2005 Annual Report 1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter? More than 60 percent of adults in the United States (US) are classified as overweight or obese. Obesity is one of the major public health problems in the US today and contributes significantly to increased disease, illness and premature death. Obesity is a problem now in people of all ages. The Determination of Energy Regulation in Aging CRIS focuses its research on understanding the etiology of body fat gain in adult life and improving dietary-based methods for prevention in treatment in adults ranging in age from young to elderly. There are three separate, but related lines of research within this CRIS: the Energy Metabolism Laboratory focuses on the energy metabolism of normal adults; the effects of aging on energy and substrate regulation; and dietary and other factors influencing energy regulation. The Obesity and Metabolism Laboratory conducts investigations on the metabolic factors related to the role of adipose tissue in whole body energy regulation, and specifically is examining the role of perilipins - proteins that coat intracellular stores of fat in adipocytes (fat cells) and are involved in regulating the breakdown of fat within adipcytes. The Body Composition Laboratory conducts research on body composition methodology, specifically to examine the progressive loss of muscle mass and general increase of percent body fat that are known to accompany aging. This work contributes to the systematic study of how the body ages with respect to energy regulation and sarcopenia (loss of muscle and function with age) by conducting physiological studies of energy regulation in relation to energy balance and nutrient balance, examining the role of fat cells in energy regulation at different stages of life, and providing body composition tools and methods specifically designed for the elderly. 2.List the milestones (indicators of progress) from your Project Plan. Energy Metabolism Laboratory (EML) EML Objective 1: To develop two healthy hypocaloric diets consistent with current dietary recommendations and compare them for their ability to promote long-term calorie restriction (CR) leading to body weight and fat losses over one year in overweight men and women. EML Objective 2: To test the hypothesis that there are metabolic and anti-aging benefits of long-term (2-year) CR in overweight men and women that are equivalent to the benefits seen in animal models. We hypothesize that there will be no significant adverse effects of long-term CR that would preclude its use in healthy adults. EML 2005 1. Develop two healthy hypocaloric diets consistent with current dietary recommendations that span the range of recommended macronutrient intakes. Objective 1. 2. Recruit 44 human subjects for 1-year study comparing the two different diets. Objective 1. 3. Enroll the 44 subjects in research study to compare the two diets for their ability to promote long-term caloric restriction and weight loss. Objective 1. EML 2006 1. Complete study of the effect of two diets on their ability to promote caloric restriction and weight loss. Objective 1. 2. Conduct data analyses comparing two diets for weight loss and body composition loss. Objective 1. 3. Conduct data analyses for metabolic predictors of weight loss. Objective 1. 4. Prepare manual of procedures for randomized clinical trial on the effects of caloric restriction on biological markers of aging. Objective 2. EML 2007 1. Conduct data analyses for psychological predictors of weight loss and cognitive effects of caloric restriction. Objective 1. 2. Conduct data analyses for effects of caloric restriction and dietary composition on metabolic efficiency. Objective 1. 3. Recruit first 50 percent of the human subjects for 2-year study of the effects of caloric restriction on biological markers of aging and enroll them in study of caloric restriction. Objective 2. EML 2008 1. Conduct data analysis on accuracy of Dietary Reference Intakes (DRIs) for determining energy requirements compared to doubly labeled water assessments of energy intake. Objective 1. 2. Conduct data analysis on the effect of caloric restriction and dietary composition on physical activity, body temperature and quality of life. Objective 1. 3. Recruit second 50 percent of the human subjects for 2-year study of the effects of caloric restriction on biological markers of aging. Objective 2. EML 2009 1. Continue outcome assessments in study of caloric restriction and biological markers of aging (primary outcomes are weight, body composition, dietary intake, insulin sensitivity, blood pressure and lipids and markers of immune function and oxidative stress). Objective 2. 2. Analyze baseline data from study of caloric restriction and biological aging. Objective 2. Obesity and Metabolism Laboratory (OML) 51000-061-02A OML Objective 1: To determine role and molecular mechanisms by which perilipin, a protein that coats stored fat in fat cells (adipocytes) regulates fat breakdown (lipolysis) and fat cell storage in adipocytes. OML Objective 2: To determine the mechanism(s) by which the absence of perilipin expression in mouse adipocytes (perilipin null mice) results in resistance to diet and genetic-induced obesity. OML Objective 3: To define how age, sex, genetic background and diet alters the susceptibility of perilipin null and wild-type mice to the development of insulin resistance and diabetes. To do this we will investigate female and male mice, young and old mice, and mice with different genetic background, comparing mice that lack perilipin (peri null mice) and normal or wild-type mice. OML 2005 1. Investigate and determine differences in adipocyte lipolysis in peri null and wild-type mice. Objective 1 2. Establish stable adipocyte cell lines. Objective 1 3. Determine serum adiponectin levels in peri null and wild-type mice. Objective2 4. Determine role of perilipin expression and adipocyte metabolism in modulating adipose tissue macrophage function and expression in humans as well as animal models of obesity. Objective 3 5. Generate backcrossed peri null mice by separately mating into C57BL6J. Objective 3 OML 2006 1. Determine role of perilipin expression and phosphorylation state in regulating hormone-sensitive lipase (HSL) translocation (movement of HSL from cytoplasm to the surface of intracellular fat droplets where fat is stored) and lipolysis. Objective 1 2. Determine how perilipin expression and phosphorylation state regulate thermogenesis in brown adipose tissue. Objective 2 3. Determine how estrogen regulates perilipin expression, adipokine function, inflammatory tone, and adipocyte metabolism. Objective 3 OML 2007 1. Determine AMPK activation state in adipose tissue, muscle, and skeletal muscle of wild-type and perilipin null mice. Objective 2 2. To determine how aging alters adipocyte metabolism, adipokine production, and adipose tissue macrophage and preadipocyte function in wild-type and perilipin null mice. Objective 3 OML 2008 1. Define how aging affects measures of insulin/glucose homeostasis, energy metabolism, and body composition in wild-type and perilipin null mice. Objective 3 OML 2009 1. Determine how a combined high fat/high sucrose diet affects adipose tissue metabolism and inflammation and measures of systemic metabolism in young and old wild-type and perilipin null mice. Objective 3 Body Composition Laboratory (BCL) 51000-061-03A BCL Objective 1: Adapt newly developed technologies to create, validate and use portable body composition methods for monitoring homebound and institutionalized elderly. BCL Objective 2: Use a new approach to dual energy x-ray absorptiometry to develop a reference method for high precision body composition analysis to replace existing technology, which focuses on bone density measurements. BCL Objective 3: Define the relationship between nutritional status, frailty, cognitive function and hydration status. Validate methods to monitor and manage dehydration and frailty in nursing home elderly. BCL Objective 4: Develop an in vivo whole-body protein status monitor based on minimally invasive fast neutron activation. BCL MILESTONES BCL 2005 1. Continuation of pilot project entitled “Hydration Status and Frailty in Nursing Home Residents” - includes recruitment of human subjects, hydration and body composition measurements, comparison between methods and measures of mental capacity and frailty. Objective 3 2. Mechanical design of the detector support system for the nitrogen monitor, design of the initial acquisition system and testing of the prototype detector. Objective 4 BCL 2006 1. Completion of the technical development of the hand-held absorptiometer, an instrument for bedside analysis of soft tissue composition designed for monitoring nutrition status in the field. Objective 1 2. Determine the optimal photon energy for soft tissue analysis as a function of tissue composition and thickness. Objective 2 3. Determine the relationship between hydration status and cognitive function in nursing home residents. Objective 3 BCL 2007 1. Completion of hydration and frailty in nursing home residents. The results will be used to design a monitoring system for assisted living and nursing homes. Objective 3 2. Evaluate the capability of multi-frequency bioelectrical impedance to measure extracellular water space in nursing home residents. Objective 3 BCL 2008 1. Validation of the portable, bedside x-ray absorptiometer against mid-thigh computerized tomography. Objective 1 2. Absolute neutron output measurements of the HNRCA neutron generator. Modifications to increase its neutron output so that protein measurements are feasible. Objective 4 3. Installation of new detector system in the whole body counter. Objective 4 BCL 2009 1. Field use and validation of portable X-ray absorptiometer. Objective 1 2. Design of full size absorptiometer with farm animals (Beltsville). Objective 2 3. Completion and data analysis from hydration study with nursing home residents. Objective 3 4. Calibration and validation of protein monitor. Objective 4 4a.What was the single most significant accomplishment this past year? Dietary variety is broadly important in old age. The Energy Metabolism Laboratory has found that dietary variety has an important association with nutrition-related health parameters in old age. Specifically, low dietary variety from energy-dense foods predicts low BMI, and low dietary variety from low-micronutrient-dense foods predicts low micronutrient status. The combination of low dietary variety from both energy dense foods and micronutrient dense foods is especially harmful because it is associated with low BMI and low micronutrient status. Because requirements for many nutrients increase with age, dietary variety may be especially important for maintenance of nutritional status in old age. 4b.List other significant accomplishments, if any. Hunger and Weight Change in Older Women The Energy Metabolism Laboratory has shown that a questionnaire rating average daily levels of hunger predicts weight change over time in older women. Specifically, women reporting low levels of hunger lose weight over time, and thus questionnaire-based ratings of hunger may provide a means to predict which individuals are at risk of undesirable weight loss in old age before it actually happens. Estrogen and Adipocyte Production in Mice Scientists in the Obesity Metabolism Laboratory have found that estrogen treatment of mice regulates the amount of perilipin in adipocytes and facilitates increased adipocyte lipolysis. This information provides mechanism to explain how different genders may vary in their ability to breakdown stored as well as a potential effect of menopause. Role of Perilipin in Regulating Subcellular Localization and Function of Lipases The Obesity and Metabolism Laboratory has completed the generation of stable adipocyte lines that do not express perilipin. We have found that perilipin regulates the translocation of HSL to the surface of stored fat. Lipolysis is blocked when perilipin cannot be phosphorylated by hormones. However, HSL translocates to the surface of lipid droplets in fat cells that contain an unphosphorylated perilipin. This data for the first time demonstrate that HSL translocation is important for stimulated lipolysis but is not sufficient. Hydration level is not related to cognitive function in nursing home elderly in the Boston area. This project, conducted by the Body Composition Laboratory was designed to study the mechanisms of dehydration and muscle loss in homebound and institutionalized elderly. The project started with a pilot study in a nursing home in the Boston area. Preliminary analysis of our pilot data has shown no correlation between body hydration and obtained cognitive function score. This finding indicates that it is the quality of care rather than thirst r mental status that regulates water intake in a tightly controlled nursing home environment. This is a significant early result of our study indicating that close monitoring of hydration in the elderly will be most beneficial in assisted and independent living environments where dehydration and sarcopenia can progress undetected. We will modify the recruitment criteria for the expanded phase of this study to utilize this early finding. 4c.List any significant activities that support special target populations. None. 4d.Progress report. None. 5.Describe the major accomplishments over the life of the project, including their predicted or actual impact. The Energy Metabolism Laboratory has provided a unique series of experiments designed to understand changes in energy regulation with aging. The laboratory was the first to demonstrate impaired regulation of food intake in old age, a finding that has subsequently been confirmed by several research groups, and have found underlying metabolic reasons explaining the reduced regulation of food intake (e.g., higher circulating levels of glucose postprandially in the elderly), and examined the practical utility of measurements of reduced hunger and satiety for predicting undesirable weight loss. These results relate to National Program 107, component 6: Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle and to performance measures: 4.1.1: Promote Healthier Individual Food Choices and Lifestyles and Prevent Obesity. The Obesity Metabolism Laboratory has completed the generation of stable adipocyte lines that do not express perilipin. We have found that perilipin regulates the translocation of HSL to the surface of stored fat. When perilipin cannot be phosphorylated by hormones, lipolysis is blocked. However, HSL translocates to the surface of lipid droplets in fat cells that contain an unphosphorylated perilipin. This data, for the first time demonstrate that HSL translocation is important for stimulated lipolysis but is not sufficient. These results relate to National Program 107, component 6: Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle and to performace measures: 4.1.1: Promote Healthier Individual Food Choices and Lifestyles and Prevent Obesity. The major accomplishment of the Body Composition Laboratory over the life of the project is the finding that hydration level is not related to cognitive function in elderly nursing home residents. This project was designed to study the mechanisms of dehydration and muscle loss in homebound and institutionalized elderly. Preliminary analysis of pilot data from a study conducted in a nursing home in the Boston area showed no correlation between body hydration and obtained cognitive function score. This finding indicates that it is the quality of care rather than thirst or mental status that regulates water intake in a tightly controlled nursing home environment. This is a significant early result of our study indicating that close monitoring of hydration in the elderly will be most beneficial in assisted and independent living environments where dehydration and sarcopenia can progress undetected. We will modify the recruitment criteria for the expanded phase of this study to utilize this early finding. This finding relates to Human Nutrition 107 program component 3: Nutrition Monitoring and to Performance Measure 4.1.2. Improve Human Health by Better Understanding the Nutrient Requirements of Individuals and the Nutritional Value of Foods. 6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? The research findings have been presented to the scientific community at a number of meetings and have also been published in prestigious peer-reviewed scientific journals. Results of this research also reach the public directly through press releases, through print and television media, and on the web, These data will be used by scientists conducting nutrition-related research, by the food industry, and by consumers. The Obesity Metabolism Laboratory has filed for the following patent with Dr. Jose Ordovas of the HNRCA Nutrition and Genomics Laboratory (CRIS 51520-010-00D), entitled: Genetic Markers for Obesity. We were awarded U.S. Patent # 6,897,019. “Methods for Treating and Preventing Insulin Resistance and Related Disorders”. A license for this patent has been granted to Celgene, Inc. 7.List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below). Drs. Roberts, Greenberg and Kehayias gave 8 invited lectures at scientific meetings and to general audiences about their research results. Susan Roberts – Invited Lectures October 25-27, 2004 United States Department of Agriculture. Conference on obesity prevention, Washington, DC. Organizer: Stephen R. Crutchfield, Ph.D. January 9-12, 2005 ‘2005 California Childhood Obesity Conference – Launching a Movement: Linking our Efforts to Make a Difference’ co-sponsored by the California Department of Health Services, California Department of Education and the Center for Weight and Health at the University of California, Berkeley, held in San Diego, California at the Manchester Grand Hyatt Hotel Organizer, Dana Gerstein, MPH, RD May 14-18, 2005 American Society of Hypertension, Inc. (ASH) 20th Annual Scientific Meeting, San Francisco Marriott, San Francisco, California. Organizer, Melissa Levine. June 3-6, 2005 ‘34th Annual Meeting combined with the 19th Annual Meeting of the American College of Clinical Gerontology’ Caloric restriction and metabolic aging Lecture, San Francisco, CA. Organizer, Andrzej Bartke. June 26-30, 2005 Scientific Committee of XVIII Congress of Gerontology of International Association of Gerontology, Rio de Janeiro, Brazil. Organized/Led Symposium and Keynote Speaker. Andy Greenberg – Invited Lectures June 21, 2005 Metabolic Syndrome: A View from the Fat Cell given at BIO2005 May 5, 2005 The Underlying Role of Adipose Tissue in the Inflammation of the Metabolic Syndrome given at IBC's Targeting Metabolic Syndrome Joseph Kehayias – Invited Lectures 2004 18th International Conference on the Application of Accelerators in Research and Industry, Conference Proceedings at the University of Texas, “Use of a portable D-T neutron generator for protein, muscle and fat measurements: design and clinical applications.” 2004 Kehayias JJ. Use of a portable D-T neutron generator for protein, muscle and fat measurements: design and clinical applications. Invited lecture, 18th International Conference on the Application of Accelerators in Research and Industry, Univ of North Texas, Denton 2004. Susan Roberts – Press North Jersey Record http://www.bergen.com/page.php?qstr=eXJpcnk3ZjczN2Y3dnFlZUVFeXkzJmZnYmVsN2Y3dnFlZUVFeXk2NjAzNTE4JnlyaXJ5N2Y3MTdmN3ZxZWVFRXl5Mg== Ultra-low-calorie diet high on promise Sunday, October 24, 2004 By MARY JO LAYTON STAFF WRITER WebMD Medical News October 26, 2004 Fewer Food Choices May Battle Obesity Research Points to Wide Variety as Culprit in Overeating By Todd Zwillich WebMD Medical News Reviewed By Charlotte Grayson, MD on Tuesday, October 26, 2004 Capital 9 News November 19, 2004 http://www.capitalnews9.com/content/health_team_9/?ArID=104841&SecID=17 Man eats his way to longer life By: Elizabeth Cohen CNN broadcast transcript Anderson Cooper Show 11.18.04 Some people look for the fountain of youth in the plastic surgeons office, but others are turning to diet. CNN Medical Correspondent Elizabeth Cohen introduces to a man who hopes to stay younger and live longer because of the way he eats. Wall Street Journal December 7, 2004; Page D1 HEALTH JOURNAL By TARA PARKER-POPE Added Calories Sneak Into Kids' Diets As Food Makers Tweak Snack Offerings Wall Street Journal December 14, 2004, page D6 Health Mailbox Columnist Tara Parker-Pope answers readers' questions. Washington Post January 12, 2005 Wednesday Final Edition http://www.washingtonpost.com/wp-dyn/articles/A180-2005Jan11.html Food; F04 , DIET SMART Katherine Tallmadge Supermarket Dining: 10 Smart Ways to Eat In By Katherine Tallmadge Worcester Telegram & Gazette, Inc. February 9, 2005 UMass study links good carbs, lower weight by Elizabeth Cooney; TELEGRAM & GAZETTE STAFF O, The Oprah Magazine, May 2005 v6 i5 p161(3) Even weight experts get the munchies: how 20 specialists control their own diets (or don't). Sarah Wildman reports. (body wise) Andy Greenberg – Press Cinnamon joins cholesterol battle. Boston Globe. HEALTH SENSE, August 24, 2004 By Judy Foreman Review Publications Prelack, K., Dwyer, J., Dallal, G., Rand, W.M., Yu, Y.M., Kehayias, J.J., Antoon, A., Sheridan, R. 2007. Growth Deceleration and Restoration After Serious Burn Injury. Journal of Burn Care and Rehabilitation. 28(2):262-268. Kehayias, J.J., Stamatelatos, I.E., Sheahan, C., O'Neil, M. 2003. A field method for assessing body composition by portable xrf bromine analysis: validation against instrumental neutron activation. In: Proceedings of the International Conference on Isotopic and Nuclear Analytical Techniques for Health and Environment, June 10-13, 2003, Vienna, Austria. 2004 CDROM. Kehayias, J.J., Sheahan, C.A., Murphy-Gismondi, P., Laughery, J., Maxwell, B., O'Neill, M. 2004. Use of new field methods to assess body composition, dehydration and frailty in nursing homes. In: The Journal of Nutrition, Health & Aging. Fourth European Congress on Nutrition and Health in the Elderly, November 4-5, 2004, Toulouse, France. 8(6):444-445. Das, S.K., Saltzman, E., Mccrory, M.A., Hsu, L.K., Shikora, S.A., Dolnikowski, G., Kehayias, J.J., Roberts, S. 2004. Energy expenditure is very high in extremely obese women. Journal of Nutrition. 134(6):1412-1416. Roberts, S.B., Hajduk, C., Howarth, N.C., Russell, R., Mccrory, M. 2005. Dietary variety predicts low body mass index and inadequate macronutrient and micronutrient intakes in community-dwelling older adults. Journal of Gerontology Medical Science. 60(5):613-621. HAYS, N.P., BATHALON, G.P., MCCRORY, M.A., ROUBENOFF, R., LIPMAN, R., ROBERTS, S.B. EATING BEHAVIOR CORRELATES OF ADULT WEIGHT GAIN AND OBESITY IN HEALTHY WOMEN AGED 55-65Y. AMERICAN JOURNAL OF CLINICAL NUTRITION. 2002;75:476-83. Huang, T.T., Howarth, N.C., Lin, B., Roberts, S.B., Mccrory, M.A. 2004. Energy intake and meal portions: Associations with BMI percentile in U.S. children. Obesity Research. 12(11):1875-1885. Huang, T.T., Harris, K.J., Lee, R.E., Nazir, N., Born, W., Ahluwalia, H.K. 2003. Assessing overweight, obesity, diet and physical activity in college students. Journal of American College Health. 52(2):83-86. Howarth, N., Huang, T.T., Roberts, S.B., Mccrory, M.A. 2004. Dietary fiber and fat associations with excess weight in U.S. adults [abstract]. Obesity Research. 12Suppl:A184. Pittas, A.G., Hariharan, R., Stark, P.C., Hajduk, C., Greenberg, A.S., Roberts, S.B. 2004. Interstitial glucose level is a significant predictor of energy intake in free-living individuals with health body weight. Journal of Nutrition. 135:1070-1074. Das, S., Hajduk, C., Golden, J., Pittas, A., Mccrory, M., Hadley, E., Rochon, J., Fuss, P., Tyler, S., Tsay, M., Cheatham, R., Saltzman, E., Roberts, S. 2004. Caloric restriction, weight loss and dietary composition [abstract]. Obesity Research. 12Suppl:A65-66. Pittas, A.G., Das, S., Hajduk, C., Kim, J., Saltzman, E., Golden, J., Greenberg, A.S., Roberts, S. 2004. The effects of the dietary glycemic index and carbohydrate content on insulin sensitivity and acute insulin response in a 6-month randomized controlled feeding trial [abstract]. Obesity Research. 12Suppl:A10-11. Hajduk, C., Das, S., Kim, J., Saltzman, E., Bales, C., Mccrory, M., Pittas, A., Golden, J., Elder, S., Tyler, S., Roberts, S. 2004. Effects of a fiber supplement on hunger and dietary compliance during calorie restriction [abstract]. Obesity Research. 12Suppl:A65-66. Pittas, A.G., Hariharan, R., Stark, P.C., Greenberg, A.S., Hajduk, C., Roberts, S. 2004. Continuous glucose measurement and meal patterns in free-living ambulatory individuals [abstract]. Obesity Research. 12Suppl:A113-114. Golden, J., Das, S.K., Hajduk, C., Pittas, A., Cheatham, R., Tyler, S., Fuss, P., Mccrory, M., Roberts, S., Saltzman, E. 2004. Blood pressure and health inventory outcomes during the first 6 months of a year-long caloric restriction pilot study [abstract]. Obesity Research. 12Suppl:A157. D'Eon, T.M., Souza, S.C., Greenberg, A.S. 2005. Estrogen regulates lipolysis and perilipin expression by decreasing adiposity and adipocyte size in pairfed ovariectomized mice [abstract]. Journal of Federation of American Societies for Experimental Biology. Paper No. A131.3.