Rob M. van Dam, PhD; Walter C. Willett, MD; JoAnn E. Manson, MD; Frank B. Hu, MD
Acknowledgment: The authors thank the participants of the Nurses' Health Study II for their continued cooperation.
Grant Support: By the National Institutes of Health (grant CA50385).
Potential Financial Conflicts of Interest: None disclosed.
Corresponding Author: Rob M. van Dam, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Building II, Boston, MA 02115; e-mail, email@example.com.
Current Author Addresses: Drs. van Dam, Willett, and Hu: Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Building II, Boston, MA 02115.
Dr. Manson: Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Third Floor, Boston, MA 02215.
Author Contributions: Conception and design: R.M. van Dam, W.C. Willett, J.E. Manson, F.B. Hu.
Analysis and interpretation of the data: R.M. van Dam, J.E. Manson, F.B. Hu.
Drafting of the article: R.M. van Dam.
Critical revision of the article for important intellectual content: R.M. van Dam, W.C. Willett, J.E. Manson, F.B. Hu.
Final approval of the article: R.M. van Dam, W.C. Willett, J.E. Manson, F.B. Hu.
Statistical expertise: R.M. van Dam, J.E. Manson, F.B. Hu.
Obtaining of funding: W.C. Willett, F.B. Hu.
Administrative, technical, or logistic support: J.E. Manson, F.B. Hu.
Collection and assembly of data: W.C. Willett.
van Dam R., Willett W., Manson J., Hu F.; The Relationship between Overweight in Adolescence and Premature Death in Women. Ann Intern Med. 2006;145:91-97. doi: 10.7326/0003-4819-145-2-200607180-00006
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Published: Ann Intern Med. 2006;145(2):91-97.
The prevalence of overweight and obesity is increasing in the United States and worldwide in children and adults (1-3). Being overweight during childhood and adolescence can have detrimental consequences on psychological and social factors, cardiovascular risk factors, and risk for chronic diseases and is associated with a higher prevalence of obesity in adulthood (4). Several studies have examined whether adiposity in childhood and adolescence is also related to premature death in adulthood (5-15). However, these studies largely concerned older birth cohorts that included few participants who were overweight during youth and few who never smoked (6, 8-10, 12-14). In addition, data from more recent studies are needed to address the proposition that the impact of obesity on death may have decreased recently because of advances in public health and medical care (16).
Jerome L Sullivan
University of Florida College of Medicine
July 26, 2006
Obesity, inflammation, mortality, and iron.
Van Dam et al (1) found that higher adiposity at age 18 years is associated with increased premature death in women. Hazard ratios for death were adjusted for potential confounders, including smoking, alcohol use, and physical activity. They were unable to exclude residual confounding by "unknown confounders" (1). A potential confounder not addressed by the authors is iron storage level.
Stored iron level may be associated with mortality from multiple causes including cardiovascular diseases, neoplasms and infectious diseases (2). Iron accumulation is also positively associated with adiposity (3). Complex interactions may be involved in the association of iron stores with BMI, however these likely include the simple mechanism of a net increase in iron absorption from increased exposure of gut mucosa to an absolute increase in iron associated with elevated food consumption.
Storage iron is regarded as normal. Humans have a system to assure that unused iron is stored in the body under conditions of excess dietary iron. An evolved system is also in place to assure that excess food is stored as fat. Those with an uninterrupted super-sized abundance of food tend to become overweight with the passage of decades. Higher than optimal set points for stored iron and stored fat may have evolved to assure adequate supplies of both in times of deprivation. Both set points may be excessively high for conditions of continuous excesses of available food and highly absorbable iron. Iron and food intakes may each have two optima: high levels associated with maximal growth rates, but much lower levels to assure maximal longevity (2).
Stored iron is an obesity-associated factor that can be manipulated more easily than other confounders such as smoking, alcohol use or physical activity. Long term maintenance of a state of iron depletion, e.g. by a series of phlebotomies, is more feasible than successful weight reduction. Iron stores can be controlled by non-dietary methods independently of BMI.
Increased iron may in part explain the association of obesity with oxidative stress and inflammation (4). Removal of all storage iron or induction of a state of "near iron deficiency" (5) can be accomplished without reduction in BMI. It should thus be possible in a clinical trial to determine the contribution of increased stored iron to the effects of obesity on biomarkers of oxidative stress and inflammation. In a number of experimental systems, removal of stored iron is protective against oxidative or inflammatory injury (2).
(1) van Dam RM, Willett WC, Manson JE, Hu FB. The Relationship between Overweight in Adolescence and Premature Death in Women. Ann Intern Med. 2006;145:91-97.
(2) Sullivan J. Is stored iron safe? J Lab Clin Med. 2004;144:280- 284.
(3) Liu JM, Hankinson SE, Stampfer MJ, Rifai N, Willett WC, Ma J. Body iron stores and their determinants in healthy postmenopausal US women. Am J Clin Nutr. 2003;78:1160-1167.
(4) Vincent HK, Taylor AG. Biomarkers and potential mechanisms of obesity-induced oxidant stress in humans. Int J Obes. 2005;30:400-418.
(5) Facchini FS, Saylor KL. Effect of iron depletion on cardiovascular risk factors: studies in carbohydrate-intolerant patients. Ann N Y Acad Sci. 2002;967:342-51.
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