Aging
Conditions
Keywords
dietary restriction, disease /disorder prevention /control, nutrition of aging, bioenergetics, cardiovascular function, disease /disorder proneness /risk, insulin sensitivity / resistance
Brief summary
The purpose of this study is to test the hypothesis that two years of sustained 25% caloric restriction (CR) in men age 21-50 (inclusive) and women age 21-47 (inclusive) will slow aging and protect against age-related disease processes.
Detailed description
The overall aim of CALERIE Phase 2 is to test the hypothesis that two years of sustained caloric restriction (CR), involving a reduction in energy intake to 75% of baseline (25% CR), in healthy, non-obese men aged 21-50 (inclusive) and women aged 21-47 (inclusive), will result in the same adaptive changes that were observed in a wide variety of animal studies. Particular emphasis is on the adaptive responses thought to be involved in slowing the aging process and protecting against age-related disease processes. Primary outcomes include core body temperature and resting metabolic rate. Secondary outcomes include risk factors for cardiovascular disease, inflammatory markers, immune function, psychological and physical function; oxidative changes in lipids, proteins, and DNA; and, risk factors for age-related conditions such as diabetes and body composition. An important secondary aim is to identify potential adverse effects of CR in humans. The study will be conducted as a multi-center, parallel-group, randomized, controlled trial (RCT). A sample of 200 participants will be enrolled, and assigned to either the CR intervention or a control group. Control participants will be advised to simply continue their current diets. Participants in both treatment arms will be followed over a period of 24 months. A comprehensive set of evaluations will be performed prior to initiating the intervention, with follow-up evaluations at 1, 3, 6, 9, 12, 18 and 24 months afterwards.
Interventions
BEHAVIORALCaloric Restriction (CR)
Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months
BEHAVIORALControl
Participants continue their current diet for 24 months
Sponsors
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
all lab based assays were masked due to de-identified person and time interval measured. All physical measures were masked to intervention group status.
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Core Body Temperature, Baseline to 12 Months | Baseline to 12 months |
| Change in Core Temperature, Baseline to 24 Months | Baseline to 24 months |
| Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition, Baseline to 12 Months | Baseline, 12 months |
| Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition | Baseline, 24 months |
Secondary
| Measure | Time frame |
|---|---|
| Change in Tumor Necrosis Factor-α (TNF-α), Baseline to 12 Months | change baseline to 12 months |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Fat Mass | change 0 to 24 months | Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) was determined for the whole body. |
Countries
United States
Participant flow
Pre-assignment details
238 Participants were eligible, 18 participants withdrew prior to randomization, 220 participants were randomized to the study, and 2 participants withdrew prior to initiating the intervention.
Participants by arm
| Arm | Count |
|---|---|
| Caloric Restriction (CR) 25% caloric restriction
Caloric Restriction (CR): Participants follow a diet with 25% fewer calories than calculated at baseline over a period of 24 months | 143 |
| Ad Libitum Ad libitum energy intake
Control: Participants continue their current diet for 24 months | 75 |
| Total | 218 |
Baseline characteristics
| Characteristic | Ad Libitum | Total | Caloric Restriction (CR) |
|---|---|---|---|
| Age, Continuous | 38.1 years STANDARD_DEVIATION 6.9 | 38.1 years STANDARD_DEVIATION 7.2 | 38.2 years STANDARD_DEVIATION 7.3 |
| Race/Ethnicity, Customized African-American | 11 Participants | 26 Participants | 15 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 24 Participants | 17 Participants |
| Race/Ethnicity, Customized White | 57 Participants | 168 Participants | 111 Participants |
| Sex: Female, Male Female | 53 Participants | 152 Participants | 99 Participants |
| Sex: Female, Male Male | 22 Participants | 66 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 143 | 0 / 75 |
| other Total, other adverse events | 136 / 143 | 72 / 75 |
| serious Total, serious adverse events | 1 / 143 | 7 / 75 |
Outcome results
Primary
Change in Core Body Temperature, Baseline to 12 Months
Time frame: Baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caloric Restriction (CR) | Change in Core Body Temperature, Baseline to 12 Months | -0.05 degrees Celsius | Standard Deviation 0.02 |
| Ad Libitum | Change in Core Body Temperature, Baseline to 12 Months | -0.03 degrees Celsius | Standard Deviation 0.02 |
Comparison: All analysis under intention-to-treat. All observations were included The primary analytic was a repeated measures analysis. The dependent variable was the change from baseline 12 \& 14mos., with treatment, time, and the treatment × time interaction as independent variables. Site, sex, BMI stratum, and the baseline value of the outcome were included as covariates. The predicted mean changes ± standard errors are the adjusted values from the contrasts of the multiple timepoints.p-value: 0.795% CI: [-0.019, 0.059]Mixed Models Analysis
Primary
Change in Core Temperature, Baseline to 24 Months
Time frame: Baseline to 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caloric Restriction (CR) | Change in Core Temperature, Baseline to 24 Months | -0.05 degrees Celsius | Standard Deviation 0.02 |
| Ad Libitum | Change in Core Temperature, Baseline to 24 Months | -0.02 degrees Celsius | Standard Deviation 0.02 |
p-value: 0.8495% CI: [-0.0092, 0.069]Mixed Models Analysis
Primary
Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition
Time frame: Baseline, 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caloric Restriction (CR) | Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition | -71 Kcal/day | Standard Deviation 12 |
| Ad Libitum | Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition | -7 Kcal/day | Standard Deviation 16 |
p-value: <0.000195% CI: [-90.5, -37.5]Mixed Models Analysis
Primary
Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition, Baseline to 12 Months
Time frame: Baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caloric Restriction (CR) | Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition, Baseline to 12 Months | -83 Kcal/day | Standard Deviation 10 |
| Ad Libitum | Change in Resting Metabolic Rate (RMR) Corrected for Changes in Body Composition, Baseline to 12 Months | -1 Kcal/day | Standard Deviation 13 |
p-value: <0.00195% CI: [-103.8, -60.2]Mixed Models Analysis
Secondary
Change in Tumor Necrosis Factor-α (TNF-α), Baseline to 12 Months
Time frame: change baseline to 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caloric Restriction (CR) | Change in Tumor Necrosis Factor-α (TNF-α), Baseline to 12 Months | -0.30 pg/mL | Standard Deviation 0.09 |
| Ad Libitum | Change in Tumor Necrosis Factor-α (TNF-α), Baseline to 12 Months | -0.34 pg/mL | Standard Deviation 0.12 |
p-value: 0.8295% CI: [-0.16, 0.23]Mixed Models Analysis
Other Pre-specified
Change in Fat Mass
Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) was determined for the whole body.
Time frame: change 0 to 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caloric Restriction (CR) | Change in Fat Mass | -6.1 kg | Standard Deviation 0.22 |
| Ad Libitum | Change in Fat Mass | -0.2 kg | Standard Deviation 0.28 |
Comparison: Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) and Fat Free Mass (FFM) were determined for the whole body.p-value: <0.00195% CI: [-6.5, -5.3]Mixed Models Analysis
Other Pre-specified
Change in Fat Mass
Difference in change in Fat Mass between prescribed 25% Caloric Restriction (CR) and Ad Libitum (AL) at 12 and 24 months as measured by dual X-ray absorptiometry (DXA) using the Hologic 4500A, Delphi W or Discovery A, by a standardized protocol according to a standardized protocol. Fat Mass (FM) was determined for the whole body.
Time frame: baseline, 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Caloric Restriction (CR) | Change in Fat Mass | -6.1 Kg | Standard Deviation 0.22 |
| Ad Libitum | Change in Fat Mass | -0.3 Kg | Standard Deviation 0.28 |
Comparison: Comparison of change in FM in 2 groups over at 24 mos, controlling for site, sex, BMI group, and baseline FM. A repeated measures Mixed Model was employed for the analysis. For any outcome, Type I error was controlled using a hierarchical gatekeeping strategy testing, first, the GroupXTime interaction, and, if non-significant, the main effects of these two factors. Bonferroni corrections were employed for non-significant effects. All tests were at p\<0.05p-value: <0.000195% CI: [-6.4, -5.3]Mixed Models Analysis