In this large, pooled analysis of prospective studies, both overweight and obesity (and possibly underweight) were associated with increased all-cause mortality in analyses restricted to participants who never smoked and did not have diagnosed cancer or heart disease. Thus, analyses of this subgroup should be minimally confounded by smoking or prevalent illness. The associations were strongest among participants whose BMI was ascertained before the age of 50 years. The lowest all-cause mortality was generally observed in the BMI range of 20.0 to 24.9. Longer follow-up attenuated the associations with lower BMI levels.
Our findings are broadly consistent with those of the Prospective Studies Collaboration, which showed an optimal BMI of 22.5 to 25.0 in analyses of all study participants3
and of 20.0 to 25.0 in analyses restricted to participants who never smoked.40
Results from two cohorts that were not included in either of the pooled analyses, Cancer Prevention Study II and the European Prospective Investigation into Cancer and Nutrition, also support an optimal BMI range of 20.0 to 24.9.6,8
In addition, the current study and these previous studies all showed that being overweight is associated with increased all-cause mortality.3,6–8
Among healthy persons who never smoked, our estimated hazard ratio per 5-unit increase in BMI was similar to the estimate in the Prospective Studies Collaboration — 1.31 (95% CI, 1.29 to 1.33) and 1.32 (95% CI, 1.29 to 1.36), respectively, for the BMI range of 25.0 to 49.9. In contrast, analyses of NHANES data and the Canadian National Health Survey, which included smokers and persons with preexisting diseases, showed that being overweight was not associated with increased all-cause mortality.4,5
These studies were smaller than our pooled study, with only about 11,000 deaths combined (7% of the total deaths in our study), so it is unlikely that their inclusion would have altered the main results of the current analysis. A recent study that used NHANES data to forecast the effects of overweight and obesity on life expectancy may also have underestimated these effects.41
Debate over the importance of overweight and obesity for all-cause mortality generally focuses on whether it is appropriate to exclude from analyses all smokers and persons with prevalent diseases. It is argued that smoking and preexisting illness contribute disproportionately to deaths that occur before average life expectancy, so the results of analyses that exclude them cannot be extrapolated to the general population. The counterargument is that smoking and preexisting conditions that cause weight loss are powerful confounders and analyses that include them lack validity — an attribute that is more important in etiologic studies than is generalizability. Stratification or exclusion rather than adjustment is necessary because smoking is so strongly related to obesity and mortality (Tables 2 and 9 in the Supplementary Appendix
), making it difficult to avoid residual confounding by means of typical adjustments for smoking status and number of cigarettes smoked per day. Two aspects of our findings support our approach of focusing on healthy participants who never smoked. First, long-term follow-up strengthened rather than weakened the association between obesity and all-cause mortality, which is the expected result if preexisting illness confounds this association, especially early during follow-up. Second, the relationship between low BMI and all-cause mortality is stronger among former smokers who quit less than 20 years ago than among current smokers (Table 9 in the Supplementary Appendix
). This result is probably a reflection of cessation of smoking because of illness.
Two findings suggest that the association between a low BMI (less than 20.0) and increased mortality is probably, at least in part, an artifact of preexisting disease. First, the association between underweight and increased mortality was substantially weaker after 15 years of follow-up (hazard ratio, 1.21) than after 5 years of follow-up (hazard ratio, 1.73), which is consistent with greater confounding by other prevalent diseases (diseases that were undiagnosed or those we did not have data for) in the early years of follow-up. Second, the association was somewhat weaker among persons who were physically active (those who were lean and fit) than among persons who were inactive (those with illness-induced wasting). However, another factor that could attenuate the hazard ratios for underweight people with longer follow-up is weight gain over time. Therefore, we cannot rule out the possibility that being underweight is associated with increased mortality.
The strengths of our study include the very large and diverse study population, long-term follow-up with the majority of deaths occurring in the last decade, and the broad age range. This permitted statistically precise estimates of the relationship between BMI and mortality across a wide range of BMI categories even in analyses restricted to healthy participants who never smoked. In our study, there were more than five times as many deaths among participants in the highest obesity categories (BMI of 35.0 to 39.9 and 40.0 to 49.9) than in previous studies3,6,8
because severe obesity had become more common. Among non-Hispanic persons in the United States as a whole, an estimated 11% of men and 17% of women had a BMI of 35 or higher in 2008.
The principal limitation of our study is its reliance on height, weight, and preexisting conditions at a single point in time. As explained above, changes in these factors may contribute to the change in hazard ratios over time (), but without repeated measures of these factors, we cannot assess their relative contributions. Although BMI is not a perfect measure of adiposity, since it does not distinguish fat from lean body mass, height and weight are more easily measured or self-reported than other indexes of excess adiposity, such as waist circumference.42
Nevertheless, there will be errors in recall and self-reporting of height and weight. Prevalent diseases were also self-reported, and details varied across studies. Finally, an important limitation in terms of generalizability was the fact that the population was restricted to non-Hispanic whites.
We conclude that for non-Hispanic whites, both overweight and obesity are associated with increased all-cause mortality, and underweight may be as well. All-cause mortality is generally lowest within the BMI range of 20.0 to 24.9. The results of our analysis are most relevant to whites living in affluent countries; similar analyses are under way in other populations.