CALERIE: Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy

Inclusion Criteria: * Age must be between 21-50 (inclusive) for men and 21-47 (inclusive) for women * Body mass index (BMI) must be greater than or equal to 22 and less than 28 * Female participants must use acceptable forms of contraception (barrier method, oral contraceptive, intra-uterine device, or similar) and be willing to continue using such a method while enrolled in the study Exclusion Criteria: * History or clinical manifestation of cardiovascular disease or an elevated blood pressure (greater than 140/90 mm Hg) * Abnormal resting ECG * History or clinical manifestation of diabetes * History or clinical manifestation of cholelithiasis (the presence or formation of gallstones in the gallbladder or bile ducts) * History of anaphylaxis, severe allergies, or asthma * History or clinical manifestation of any other significant metabolic, hematologic, pulmonary, cardiovascular, gastrointestinal, neurologic, immune, hepatic, renal, urologic disorders, or cancer that, in opinion of the investigator, would make the candidate ineligible for the study * History of stomach or intestinal surgery (except appendectomy) or major abdominal, thoracic or non-peripheral vascular surgery within one year prior to the randomization date * Any disease or condition that seriously affects body weight and/or body composition * Potassium level above the upper limit of normal at the screening visit confirmed by a test repeated within two weeks * Hemoglobin, hematocrit, RBC, or iron level below the lower limit of normal at the screening visit confirmed by a test repeated within two weeks * Evidence of active liver disease or ALT levels above 1.5 times the upper limit of normal * Practice a vegan dietary lifestyle * History or clinical manifestation of any eating disorder * Any history of pharmacologic treatment for a psychiatric disorder within one year prior to the randomization date or a history of more than one episode of a pharmacologic treatment for a psychiatric disorder within lifetime * History of drug or alcohol abuse (up to 14 drinks a week are allowed) within the past two years * BDI (Beck Depression Inventory) score of 20 or higher at screening or baseline * Treatment with steroids for more than a month within five years prior to the randomization date, or short-term (less than a month) treatment with steroids within six months prior to the randomization date * Regular use of other medications, except contraceptives * Participated in the CALERIE Phase 1 studies * Lost or gained 3 kg or more over the past six months * A volunteer must be either a never-smoker of tobacco products or an ex-smoker who quit completely at least 12 months prior to the screening visit * Donated blood within 30 days prior to the randomization date * Concurrent participation in any other interventional study * Breast-feeding or pregnant women or women intending to become pregnant before the scheduled end of the intervention * Engaged in a regular program of physical fitness involving some kind of heavy physical activity (e.g., jogging, running or riding fast on a bicycle for 30 minutes or more) five or more times per week over the past year * Unwilling to be assigned at random to the CR or control intervention * Unwilling or unable to adhere to the rigors of the CR intervention over the entire two-year intervention period * Unable or unwilling to discontinue dietary supplements or adhere to the alcohol consumption restrictions during the study * Unwilling or unable to adhere to the rigors of the data collection and clinical evaluation schedule over the entire two-year period follow-up period