Trial Outcomes & Findings for Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function (NCT NCT02460783)

Results Overview

IRS-1 is an intracellular adaptor molecule that is being recruited and activated by the binding of insulin and insulin-like growth factor to their respective receptors and in insulin resistance (IR) it shows aberrant phosphorylation in serine residues resulting in impaired downstream signal propagation. pS312-IRS-1 is considered an index of brain insulin resistance and a therapeutic response biomarker for interventions targeting brain IR. A decrease in its levels indicates target engagement with the intervention and improvement in brain IR.

Recruitment status

COMPLETED

Study phase

NA

Target enrollment

129 participants

Primary outcome timeframe

Week 0, Week 4, Week 8

Results posted on

2024-04-02

Participant Flow

Recruitment took place between 22 June 2015 and 23 December 2022.

129 participants underwent screening; 80 were not eligible, 3 withdrew prior to randomization, and 46 participants were randomized, 22 to 5-2 CR and 24 to HL.

Participant milestones

Participant milestones
Measure	5-2 CR Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Overall Study STARTED	22	24
Overall Study COMPLETED	20	20
Overall Study NOT COMPLETED	2	4

Reasons for withdrawal

Reasons for withdrawal
Measure	5-2 CR Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Overall Study Withdrawal by Subject	1	3
Overall Study Lost to Follow-up	1	1

Baseline Characteristics

Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency	Total n=40 Participants Total of all reporting groups
Age, Continuous	63.5 years STANDARD_DEVIATION 4.2 • n=5 Participants	63.0 years STANDARD_DEVIATION 6.1 • n=7 Participants	63.2 years STANDARD_DEVIATION 5.2 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	11 Participants n=7 Participants	24 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	9 Participants n=7 Participants	16 Participants n=5 Participants
Race/Ethnicity, Customized White/Caucasian	14 Participants n=5 Participants	11 Participants n=7 Participants	25 Participants n=5 Participants
Race/Ethnicity, Customized Black/African American	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Height	168.0 cm STANDARD_DEVIATION 9.2 • n=5 Participants	168.0 cm STANDARD_DEVIATION 9.5 • n=7 Participants	168.0 cm STANDARD_DEVIATION 9.2 • n=5 Participants
Body weight	99.0 kg STANDARD_DEVIATION 16.0 • n=5 Participants	95.4 kg STANDARD_DEVIATION 10.7 • n=7 Participants	97.2 kg STANDARD_DEVIATION 13.6 • n=5 Participants
Body Mass Index (BMI)	35.0 kg/m^2 STANDARD_DEVIATION 4.0 • n=5 Participants	33.8 kg/m^2 STANDARD_DEVIATION 3.1 • n=7 Participants	34.4 kg/m^2 STANDARD_DEVIATION 3.6 • n=5 Participants
Homeostatic Model Assessment of Insulin Resistance 2 (HOMA2-IR)	2.4 (μU/mmol/L)2 STANDARD_DEVIATION 0.7 • n=5 Participants	2.3 (μU/mmol/L)2 STANDARD_DEVIATION 1.0 • n=7 Participants	2.3 (μU/mmol/L)2 STANDARD_DEVIATION 0.9 • n=5 Participants
Mini-Mental State Examination (MMSE) score	29.7 units on a scale STANDARD_DEVIATION 0.6 • n=5 Participants	29.3 units on a scale STANDARD_DEVIATION 0.8 • n=7 Participants	29.5 units on a scale STANDARD_DEVIATION 0.7 • n=5 Participants
ApoE ε4 carrier status Non-carrier	17 Participants n=5 Participants	12 Participants n=7 Participants	29 Participants n=5 Participants
ApoE ε4 carrier status Carrier	3 Participants n=5 Participants	8 Participants n=7 Participants	11 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

IRS-1 is an intracellular adaptor molecule that is being recruited and activated by the binding of insulin and insulin-like growth factor to their respective receptors and in insulin resistance (IR) it shows aberrant phosphorylation in serine residues resulting in impaired downstream signal propagation. pS312-IRS-1 is considered an index of brain insulin resistance and a therapeutic response biomarker for interventions targeting brain IR. A decrease in its levels indicates target engagement with the intervention and improvement in brain IR.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine312-insulin Receptor Substrate-1 (pS312-IRS-1) Week 4 - Week 0	79.01 pg/mL Standard Error 287.16	443.72 pg/mL Standard Error 182.56
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine312-insulin Receptor Substrate-1 (pS312-IRS-1) Week 8 - Week 4	-337.70 pg/mL Standard Error 256.08	-608.92 pg/mL Standard Error 269.84

PRIMARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

IRS-1 is an intracellular adaptor molecule that is being recruited and activated by the binding of insulin and insulin-like growth factor to their respective receptors and in insulin resistance (IR) it shows aberrant phosphorylation in tyrosine residues resulting in impaired downstream signal propagation. pY-IRS-1 is considered an index of brain insulin resistance and a therapeutic response biomarker for interventions targeting brain IR. A decrease in its levels indicates target engagement with the intervention and improvement in brain IR.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) P-pan-Tyrosine-IRS-1 (pY-IRS-1) Week 8 - Week 4	-24.72 Arbitrary Units (AU) Standard Error 10.76	-54.23 Arbitrary Units (AU) Standard Error 31.72
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) P-pan-Tyrosine-IRS-1 (pY-IRS-1) Week 4 - Week 0	5.05 Arbitrary Units (AU) Standard Error 10.43	33.88 Arbitrary Units (AU) Standard Error 32.28

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Body Weight	-4.06 kg Standard Error 0.72	-2.33 kg Standard Error 0.62

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Body Mass Index (BMI)	-1.41 kg/m^2 Standard Error 0.26	-0.80 kg/m^2 Standard Error 0.20

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Waist Circumference	-2.84 cm Standard Error 0.63	-1.64 cm Standard Error 0.82

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Fasting Glucose	0.57 mg/dL Standard Error 1.64	2.16 mg/dL Standard Error 1.64

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Fasting Insulin	-4.48 μIU/mL Standard Error 1.08	-2.87 μIU/mL Standard Error 1.52

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Homeostatic Model Assessment of Insulin Resistance Index 2 (HOMA2-IR) is a marker of peripheral insulin resistance and is calculated by fasting insulin (μIU/L) multiplied by fasting glucose (mg/dL), and divided by a constant (405). A higher score indicates higher insulin resistance. A cut-off of 1.8 was used to indicate peripheral insulin resistance.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Homeostatic Model Assessment of Insulin Resistance 2 (HOMA2-IR)	-0.49 μIU/L*mg/dL Standard Error 0.12	-0.33 μIU/L*mg/dL Standard Error 0.18

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glycosylated Hemoglobin (HbA1c)	-0.20 percentage Standard Error 0.08	-0.02 percentage Standard Error 0.06

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in White Blood Cells (WBCs)	-0.31 cells x 10^9/L Standard Error 0.23	-0.23 cells x 10^9/L Standard Error 0.20

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Red Blood Cells (RBCs)	-0.12 cells x 10^12/L Standard Error 0.06	-0.04 cells x 10^12/L Standard Error 0.05

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Platelets	2.18 cells x 10^3/L Standard Error 5.15	8.07 cells x 10^3/L Standard Error 4.10

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Hemoglobin	-0.29 g/dL Standard Error 0.18	-0.143 g/dL Standard Error 0.15

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Hematocrit	-1.08 percentage Standard Error 0.49	-0.20 percentage Standard Error 0.39

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

The International Normalized Ratio (INR) is derived from prothrombin time (PT) which is calculated as a ratio of the patient's PT to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the following formula: INR = Patient PT ÷ Control PT. The higher the INR, the longer it takes for blood to clot.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in International Normalized Ratio (INR)	0.02 Ratio Standard Error 0.01	0.02 Ratio Standard Error 0.01

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Serum Beta-Hydroxybutyrate (bHB)	0.06 mmol/L Standard Error 0.03	0.03 mmol/L Standard Error 0.02

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Serum Acetoacetate (AcAc)	0.03 mmol/L Standard Error 0.01	0.01 mmol/L Standard Error 0.01

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Serum Non-Esterified Fatty Acids (NEFA)	0.09 mEq/L Standard Error 0.07	0.07 mEq/L Standard Error 0.04

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Serum Cortisol	22.89 ng/mL Standard Error 15.55	25.04 ng/mL Standard Error 12.63

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Creatinine	-0.01 mg/dL Standard Error 0.02	-0.02 mg/dL Standard Error 0.02

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Blood Urea Nitrogen (BUN)	-0.72 mg/dL Standard Error 1.04	-0.55 mg/dL Standard Error 1.03

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Alanine Aminotransferase (ALT)	-2.33 IU/L Standard Error 1.45	-0.77 IU/L Standard Error 1.49

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Aspartate Aminotransferase (AST)	0.87 IU/L Standard Error 1.70	2.95 IU/L Standard Error 2.49

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Total Cholesterol	-23.16 mg/dL Standard Error 6.17	-16.29 mg/dL Standard Error 4.60

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in HDL Cholesterol	-3.11 mg/dL Standard Error 1.34	-4.01 mg/dL Standard Error 1.45

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in LDL Cholesterol	-18.31 mg/dL Standard Error 5.82	-11.59 mg/dL Standard Error 3.71

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Triglycerides	-9.61 mg/dL Standard Error 6.72	-6.61 mg/dL Standard Error 10.03

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) Amyloid Beta 42	-43.56 pg/mL Standard Error 27.59	-30.16 pg/mL Standard Error 36.70

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) Amyloid Beta 40	-608.42 pg/mL Standard Error 434.48	-117.75 pg/mL Standard Error 565.04

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) Amyloid Beta 42 / Amyloid Beta 40 Ratio	-0.0005 Ratio Standard Error 0.001	-0.004 Ratio Standard Error 0.002

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) Total Tau	-13.45 pg/mL Standard Error 7.95	-3.61 pg/mL Standard Error 4.12

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=13 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) p181-Tau	-5.23 pg/mL Standard Error 10.67	-1.82 pg/mL Standard Error 8.77

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) Neurogranin	16.32 pg/mL Standard Error 9.25	2.70 pg/mL Standard Error 6.86

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) Light Chain Neurofilaments (Nf-L)	134.31 pg/mL Standard Error 72.60	30.23 pg/mL Standard Error 26.86

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=19 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Cerebrospinal Fluid (CSF) Glial Fibrillary Acidic Protein (GFAP)	1748.07 pg/mL Standard Error 1303.72	627.26 pg/mL Standard Error 624.30

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 42 Week 4 - Week 0	-10.82 pg/mL Standard Error 25.178	-9.58 pg/mL Standard Error 15.11
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 42 Week 8 - Week 4	-0.62 pg/mL Standard Error 22.71	10.61 pg/mL Standard Error 17.28

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 40 Week 4 - Week 0	-16.92 pg/mL Standard Error 23.41	-4.84 pg/mL Standard Error 15.80
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 40 Week 8 - Week 4	11.47 pg/mL Standard Error 20.42	15.14 pg/mL Standard Error 20.20

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 42 / Amyloid Beta 40 Ratio Week 4 - Week 0	0.01 Ratio Standard Error 0.02	-0.03 Ratio Standard Error 0.02
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 42 / Amyloid Beta 40 Ratio Week 8 - Week 0	-0.02 Ratio Standard Error 0.02	0.01 Ratio Standard Error 0.02

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Total Tau Week 4 - Week 0	-3.05 pg/mL Standard Error 25.93	-5.33 pg/mL Standard Error 19.79
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Total Tau Week 8 - Week 4	8.00 pg/mL Standard Error 24.48	20.31 pg/mL Standard Error 26.43

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) p181-Tau Week 4 - Week 0	1.70 pg/mL Standard Error 15.72	1.01 pg/mL Standard Error 8.94
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) p181-Tau Week 8 - Week 4	-1.65 pg/mL Standard Error 15.11	9.90 pg/mL Standard Error 12.26

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) p231-Tau Week 4 - Week 0	-3.47 pg/mL Standard Error 7.78	-5.60 pg/mL Standard Error 4.71
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) p231-Tau Week 8 - Week 4	-2.12 pg/mL Standard Error 7.10	0.13 pg/mL Standard Error 5.09

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Akt (or protein kinase B) is an insulin signaling cascade mediator. An increase in its levels indicates an improvement in brain insulin resistance.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Akt Week 4 - Week 0	1.30 Arbitrary Units (AU) Standard Error 2.79	-3.27 Arbitrary Units (AU) Standard Error 2.38
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Akt Week 8 - Week 4	-2.15 Arbitrary Units (AU) Standard Error 2.04	-0.48 Arbitrary Units (AU) Standard Error 2.93

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

pS473-Akt is an insulin signaling cascade mediator. An increase in its levels indicates activation of downstream insulin signaling pathway.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine473-Akt (pS473-Akt) Week 8 - Week 4	-3.33 Arbitrary Units (AU) Standard Error 3.02	-0.93 Arbitrary Units (AU) Standard Error 4.00
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine473-Akt (pS473-Akt) Week 4 - Week 0	-1.73 Arbitrary Units (AU) Standard Error 1.80	-5.13 Arbitrary Units (AU) Standard Error 3.78

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine473-Akt (pS473-Akt) / Akt Ratio Week 4 - Week 0	-0.02 Ratio Standard Error 0.02	-0.01 Ratio Standard Error 0.02
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine473-Akt (pS473-Akt) / Akt Ratio Week 8 - Week 4	-0.01 Ratio Standard Error 0.02	-0.003 Ratio Standard Error 0.02

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

pERK1/2 is an insulin signaling cascade mediator. An increase in its levels indicates activation of downstream insulin signaling pathway.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Extracellular Signal-regulated Kinase 1/2 (pERK1/2) Week 4 - Week 0	4.66 Arbitrary Units (AU) Standard Error 3.05	-2.23 Arbitrary Units (AU) Standard Error 2.82
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Extracellular Signal-regulated Kinase 1/2 (pERK1/2) Week 8 - Week 4	-2.66 Arbitrary Units (AU) Standard Error 2.90	0.37 Arbitrary Units (AU) Standard Error 3.52

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

JNK is an insulin signaling cascade mediator. Activated JNK (pJNK) inhibits insulin signaling. An increase in pJNK levels indicates inhibition of downstream insulin signaling pathway.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated c-Jun N-terminal Kinase (pJNK) Week 4 - Week 0	2.91 Arbitrary Units (AU) Standard Error 2.72	-2.88 Arbitrary Units (AU) Standard Error 3.30
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated c-Jun N-terminal Kinase (pJNK) Week 8 - Week 4	-1.44 Arbitrary Units (AU) Standard Error 3.08	8.44 Arbitrary Units (AU) Standard Error 7.93

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

p38 is an insulin signaling cascade mediator. Activated p38 (pp38) inhibits insulin signaling. An increase in pp38 levels indicates inhibition of downstream insulin signaling pathway.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated p38 (pp38) Week 4 - Week 0	5.76 Arbitrary Units (AU) Standard Error 7.10	-1.39 Arbitrary Units (AU) Standard Error 9.26
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated p38 (pp38) Week 8 - Week 4	-12.20 Arbitrary Units (AU) Standard Error 7.64	21.81 Arbitrary Units (AU) Standard Error 25.47

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) proBDNF Week 4 - Week 0	-723.76 pg/mL Standard Error 814.01	-91.37 pg/mL Standard Error 593.83
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) proBDNF Week 8 - Week 4	531.01 pg/mL Standard Error 646.66	-388.59 pg/mL Standard Error 984.13

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) BDNF Week 4 - Week 0	0.01 pg/mL Standard Error 1.22	1.07 pg/mL Standard Error 2.37
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) BDNF Week 8 - Week 4	0.98 pg/mL Standard Error 1.51	0.65 pg/mL Standard Error 3.09

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Neurogranin Week 8 - Week 4	-5.43 pg/mL Standard Error 12.50	4.07 pg/mL Standard Error 16.84
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Neurogranin Week 4 - Week 0	5.69 pg/mL Standard Error 12.14	1.08 pg/mL Standard Error 14.91

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Measurements with coefficient of variation (CV) ≥ 20% were excluded from the analysis.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Heavy Chain Neurofilaments (Nf-H) Week 4 - Week 0	-25.12 pg/mL Standard Error 47.07	4.80 pg/mL Standard Error 39.04
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Heavy Chain Neurofilaments (Nf-H) Week 8 - Week 4	-1.59 pg/mL Standard Error 45.27	54.71 pg/mL Standard Error 56.18

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) A-synuclein Week 4 - Week 0	-4.21 pg/mL Standard Error 18.18	-27.97 pg/mL Standard Error 9.23
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) A-synuclein Week 8 - Week 4	1.57 pg/mL Standard Error 13.87	17.06 pg/mL Standard Error 14.77

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) TAR DNA-binding Protein 43 (TDP-43) Week 4 - Week 0	-443.207 pg/mL Standard Error 324.78	67.84 pg/mL Standard Error 185.71
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) TAR DNA-binding Protein 43 (TDP-43) Week 8 - Week 4	64.67 pg/mL Standard Error 265.15	89.56 pg/mL Standard Error 258.47

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Monocarboxylate Transporter 1 (MCT1) Week 4 - Week 0	158.32 ng/mL Standard Error 153.93	-104.39 ng/mL Standard Error 167.54
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Monocarboxylate Transporter 1 (MCT1) Week 8 - Week 4	-5.01 ng/mL Standard Error 139.56	-141.72 ng/mL Standard Error 159.49

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Monocarboxylate Transporter 2 (MCT2) Week 4 - Week 0	1.27 ng/mL Standard Error 1.14	-1.72 ng/mL Standard Error 0.72
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Monocarboxylate Transporter 2 (MCT2) Week 8 - Week 4	-0.67 ng/mL Standard Error 0.78	1.86 ng/mL Standard Error 1.37

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Complex IV is part of the mitochondrial electron transport chain. Decreased complex IV levels in NDEVs have been found in patients with Alzheimer's disease. A decrease in its levels may indicate decreased ability of neurons for ATP production and energy crisis.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Mitochondrial Complex IV Quantity Week 8 - Week 4	-0.00051 Arbitrary Units (AU) Standard Error 0.00047	-0.00002 Arbitrary Units (AU) Standard Error 0.00051
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Mitochondrial Complex IV Quantity Week 4 - Week 0	0.00037 Arbitrary Units (AU) Standard Error 0.00076	-0.00006 Arbitrary Units (AU) Standard Error 0.00035

SECONDARY outcome

Timeframe: Week 0, Week 4, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Complex V is part of the mitochondrial electron transport chain. Decreased complex V levels in NDEVs have been found in patients with Alzheimer's disease. A decrease in its levels may indicate decreased ability of neurons for ATP production and energy crisis.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Mitochondrial Complex V Quantity Week 4 - Week 0	0.000082 Arbitrary Units (AU) Standard Error 0.0002	0.00019 Arbitrary Units (AU) Standard Error 0.0001
Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Mitochondrial Complex V Quantity Week 8 - Week 4	0.00006 Arbitrary Units (AU) Standard Error 0.00013	-0.000074 Arbitrary Units (AU) Standard Error 0.00036

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glucose concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glucose relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glucose by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.086 Ratio Standard Error 0.034	-0.013 Ratio Standard Error 0.023

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) N-acetyl-aspartate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. N-acetyl-aspartate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in N-acetyl-aspartate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.028 Ratio Standard Error 0.034	0.054 Ratio Standard Error 0.029

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Lactate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Lactate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Lactate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.016 Ratio Standard Error 0.016	-0.012 Ratio Standard Error 0.012

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glutamate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glutamate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glutamate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.014 Ratio Standard Error 0.046	0.008 Ratio Standard Error 0.047

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Gamma-Aminobutyric Acid (GABA) concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Gamma-Aminobutyric Acid (GABA) relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=15 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Gamma-Aminobutyric Acid (GABA) by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	0.002 Ratio Standard Error 0.023	0.020 Ratio Standard Error 0.016

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glutamine concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glutamine relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glutamine by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.052 Ratio Standard Error 0.029	-0.004 Ratio Standard Error 0.024

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glutathione concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glutathione relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glutathione by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.010 Ratio Standard Error 0.010	-0.018 Ratio Standard Error 0.015

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Myo-Inositol concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Myo-Inositol relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Myo-Inositol by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.046 Ratio Standard Error 0.031	-0.012 Ratio Standard Error 0.028

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) N-acetyl-aspartyl-glutamate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. N-acetyl-aspartyl-glutamate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=11 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=17 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in N-acetyl-aspartyl-glutamate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.038 Ratio Standard Error 0.015	0.013 Ratio Standard Error 0.016

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Ascorbate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Ascorbate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=15 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=18 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Ascorbate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.107 Ratio Standard Error 0.050	-0.076 Ratio Standard Error 0.033

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Alanine concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Alanine relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=17 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Alanine by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	-0.006 Ratio Standard Error 0.010	-0.017 Ratio Standard Error 0.010

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Scyllo-Inositol concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Scyllo-Inositol relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=11 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=13 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Scyllo-Inositol by Proton J-PRESS MRS of Posteromedial Cortex (PMC)	0.002 Ratio Standard Error 0.003	0.004 Ratio Standard Error 0.004

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glucose concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glucose relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=16 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glucose by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	-0.002 Ratio Standard Error 0.059	0.065 Ratio Standard Error 0.040

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Lactate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Lactate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=12 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=15 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Lactate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	0.012 Ratio Standard Error 0.019	-0.017 Ratio Standard Error 0.020

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glutamate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glutamate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=16 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glutamate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	0.010 Ratio Standard Error 0.108	-0.088 Ratio Standard Error 0.056

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glutamine concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glutamine relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=16 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glutamine by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	-0.042 Ratio Standard Error 0.046	-0.048 Ratio Standard Error 0.043

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Glutathione concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glutathione relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=16 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Glutathione by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	-0.011 Ratio Standard Error 0.014	0.030 Ratio Standard Error 0.018

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Myo-Inositol concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Myo-Inositol relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=16 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Myo-Inositol by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	0.001 Ratio Standard Error 0.036	-0.006 Ratio Standard Error 0.035

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) N-acetyl-aspartyl-glutamate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. N-acetyl-aspartyl-glutamate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=12 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=12 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in N-acetyl-aspartyl-glutamate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	0.001 Ratio Standard Error 0.040	0.042 Ratio Standard Error 0.026

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Ascorbate concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Ascorbate relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=14 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=16 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Ascorbate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	-0.039 Ratio Standard Error 0.075	0.006 Ratio Standard Error 0.078

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) Alanine concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Alanine relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=13 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=16 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Alanine by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	-0.009 Ratio Standard Error 0.022	0.001 Ratio Standard Error 0.021

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population). Metabolite measurements with Cramer-Rao lower bounds (CRLBs) ≥ 20% were excluded from the analysis.

Proton J-PRESS Magnetic Resonance Spectroscopy (MRS) glucose concentrations were determined using the Prior-Knowledge Fitting Procedure (ProFit), which fits linear combinations of simulated two-dimensional basis metabolite spectra. Glucose relative ratio to creatine was quantified.

Outcome measures

Outcome measures
Measure	5-2 CR n=7 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=11 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Scyllo-Inositol by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)	-0.002 Ratio Standard Error 0.008	0.004 Ratio Standard Error 0.004

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Executive function was assessed with the National Institutes of Health (NIH) Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) battery that comprises written, verbal, and computerized tasks that test working memory, inhibition, set shifting, fluency, planning, insight, and social cognition and behavior. The Executive function Composite is a computerized score calculated based on the individual tests. It ranges between 0 and 10. Higher score values indicate better performance.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Executive Function Composite	0.23 units on a scale Standard Error 0.05	0.07 units on a scale Standard Error 0.08

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

California Verbal Learning Test (CVLT) assesses verbal memory for unstructured information. Examinees are asked to recall words on a 16-item list after each of 5 learning trials (Immediate Free Recall; range 0-80 \[5 x 0-16\]). After a distractor list, participants are again asked to recall words spontaneously (Short Delay Free Recall; range 0-16) and with category cueing (Short Delay Cued Recall; range 0-16). Spontaneous recall (Long Delay Free Recall; range 0-16) and category cueing (Long Delay Cued Recall; range 0-16) are repeated after a 20-minute delay. Following the longer delay, participants also complete a yes/no recognition trial during which they need to discriminate between the target words and 32 distractor words (Long Delay Recognition; range 0-48 \[0-16 true positive target words + 0-32 true negative distractor words\]). Higher scores indicate better performance.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in California Verbal Learning Test (CVLT) Short Delay Free Recall	0.75 units on a scale Standard Error 0.49	1.40 units on a scale Standard Error 0.65
Mean Change in California Verbal Learning Test (CVLT) Immediate Free Recall	4.55 units on a scale Standard Error 1.26	4.55 units on a scale Standard Error 1.13
Mean Change in California Verbal Learning Test (CVLT) Short Delay Cued Recall	0.85 units on a scale Standard Error 0.33	0.75 units on a scale Standard Error 0.48
Mean Change in California Verbal Learning Test (CVLT) Long Delay Free Recall	0.90 units on a scale Standard Error 0.48	0.10 units on a scale Standard Error 0.46
Mean Change in California Verbal Learning Test (CVLT) Long Delay Cued Recall	1.40 units on a scale Standard Error 0.37	0.25 units on a scale Standard Error 0.44
Mean Change in California Verbal Learning Test (CVLT) Long Delay Recognition	0.75 units on a scale Standard Error 0.58	-0.35 units on a scale Standard Error 0.49

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Logical Memory (LM) test assesses verbal memory for structured information. It consists of two thematically independent narrative stories. Each story has 25 items, which the examinee has to recall with as much detail and precision as possible. Each item is scored the same regardless of importance level, and all correct items are summed giving a maximum score of 25 for each story. "Verbatim recall" score only includes the items that are recalled exactly and with detailed information, whereas "gist recall" score includes both the verbatim recall and the items that are recalled with only the essential elements of the information. The examinee has to recall the two stories twice, immediately after their initial administration (immediate recall) and after a 20 to 30-minute delay (delayed recall). Total maximum score for each of the subtests is 50 (25 items x 2 stories) and the minimum score is 0. Higher scores indicate better performance.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Logical Memory (LM) Test Delayed Verbatim Recall	1.30 units on a scale Standard Error 0.92	2.80 units on a scale Standard Error 1.26
Mean Change in Logical Memory (LM) Test Immediate Verbatim Recall	1.60 units on a scale Standard Error 0.78	1.10 units on a scale Standard Error 0.95
Mean Change in Logical Memory (LM) Test Immediate Gist Recall	1.65 units on a scale Standard Error 0.85	1.75 units on a scale Standard Error 1.04
Mean Change in Logical Memory (LM) Test Delayed Gist Recall	1.95 units on a scale Standard Error 0.74	3.00 units on a scale Standard Error 1.35

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Positive and Negative Affect Schedule (PANAS) is a 20-item self-report measure to assess positive and negative affect and is an index of emotional state. For positive affect, score can range from 10 - 50, with higher scores representing higher levels of positive affect. For negative affect, score can range from 10 - 50, with lower scores representing lower levels of negative affect.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Change in the Positive and Negative Affect Schedule (PANAS) Positive Affect	-2.45 units on a scale Standard Error 1.34	-1.35 units on a scale Standard Error 0.96
Change in the Positive and Negative Affect Schedule (PANAS) Negative Affect	0.51 units on a scale Standard Error 0.65	-0.06 units on a scale Standard Error 0.57

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Short Form 36-item Health Survey (SF-36) is a gauge of physical and psychosocial effects of the interventions. It consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability; the higher the score the less disability.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in the Short Form 36-item Health Survey (SF-36) Emotional well-being	1.00 units on a scale Standard Error 1.09	3.20 units on a scale Standard Error 1.73
Mean Change in the Short Form 36-item Health Survey (SF-36) Physical functioning	2.50 units on a scale Standard Error 2.49	2.00 units on a scale Standard Error 1.52
Mean Change in the Short Form 36-item Health Survey (SF-36) Role limitations due to physical health	1.25 units on a scale Standard Error 3.74	0.00 units on a scale Standard Error 5.59
Mean Change in the Short Form 36-item Health Survey (SF-36) Role limitations due to emotional problems	-5.00 units on a scale Standard Error 3.56	0.00 units on a scale Standard Error 2.36
Mean Change in the Short Form 36-item Health Survey (SF-36) Energy/fatigue	4.50 units on a scale Standard Error 3.35	3.75 units on a scale Standard Error 2.29
Mean Change in the Short Form 36-item Health Survey (SF-36) Social functioning	1.88 units on a scale Standard Error 2.21	0.00 units on a scale Standard Error 3.54
Mean Change in the Short Form 36-item Health Survey (SF-36) Pain	3.00 units on a scale Standard Error 3.96	3.38 units on a scale Standard Error 3.19
Mean Change in the Short Form 36-item Health Survey (SF-36) General health	-2.25 units on a scale Standard Error 1.56	-2.50 units on a scale Standard Error 1.79

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Total Energy Expenditure	-538.44 kilocalories Standard Error 626.72	-302.86 kilocalories Standard Error 649.62

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Daily Energy Expenditure	-18.76 kilocalories/day Standard Error 106.75	-175.79 kilocalories/day Standard Error 113.50

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Hourly Energy Expenditure	0.23 kilocalories/hour Standard Error 5.64	-9.17 kilocalories/hour Standard Error 5.86

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Metabolic Rate	0.01 Watts/sec Standard Error 0.04	-0.07 Watts/sec Standard Error 0.04

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Time in Activity Sedentary time	-0.013 percentage of time Standard Error 0.023	0.033 percentage of time Standard Error 0.021
Mean Change in Time in Activity Time in light physical activity	0.008 percentage of time Standard Error 0.014	-0.019 percentage of time Standard Error 0.012
Mean Change in Time in Activity Time in moderate physical activity	0.005 percentage of time Standard Error 0.009	-0.015 percentage of time Standard Error 0.010
Mean Change in Time in Activity Time in moderate-to-vigorous physical activity	0.005 percentage of time Standard Error 0.009	-0.015 percentage of time Standard Error 0.010

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Total Steps	-4821.93 steps Standard Error 2993.63	-2937.65 steps Standard Error 2362.82

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Steps Per Minute	-0.13 steps/minute Standard Error 0.52	-1.20 steps/minute Standard Error 0.67

SECONDARY outcome

Timeframe: Week 0, Week 8

Population: FAS (full analysis set) is all randomized participants who completed 8 weeks of diet (per protocol population).

Physical activity was monitored with an Actigraph GT3X-BT accelerometer device which measures accelerations in vertical, horizontal, and anterior-posterior directions.

Outcome measures

Outcome measures
Measure	5-2 CR n=20 Participants Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=19 Participants Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
Mean Change in Total Sedentary Bouts	-17.69 sedentary bouts Standard Error 6.44	13.41 sedentary bouts Standard Error 5.49

Adverse Events

5-2 CR

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Healthy Living Diet

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	5-2 CR n=20 participants at risk Healthy living diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Boost (R) 5-2 diet: Regular diet for 5 days/week; Calorie Restriction (480 Kcal in the form of a shake) for 2 days/week. Supplement providing 240 Kcal per shake. Participant takes 2 shakes per calorie restriction day.	Healthy Living Diet n=20 participants at risk Healthy living diet for 7 days/week Healthy Living Diet: Counseling and educational material on diet portion, consistency
General disorders Headache	15.0% 3/20 • 8 weeks	10.0% 2/20 • 8 weeks
General disorders Lightheadedness	5.0% 1/20 • 8 weeks	0.00% 0/20 • 8 weeks
General disorders Muscle cramps	5.0% 1/20 • 8 weeks	0.00% 0/20 • 8 weeks
Gastrointestinal disorders Constipation	15.0% 3/20 • 8 weeks	0.00% 0/20 • 8 weeks
Gastrointestinal disorders Loose stools	10.0% 2/20 • 8 weeks	0.00% 0/20 • 8 weeks
Gastrointestinal disorders Nausea	5.0% 1/20 • 8 weeks	0.00% 0/20 • 8 weeks
Gastrointestinal disorders Bloating	5.0% 1/20 • 8 weeks	0.00% 0/20 • 8 weeks

Additional Information

Dimitrios Kapogiannis

National Institute on Aging

Phone: +1-202-290-0433

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place