Association between physical activity energy expenditure and markers of healthspan during prolonged calorie restriction in individuals without obesity: observations from the CALERIE™ phase 2 randomized controlled trial.

BACKGROUND: It is unclear how physical activity energy expenditure (PAEE) influences calorie restriction (CR)-induced benefits in individuals without obesity. We examined associations between PAEE and healthspan markers and physical activity (PA) time during prolonged CR. METHODS: In Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)™ 2, participants without obesity were randomized to 25% CR or ad libitum control. This post-hoc analysis included baseline and 24-month data from participants in both groups who demonstrated CR. PAEE was calculated from total and resting energy expenditure, measured using doubly labelled water and indirect calorimetry, respectively, and adjusted for covariates to obtain a residual value that was used as the primary exposure variable. Outcomes included grip strength, aerobic capacity, glucose, insulin, blood lipids, and self-reported PA time. RESULTS: Overall, 136 participants (97 [71.3%] females; age: 38.6 [7.4] years; BMI: 25.3 [1.7] kg/m²) who showed CR were analyzed. A smaller decrease in PAEE was associated with improved grip strength (estimate = 0.504 [95% CI: 0.023, 0.986] kg), homeostatic model assessment of insulin resistance (estimate: -0.032 [95% CI: -0.062, -0.002]), and high-density lipoprotein-cholesterol (1.011 [95% CI: 0.356, 1.666] mg/dL; P ≤ 0.040). PAEE change was not associated with aerobic capacity, low-density lipoprotein-cholesterol, triglycerides, glucose, or insulin (P ≥ 0.053). A smaller PAEE decline was associated with more PA minutes (P = 0.028). For some blood lipids, change in PAEE interacted with baseline BMI class (P ≤ 0.029): in participants who were overweight, higher PAEE was associated with lower triglyceride and triglyceride: high-density lipoprotein-cholesterol ratio (P ≤ 0.022), whereas in participants who were normal weight, it was related to increased total-cholesterol (P = 0.006). CONCLUSION: A smaller reduction in PAEE during CR was associated with small improvements in several healthspan markers and greater PA time. Maintaining PAEE during CR may enhance healthspan in individuals without obesity. TRIAL REGISTRATION: clinicaltrials.gov registration (NCT00427193). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12966-025-01825-5.

Duke Scholars

Author Kim Marie Huffman Medicine, Rheumatology and Immunology

Author William Erle Kraus Medicine, Cardiology