several studies reported no increase in the risk of death among overweight subjects even after those who died during the initial years of follow-up were excluded or subjects were stratified according to smoking status.25,26,27,28,29 Recently, Flegal et al. reported that overweight was not associated with an excess risk of death in the nationally representative samples of U.S. adults drawn from the National Health and Nutrition Examination Survey.29 They speculated that possible causes for their finding might be improved medical management of obesity-related chronic disease or differences between the U.S. general population and populations in other studies.29 Others have suggested that inadequate control for the combined effects of smoking and chronic illnesses could be the explanation.30 Smoking is associated with both a lower BMI and an increased risk of death and can therefore distort the relation between BMI and the risk of death. Statistical adjustment for smoking status does not fully address the problem; the adjusted findings represent a potentially complex combination of the associations between BMI and the risk of death among current smokers, former smokers, and those who have never smoked. Restriction of analyses to persons who have never smoked is a powerful tool for addressing this potential bias. Our cohort included more than 186,000 men and women who had never smoked. When we restricted our analyses to these persons, the relation of obesity to the risk of death was substantially strengthened, and significant increases emerged in the risk of death, even among overweight participants.
Preexisting disease is linked to both decreased weight and an increased risk of death. Bias related to preexisting disease can be circumvented by restricting the analysis to healthy subjects and excluding those who died during the first years of follow-up (when deaths are more likely to reflect preexisting disease). In our data, the association between overweight or obesity and the risk of death among both men and women was strengthened by the use of these techniques.
An alternative approach to addressing bias related to preexisting disease is to examine weight at an earlier age (50 years in our study), a time of life reflecting typical adult weight and largely unaffected by the onset of diagnosed disease. When we analyzed BMI at the age of 50 years in relation to the risk of death, the results were stronger than those based on the current BMI after the exclusion of participants who died during the early years of follow-up. This suggests that within the 10-year time frame of our study, using weight at a younger age was more effective in accounting for preexisting disease than using current BMI and excluding participants who died during the initial years of follow-up. Finally, we observed the strongest associations between BMI and the risk of death when we combined analytic techniques for addressing bias from both preexisting disease and smoking by examining the relation of adiposity to the risk of death using BMI at the age of 50 years among those who had never smoked.
Large prospective studies are especially valuable for determining a more precise dose–response gradient for the connection between BMI and the risk of death. Our large cohort enabled us to estimate risks of death according to narrow categories of BMI with great precision and to discern not only an elevated risk for most categories of overweight but also substantially enhanced risk among the obese.
Although we did not compare our participants' assessments of height and weight with directly measured values, self-reported height and weight are generally known to be accurate. The correlation between BMI based on self-reported height and weight and that based on measured height and weight is typically greater than 0.9,31 and weight recalled from 28 years previously by elderly people has been reported to have a correlation of more than 0.8 with measured weight at that time.32 Some evidence suggests that obese persons are more likely to underestimate their weight than are persons of normal weight.33 This bias may be offset if underweight persons at higher risk for death report normal weight and are thus misclassified in the reference group. On balance, and given the strong correlation between self-reported and measured weight, including weight at the age of 50 years, the combined effect of random and systematic reporting error on the observed association between BMI and the risk of death is probably minimal.
We adjusted for several variables, including level of education, race or ethnic group, alcohol consumption, and physical activity, which allowed us to minimize the potential for confounding by these factors. Because we cannot rule out the possibility that unmeasured or unknown confounding factors accounted for the associations observed in our study, we cannot conclude with complete certainty that the relation between adiposity and the risk of death is causal.
The biomedical foundation for an association between excess body fat and the risk of death is well established. Medical complications of adiposity include hypertension, type 2 diabetes mellitus, cardiovascular disease, pulmonary disease, and cancer.34 Pathophysiologic processes that could plausibly mediate the connection between BMI and the risk of death include insulin resistance, lipid abnormalities, hormonal alterations, and chronic inflammation.35,36
The NIH–AARP Diet and Health Study is a contemporary investigation with vital status ascertained from 1995–1996 through the end of 2005. Many of the participants, who were 50 to 71 years old at baseline, are from the baby-boomer generation. Much has been written recently about the rise in obesity — and its medical consequences — in this segment of the population.37,38 Even against the background of advances in the management of obesity-related chronic diseases in the past few decades, our findings suggest that adiposity, including overweight, is associated with an increased risk of death.
Supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
No potential conflict of interest relevant to this article was reported.
The views expressed are those of the authors.
We are indebted to the participants in the NIH–AARP Diet and Health Study for their outstanding cooperation, to Dr. Anne Thiebaut for statistical advice, and to Leslie Carroll and David Campbell at Information Management Services and Tawanda Roy at the Nutritional Epidemiology Branch for research assistance.
Source Information
From the Nutritional Epidemiology Branch (K.F.A., A.S., T.M., M.F.L.), Division of Cancer Epidemiology and Genetics and the Biometry Research Group (V.K.), Division of Cancer Prevention, and the Division of Cancer Control and Population Sciences (R.B.-B.), National Cancer Institute, and the Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging (T.B.H.), the National Institutes of Health, Bethesda, Md.; and the AARP, Washington, D.C. (A.H.).
Address reprint requests to Dr. Adams at the Nutritional Epidemiology Branch, 6120 Executive Blvd., Suite 320, Rockville, MD 20852, or at adamske@mail.nih.gov.
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